WNT-1/2B/3A/4/5A : Time behavioural study of 3rd order combinations in WNT3A stimulated HEK 293 cells

WNT-1/2B/3A/4/5A : Time beha iou al s udy o 3 d o de
combina ions in WNT3A s imula ed HEK 293 cells
sh ip akash sinha
Independen Resea che ; O cid ID : o cid.o g/0000-0001-7027-5788
104-Madhu isha Heigh s Phase 1, Risali, Bhilai-490006, India
Abs ac
The WNT p o eins a e a amily o a numbe o cys eine- ich glycop o eins which ac-
i a e signal ansduc ion cascades ia h ee di e en pa hways, he canonical WNT
pa hway, he noncanonical plana cell pola i y (PCP) pa hway, and he noncanonical
WNT/Ca2+pa hway. He e, a ime beha iou al s udy o 3 d o de WNT combina ions
in WNT3A s imula ed HEK 293 cells is p esen ed. Guj al and MacBea h [1] p o ides
a quan i a i e, and dynamic s udy o WNT3A-media ed s imula ion o HEK 293 cells,
whe e hey eco d ime based exp ession p o iles o se e al esponse genes which co -
ela ed signi ican ly wi h p oli e a ion and mig a ion. By moni o ing he dynamics o
gene exp ession using sel -o ganizing maps, hey iden i ied clus e s o genes ha ex-
hibi simila exp ession dynamics and unco e ed p e iously un ecognized posi i e and
nega i e eedback loops. Howe e , hei s udy depic s/uses singula measu emen s o
indi idual gene exp ession a di e en ime snapsho s/poin s o in e he sys em wide
analysis o he pa hway. A any pa icula ime poin , i is o en he case ha genes a e
wo king syne gis ically in combina ions, e en hough hei exp ession measu emen s
a e singula in na u e. He e, I •enume a e and ank all 2415 WNT (pa icula amily
membe ) ela ed 3 d o de combina ions in a o es o 71C3combina ions using ou
di e en sensi i i y me hods; •show he conse ed ankings o WNT-X-X combina-
ions, which poin o exis ence o biological syne gy o some o hese combina ions
ac oss he di e en sensi i i y me hods; and •s udy he beha iou o some o hese
combina ions ela ed o WNT3A esponse genes ha a e anked by he machine lea n-
ing sea ch engine (Sinha [2]) in ime. Pa e ns o combina ions eme ge, some o which
ha e been es ed in we lab, while o he s equi e u he we lab analysis.
Keywo ds: Sensi i i y analysis, Suppo ec o anking, Hilbe Schmid
Independence C i e ion indices (HSIC) and Sobol indicies, WNT3A
ITime beha iou al s udy o 3-od WNT comb. in WNT3A s imula ed cells
Email add ess: [email p o ec ed] (sh ip akash sinha)
1Aspec s o unpublished wo k we e p esen ed in a pos e session a Cell Symposia: Technology. Biology.
Da a Science, 9-11 Oc obe 2016, Be keley, Cali o nia, USA.
P ep in submi ed o P ep in Feb ua y 18, 2025
1. Signi icance
Sinha [2] ecen ly demons a ed he use o machine lea ning based sea ch engine o
ank/ e eal gene combina ions a 2nd o de o he ime se ies da a by Guj al and
MacBea h [1] and showed how i is possible o loca e combina ions o p io i y ha
migh be wo king syne gis ically, using sensi i i y me hods and powe ul suppo ec-
o anking algo i hm. Howe e , he p oblem explodes combina o ially wi h e en a
small se o 71 eco ded genes in he s udy by Guj al and MacBea h [1], when one
s eps o explo e 3 d o de combina ions. Wi h he o al numbe o 71C3(= 57155)
combina ions, i becomes nea ly impossible o any biologis o s udy he sys em wide
dynamics o any pa hway. Also, he amoun o ime usually needed o sea ch o and
es a combina ion is a mo e han he sea ch down by he machine lea ning based
sea ch engine. He e, I ex end he esea ch wo k by Sinha [2] o conduc a beha io al
s udy o 3 d o de WNT ela ed combina ions using indi idual gene exp essions mea-
su ed in ime, in WNT3A s imula ed HEK 293 cells.
2. In oduc ion
The de ails o he machine lea ning based sea ch engine has been ecen ly published in
Sinha [2] and deployed o explo e he 2nd o de combina ions o genes in he da a se
p o ided by Guj al and MacBea h [1]. Ne e heless, he e, I poin o he undamen als
o he published wo k o comple eness.
2.1. A combina o ial p oblem
Sensi i i y analysis plays a majo ole in compu ing he s eng h o he in luence o
in ol ed ac o s in any phenomena unde in es iga ion. When applied o exp ession
p o iles o a ious in a/ex acellula ac o s ha o m an in eg al pa o a signaling
pa hway, he a iance and densi y based analysis yields a ange o sensi i i y indices
o indi idual as well as a ious combina ions o ac o s. These combina ions deno e
he highe o de in e ac ions among he in ol ed ac o s. Compu a ion o highe o -
de in e ac ions is o en ime consuming bu i gi es a chance o explo e he a ious
combina ions ha migh be o in e es in he wo king mechanism o he pa hway. Fo
example, in a ange o ou h o de combina ions among he a ious ac o s o he Wn
pa hway, i would be easy o assess he in luence o he des uc ion complex o med by
APC, AXIN, CSKI and GSK3 in e ac ion. Bu he e ec o hese combina ions a y
o e ime as measu emen s o old changes and de ia ions in old changes a y. So
i is impe a i e o know how an in e ac ion o a combina ion o he in ol ed ac o s
beha e in ime and Sinha [2] de elops a p ocedu e o ack he beha iou by exploi ing
he in luences o hese in ol ed ac o s.
2.2. A possible solu ion
In his wo k, a e es ima ing he indi idual e ec s o ac o s o a highe o de combi-
na ion, he indi idual indices a e conside ed as disc imina i e ea u es. A combina ion,
2
hen, is a ea u e se in highe o de (≥2 ,i.e mul i a ia e). Wi h an excessi ely la ge
numbe o ac o s in ol ed in he pa hway, i is di icul o sea ch o impo an com-
bina ions in a wide sea ch space o e di e en o de s. Exploi ing he analogy wi h
he issues o p io i izing webpages using anking algo i hms, o a pa icula o de , a
ull se o combina ions o in e ac ions can hen be p io i ized based on hese ea u es
using a powe ul anking algo i hm ia suppo ec o s Joachims [3]. Reco ding he
changing ankings o he combina ions o e ime e eals how highe o de in e ac ions
beha e wi hin he pa hway and when an in e en ion migh be necessa y o in luence
he in e ac ion wi hin he pa hway.
2.3. Wn signaling and sec e ion
Sha ma [4]’s acciden al disco e y o he Wingless played a pionee ing ole in he eme -
gence o a widely expanding esea ch ield o he Wn signaling pa hway. A majo i y
o he wo k has ocused on issues ela ed o • he disco e y o gene ic and epige-
ne ic ac o s a ec ing he pa hway Tho s ensen e al. [5] & Ba on and Kneissel [6],
•implica ions o mu a ions in he pa hway and i s dominan ole on cance and o he
diseases Cle e s [7], •in es iga ion in o he pa hway’s con ibu ion owa ds emb yo
de elopmen Sokol [8], homeos asis Pin o e al. [9] & Zhong e al. [10] and apop o-
sis Pe´
cina-ˇ
Slaus [11] and •sa e y and easibili y o d ug design o he Wn pa hway
Kahn [12], Ga be [13], Vo onko and K auss [14], Blagoda ski e al. [15] & Cu in
and Lo enzi [16].
The Wn phenomena can be oughly seg ega ed in o signaling and sec e ion pa .
The Wn signaling pa hway wo ks when he WNT ligand ge s a ached o he F iz-
zled(FZD)/LRP co ecep o complex. FZD may in e ac wi h he Dishe elled (DVL)
causing phospho yla ion. I is also hough ha Wn s cause phospho yla ion o he
LRP ia casein kinase 1 (CK1) and kinase GSK3. These de elopmen s u he lead o
a ac ion o Axin which causes inhibi ion o he o ma ion o he deg ada ion complex.
The deg ada ion complex cons i u es o AXIN, he β-ca enin anspo a ion complex
APC, CK1 and GSK3. When he pa hway is ac i e he dissolu ion o he deg ada ion
complex leads o s abiliza ion in he concen a ion o β-ca enin in he cy oplasm. As
β-ca enin en e s in o he nucleus i displaces he GROUCHO and binds wi h ansc ip-
ion cell ac o TCF hus ins iga ing ansc ip ion o Wn a ge genes. GROUCHO ac s
as lock on TCF and p e en s he ansc ip ion o a ge genes which may induce cance .
In cases when he Wn ligands a e no cap u ed by he co ecep o a he cell memb ane,
AXIN helps in o ma ion o he deg ada ion complex. The deg ada ion complex phos-
pho yla es β-ca enin which is hen ecognised by F BOX/WD epea p o ein β-TRCP.
β-TRCP is a componen o ubiqui in ligase complex ha helps in ubiqui ina ion o
β-ca enin hus ma king i o deg ada ion ia he p o easome.
Con a y o he signaling phenomena, he sec e ion phenomena is abou he e-
lease and anspo a ion o he WNT p o ein/ligand in and ou o he cell, espec i ely.
B ie ly, he WNT p o eins ha a e syn hesized wi h he endoplasmic e iculum (ER),
a e known o be palmi oylea ed ia he Po cupine (PORCN) o o m he WNT ligand,
which is hen eady o anspo a ion. I is belie ed ha hese ligands a e hen ans-
po ed ia he EVI/WNTLESS ansmemb ane complex ou o he cell B¨
anzige e al.
[17] & Ba sche e e al. [18]. The EVI/WNTLESS hemsel es a e known o eside
3
in he Golgi bodies and in e ac ion wi h he WNT ligands o he la e ’s glycosyla ion
Ku ayoshi e al. [19] & Gao and Hannoush [20]. Once ou side he cell, he WNTs
hen in e ac wi h he cell ecep o s, as explained in he o egoing pa ag aph, o in-
duce he Wn signaling. O impo ance is he ac ha he EVI/WNTLESS also need a
anspo e in he om o a complex e med as Re ome .
3. Ch onological li e a u e e iew o ime se ies analysis
o WNT signaling pa hway
Cyclic ac i a ion o he Wn /β-ca enin signaling pa hway con ols cell usion-media ed
soma ic cell ep og amming. TCFs in complex wi h β-ca enin, bind and egula e WNT
a ge genes. Aulicino e al. [21] show ha WNT/ β-ca enin signaling needs o be
o du ing he ea ly ep og amming phases o mouse emb yonic ib oblas s (MEFs)
in o iPSCs. In MEFs unde going ep og amming, senescence genes a e ep essed and
mesenchymal- o-epi helial ansi ion is a o ed. This is co ela ed wi h a ep essi e
ac i i y o TCF1, which con ibu es o he silencing o WNT/β-ca enin signaling a
he onse o ep og amming. In con as , he WNT pa hway needs o be ac i e in he
la e ep og amming phases o achie e success ul ep og amming. The au ho s show
ha ime-dependen ac i a ion o WNT/β-ca enin pa hway con ols ep og amming o
ou - ac o -induced MEFs by p esen ing expe imen al scheme o ime cou se analysis
o FACS-so ed cells and ime-dependen exp ession o MET and senescence ma ke s.
They conclude ha con inued ac i a ion o inhibi ion o he WNT/β-ca enin signaling
pa hway is de imen al o he ep og amming o MEFs while, empo al pe u ba ion o
he pa hway is essen ial o e icien ep og amming, and he ”WNT-o ” s a e can be
conside ed an ea ly ep og amming ma ke .
Expe imen al and compu a ional s udies ha e e ealed cha ac e is ics o he WNT
pa hway, howe e a cell-speci ic spa ial pe spec i e ha e been lacking. Tan e al. [22]
p o ide a no el 3D con ocal quan i a ion p o ocol o acqui e spa ial ( wo cellula com-
pa men s: nucleus and cy osol-memb ane) and empo al quan i a i e da a on a ge
p o ein (e.g. β-ca enin and N-cadhe in) concen a ions in Human Epi helial Kidney
cells (HEK293T) du ing pe u ba ion (wi h ei he cycloheximide o WNT3A). Compu-
a ional models o he Wn pa hway a e cons uc ed and in e oga ed based on his da a.
Huang e al. [23] showed by ansc ip ome analysis o cells along human plu ipo en
s em cells (PSC) di e en ia ion o ea ly and de ini i e neu oepi helia ia ime-cou se
da a, ha down egula ion o genes associa ed wi h TGF-βand canonical WNT/β-
CATENIN signaling, con i med he oles o classical signaling in human neu al in-
duc ion. Thei s udy e ealed known and no el exp ession pa e ns o genes ha a e
in ol ed in DNA me hyla ion, his one modi ca ion, as well as epi helial-mesenchymal
ansi ion, which play c ucial oles o hose genes and signaling pa hways du ing neu al
di e en ia ion.
To examine signal p opoga ion and i s e ec on ansc ip ion le els in indi idual
cells wi hin a popula ion, Ka i e al. [24] conduc ed eal- ime β-ca enin dynamics in
a cell popula ion in esponse o WNT signaling. They obse ed ha β-ca enin le els
inc eased simul aneously a adhe ens junc ions and he cen osome, and a memb ane-
4
cen osome anspo sys em was e ealed. Co ela ing β-ca enin nuclea dynamics o
CCND1 ansc ip ional ac i a ion showed ha he nuclea accumula ion a e o change
o he signaling ac o co ela ed wi h he ansc ip ional ou pu o he pa hway.
Madan e al. [25] pe o med ime-cou se analysis o WNT-dependen signaling
pa hways in an o ho opic model o WNT-addic ed panc ea ic cance , using a PORCN
inhibi o and alida ed key esul s in addi ional WNT-addic ed models. Thei empo al
analysis o he d ug-pe u bed ansc ip ome demons a ed di ec and indi ec egula-
ion o mo e han 3,500 WNT-ac i a ed genes. Fu he , hei s udy iden i ied a cen al
ole o WNT/β-ca enin/MYC/ ibosome axis, in cance p oli e a ion.
Using a combina ion o ime- esol ed CUT&RUN agains β-ca enin, ATAC-seq,
and pe u ba ion assays in di e en cell ypes, Pagella e al. [26] showed ha WNT/β-
ca enin physical a ge s a e issue-speci ic, β-ca enin ”mo es” on di e en loci o e
ime, and i s associa ion o DNA accompanies changing ch oma in accessibili y land-
scapes ha de e mine cell beha io .
In all he abo e expe imen al esul s ill now, we ind ha ime cou se analysis is
a common way o s udy and deciphe he dynamics o he signaling pa hway. How-
e e , hei s udies depic s/uses singula measu emen s o indi idual gene exp ession
a di e en ime snapsho s/poin s o in e he sys em wide analysis o he WNT pa h-
way. A any pa icula ime poin , i is o en he case ha genes a e wo king syne -
gis ically in combina ions, e en hough hei exp ession measu emen s a e singula in
na u e. Sinha [2] ecen ly demons a ed he use o machine lea ning based sea ch en-
gine o ank/ e eal gene combina ions a 2nd o de o he ime se ies da a by Guj al
and MacBea h [1] and showed how i is possible o loca e combina ions o p io i y
ha migh be wo king syne gis ically, using sensi i i y me hods and powe ul suppo
ec o anking algo i hm. Howe e , he p oblem explodes combina o ially wi h e en
a small se o 71 eco ded genes in he s udy by Guj al and MacBea h [1], when one
s eps o explo e 3 d o de combina ions. Wi h he o al numbe o 71C3(= 57155)
combina ions, i becomes nea ly impossible o any biologis o s udy he sys em wide
dynamics o any pa hway. Also, he amoun o ime usually needed o sea ch o and
es a combina ion is a mo e han he sea ch down by he machine lea ning based
sea ch engine. He e, I ex end he esea ch wo k by Sinha [2] o conduc a ime beha -
io al s udy o 3 d o de WNT-(1,2B,3A,4,5A) ela ed combina ions using indi idual
gene exp essions measu ed in ime, in WNT3A s imula ed HEK 293 cells. Using his
me hod, i is possible o ind in ime, which combina ions a 3 d o de a e wo king
syne gis ically. The wo k can be ex ended o explo e highe o de combina ions also
(i.e ≥4), wi h adequa e compu a ional esou ces.
Finally, om he compu a ional pe spec i e, Ding and Ba -Joseph [27] p o ide a
e iew o da a, me hods, and analysis o econs uc ing dynamic egula o y ne wo k
models om high- h oughpu ime-se ies da a se s. They enlis a ange o so wa es o
ime-se ies GRN analysis me hods ha a e basically based on co ela ion, eg ession,
G ange causali y, P obabilis ic g aph model and G aphical embedding. In compa i-
son wi h hese me hods, he cu en manusc ip uses sensi i i y analysis based indices
(compu ed ia package in R by Pujol e al. [28]) o cap u e in luence o in ol ed ac o s
in he signaling pa hway and u he use i as ea u e ec o s in ad anced suppo ec-
o anking algo i hm by Joachims [3]. Thus, his is he i s machine lea ning based
me hod ha can cap u e/iden i y/ e eal highe o de combina ions in ime and help
5

biologis s s udy he wo king o pa hway.
4. Me hods
Please e e o sec ions o Sinha [2] o me hods, design o s udy and analysis o da a
o 2nd o de combina ions. The same me hod and design o s udy is used o gene a e
esul s o 3 d o de combina ions p esen ed in his s udy.
5. Time se ies da a
Guj al and MacBea h [1] p esen a se o 71 WNT- ela ed gene exp ession alues o 6
di e en imes poin s o e a ange o 24-hou pe iod using qPCR. The changes ep e-
sen he old-change in he exp ession le els o genes in 200 ng/mL WNT3A-s imula ed
HEK 293 cells in ime ela i e o hei le els in uns imula ed, se um-s a ed cells a 0-
hou . Guj al and MacBea h [1] s a e ha qPCR da a a e he means o h ee biological
eplica es. Only genes whose mean ansc ip le els changed by mo e han wo- old a
one o mo e ime poin s du ing he 24-hou ime cou se we e conside ed signi ican .
Posi i e (nega i e) numbe s ep esen up (down) - egula ion. We ha e al eady co e ed
he issues ela ed o hese da a se s in de ail in Sinha [29]. Reade s a e eques ed o
go h ough hem in he poin ed e e ence. The ools o s udy which a e used he e ha e
been published in ano he ounda ional wo k in Sinha [29].
6. Design o expe imen
6.1. Pipeline o ime se ies da a
Fo he case o ime se ies da a, in e ac ions among he con ibu ing ac o s a e s udied
by compa ing iple s o old-changes a single ime poin s. The p odecu e begins wi h
he gene a ion o dis ibu ion a ound measu emen s a single ime poin s wi h added
noise is done o es ima e he indices. A dis ibu ion is gene a ed o he old changes
a single ime poin s. Then o e e y gene, he e is a ec o o alues ep esen ing old
changes as well as de ia ions in old changes o di e en ime poin s and du a ions
be ween ime poin s, espec i ely. Nex a lis ing o all Cn
kcombina ions o knumbe
o genes om a o al o ngenes is gene a ed. kis ≥2 and ≤(n−1). Each o he com-
bina ion o o de k ep esen s a unique se o in e ac ion be ween he in ol ed gene ic
ac o s. A e his, he da ase s a e combined in a speci ed o ma which go as inpu
as pe he equi emen o a pa icula sensi i i y analysis me hod. Thus o each p h
combina ion in Cn
kcombina ions, he da ase is p epa ed in he equi ed o ma om
he dis ibu ions o wo sepa a e cases which ha e been discussed abo e. (See .R code
in mainSc ip -1-1.R). A e he da a has been ans o med, ec o ized p og amming
is employed o densi y based sensi i i y analysis and looping is employed o a i-
ance based sensi i i y analysis o compu e he equi ed sensi i i y indices o each o
he pcombina ions. This p ocedu e is done o di e en kinds o sensi i i y analysis
me hods.
6
A e he abo e sensi i i y indices ha e been s o ed o each o he p h combina-
ion, he nex s ep in he design o expe imen is conduc ed. Since he e is only one
eco ding o sensi i i y index pe combina ion, each combina ion o ms a aining ex-
ample which is allo ed a aining index and he sensi i i y indices o he indi idual
gene ic ac o s o m he aining example. Thus he e a e Cn
k aining examples o k h
o de in e ac ion. Using his aining se SVMRank
lea n Joachims [3] is used o gene a e a
model on de aul alue C alue o 20. In he cu en expe imen on oy model C alue
has no been unned. The aining se helps in he gene a ion o he model as he di -
e en gene combina ions a e numbe ed in o de which a e used as ank indices. The
model is hen used o gene a e sco e on he obse a ions in he es ing se using he
SV MRank
classi y Joachims [3]. No e ha due o a ailabili y o only one example pe com-
bina ion, a e he model has been buil , he same aining da a is used as es da a o
gene a es he sco es. This p ocedu e is execu ed o each and e e y sensi i i y analysis
me hod. This is ollowed by so ing o hese sco es along wi h he ank indices (i.e he
aining indices) al eady assigned o he gene combina ions. The end esul is a so ed
o de o he gene combina ions based on he anking sco e lea ned by he SV MRank
algo i hm. Finally, his en i e p ocedu e is compu ed o sensi i i y indices gene a ed
o each and e e y old change a ime poin and de ia ions in old change a di e en
du a ions. Obse ing he changing ank o a pa icula combina ion a di e en imes
and di e en ime pe iods will e eal how a combina ion is beha ing.
No e ha he ollowing is he o de in which he iles should be execu ed in R, in
o de , o ob aining he desi ed esul s (No e ha he code will no be explained he e) - •
use sou ce(”mainSc ip -1-1.R”) wi h a gumen s o Dynamic da a •sou ce(”SVMRank-
Resul s-D.R”), o ank he in e ac ions (again his needs o be done sepa a ely o
di e en kinds o SA me hods), •use sou ce(”Combine-Time- iles.R”), i compu -
ing indices sepa a ely ia p e ious ile, •sou ce(”So -n-Plo -D.R”) o so he in e -
ac ions. No e ha he so ing is chages he in e ac ion anking in ime. Thus •use
sou ce(”In e ac ion-P io i y-In ime.R”) o ind he p io i ized anking o each and e -
e y in e ac ion o e he di e en ime poin s and inally •use sou ce(”P in -Ranking-
AND-In e ac ion-Rank.R”) o p in indi idual anking o he equi ed inpu ac o wi h
o he in e ac ion ac o s.
7. Resul s & Discussion
7.1. Time se ies da a by Guj al and MacBea h [1]
NOTE - Ranking was assigned on sco es ha we e so ed in DECREASING alues.
So, 1 was assigned o highes sco e and ice e sa.
Resul s o he 3 d o de in e ac ions a e p esen ed he e. The esul s i s discuss
he beha iou o in e ac ions ac oss he snapsho s o ime using he compu ed sensi-
i i ies on old change measu emen s pe ime snapsho . The analysis was done us-
ing 4 di e en sensi i i y indices. Ou o he 71C3combina ions, I conside /p esen
only hose combina ions ha show a anking wi hin i s 10,000 ou o 57,155. This
choice is libe al and biologis s/oncologis s can ha e a mo e s ic e choice as pe need.
Two obse a ions a e made, • he anking o a pa icula combina ion is conse ed (i.e
7
wi hin he 10,000 ange) in a pa icula ime poin o in he ea ly phase o la e phase
o WNT3A s imula ion, ac oss he majo i y o he ou sensi i i y me hods, which is a
s ic c i e ia o assessmen o • he anking o a pa icula combina ion is conse ed
ac oss ime poin s/phase (i.e hey a e wi hin he 10,000 ange) and he majo i y o he
ou sensi i i y me hods, which is elaxed c i e ia o assessmen . Applying his il e
helps e eal impo an combina ions o in e es ha migh be wo king syne gis ically
a a highe o de le el in he cell.
Rega ding echnical poin s o implemen a ion, he ankings we e gene a ed wi h-
ou scaling/no malizing he ime se ies da a p o ided by Guj al and MacBea h [1].
Fo es ima ing he sensi i i y indices, a small gaussian dis ibu ion using he unc ion
no m ha gene a es a ec o o no mally dis ibu ed andom a iables gi en a ec o
leng h n (he e 9, he 10 h one is he mean/ eco ded gene egula ion i sel ), a popula ion
mean µand popula ion s anda d de ia ion σ. The syn ax o using no m is as ollows:
no m(n, mean, sd). Fu he , I use he ji e un ion o add a li le bi o noise o he
da a. This helps o see i he gene a ed ankings a e obus o no .
7.2. Enume a ion and anking o 2415 WNT-X-X combina ions om
Guj al and MacBea h [1]
In he supplemen a y sec ion, I p esen ou iles ( o each o he WNT membe anal-
ysed he e) each con aining he ankings o 3 d o de combina ions, ha wa y in ime
(shown o 5 ime poin s). Each ile ep esen s he ankings compu ed using a pa icula
sensi i i y me hod. The changing ankings in ime o a pa icula combina ion ep e-
sen s he impo ance o con ibu ion/ ole ha combina ion plays in he cell s imula ed
wi h WNT3A. The sensi i i y me hods used a e Hilbe Schmid Independence C i e-
ion indices (HSIC) indices (wi h b and linea ke nel in Da Veiga [30]) and Sobol
indicies (wi h 2002 implemen a ion in Sal elli [31] and ma inez implemen a ion in
Ma inez [32] and Baudin e al. [33]).
8
7.3. Conse ed machine lea ning ankings o es ed WNT1-X-X
combina ions
A o al o 2415, 3 d o de combina ions in ol ing WNT1 we e ob ained om a ull se
o 71C3= 57155 combina ions. Fu he , om his selec ed se , using he abo e c i e ia
o conse ed ankings, I epo / abula e he meaning ul combina ions ha migh be
wo king syne gis ically. Tables 2, 3 and 4 show he ankings o he same combina-
ions as in able 1, bu using b ke nel o HSIC, 2002 implemen a ion o SOBOL
and ma inez implemen a ion o SOBOL, espec i ely. As one allies he ankings o
ac oss hese ables o a pa icula combina ion, one inds ha he ole o he combina-
ion o in e es is conse ed. This conse a ion poin s o he exis ence o he biological
syne gy, whe he he combina ion has been es ed o unexplo ed/un es ed.
7.3.1. Examining he beha iou o FZD-WNT1-X combina ions
In hei e iew, Co da and Sala [34] obse e ha izzled class ecep o 6 (FZD6) binds
o WNT1, along wi h o he membe s o WNT amily. Looking a he ables abo e,
one inds he ollowing combina ions o membe s o FZD amily along wi h WNT1,
o be p ominen a 3 d o de le el - FZD6-WNT1-WNT2B, FZD1-WNT1-WNT2,
FZD6-WNT1-WNT2, FZD5-WNT1-WNT2, FZD6-WNT1-WNT3A, FZD8-WNT1-
WNT5A, FZD2-WNT1-WNT3A, FZD2-WNT1-WNT2, FZD2-WNT1-WNT5A, FZD5-
WNT1-WNT4, FZD7-WNT1-WNT3A, FZD5-WNT1-WNT3A, FZD6-WNT1-WNT4,
and FZD7-WNT1-WNT2B. All hese combina ions indica e he exis ence o a syne gy
when hey ake a highe ank in he lis o combina ions. In e es ingly, i can also be
obse ed ha he WNT1 o ms combina ions wi h o he WNT membe s. This phe-
nomena is no seen o combina ions o o he WNT membe s as will be discussed la e .
7.3.2. Examining he beha iou o LRP-WNT1-X combina ions
Belenko e al. [35] showed ha da a analysis o he g oup wi h obs uc i e co o-
na y a e y disease indica ed a mode a e co ela ion be ween WNT1 and low den-
si y lipop o ein ecep o - ela ed p o ein 6 (LRP6). Looking a he ables abo e, one
inds he ollowing combina ions o membe s o LRP amily along wi h WNT1, o
be p ominen a 3 d o de le el - LRP5-WNT1-WNT2, LRP6-WNT1-WNT2B, LRP6-
WNT1-WNT4, LRP5-WNT1-WNT4, LRP5-WNT1-WNT2B, and LRP5-WNT1-WNT5A.
All hese combina ions indica e he exis ence o a syne gy when hey ake a highe ank
in he lis o combina ions.
7.3.3. Examining he beha iou o RHOU-WNT1-X combina ions
as homolog amily membe U (RHOU) was i s iden i ied as a WNT-1-inducible
mRNA and subsequen ly shown o ac on he ac in cy oskele on by s imula ing ilopo-
dia o ma ion and s ess ib e dissolu ion. Schia one e al. [36] in hei s udy, show ha
WNT-1-media ed RHOU induc ion occu s a he ansc ip ional le el. The ables show
one combina ion o RHOU-WNT1-WNT4 o be p ominen among he combina ions,
wo king in ime.
9
RANKING @ iUSING HSIC - LINEAR
3 d o de comb. 1 3 6 12 24 3 d o de comb. 1 3 6 12 24
CTNNBIP1-WIF1-WNT2B 5 716 18217 51222 29536 AES-AXIN1-WNT2B 21 42226 26426 31368 54700
LRP6-TCF7-WNT2B 43 10692 4853 48176 26671 DKK1-JUN-WNT2B 56 5221 53944 55625 44612
CXXC4-PORCN-WNT2B 60 17097 46765 26682 32940 TLE1-WIF1-WNT2B 65 13326 20278 36821 11947
CSNK1D-FGF4-WNT2B 82 23581 20638 52449 10903 CCND1-WIF1-WNT2B 86 32096 35653 38353 29538
APC-DIXDC1-WNT2B 89 27000 33475 27891 27710 FZD7-NKD1-WNT2B 140 22580 30435 30959 23507
TLE2-WIF1-WNT2B 162 206 11704 50552 55877 FOXN1-KREMEN1-WNT2B 170 28253 38493 15670 30910
CSNK2A1-T-WNT2B 184 3390 21468 32926 48474 TLE2-WNT1-WNT2B 189 20461 1429 13090 57105
FRAT1-FZD1-WNT2B 227 40140 33748 53349 33191 CCND1-FGF4-WNT2B 236 52522 47611 46447 13813
DVL1-EP300-WNT2B 247 6893 42213 52392 47037 CSNK1D-SFRP1-WNT2B 268 48716 36593 46538 17001
PPP2CA-SFRP4-WNT2B 341 52722 25356 52978 1988 DVL2-JUN-WNT2B 350 44599 38931 37935 16078
FGF4-SFRP1-WNT2B 370 37435 43048 42260 31787 FZD6-PORCN-WNT2B 379 19259 55786 24330 16739
DKK1-DVL2-WNT2B 389 6767 19714 49653 54386 AXIN1-FZD2-WNT2B 416 21758 21068 33734 11136
TLE1-WNT1-WNT2B 422 24710 2210 9746 55494 TCF7L1-WNT1-WNT2B 434 3116 2757 14471 57112
LRP5-SFRP1-WNT2B 435 20296 30967 34267 33184 FZD5-NKD1-WNT2B 450 18227 31166 30382 5811
CXXC4-FZD7-WNT2B 472 12278 44001 31202 33433 AES-DVL1-WNT2B 520 45445 49972 36707 54854
CSNK1D-PORCN-WNT2B 573 51683 44617 47981 16208 FBXW11-GSK3B-WNT2B 592 49622 2389 29900 47620
PITX2-PORCN-WNT2B 630 42884 44910 50269 15186 DKK1-GSK3A-WNT2B 637 11948 24932 51752 48181
CSNK2A1-MYC-WNT2B 662 17569 55958 14302 27991 FOSL1-PORCN-WNT2B 670 19667 46545 40946 19709
FSHB-NKD1-WNT2B 699 45757 26960 8191 17214 SENP2-WNT1-WNT2B 701 40779 2190 9179 41846
PYGO1-WNT2-WNT2B 707 39634 53492 38813 24079 FOSL1-WIF1-WNT2B 727 2770 23114 37617 17980
LEF1-T-WNT2B 739 5852 6639 47821 35271 FZD8-WNT1-WNT2B 745 1694 1668 7586 57148
FBXW11-TCF7-WNT2B 768 56201 14780 53735 24876 DAAM1-FGF4-WNT2B 773 44990 54366 44263 16007
FBXW11-JUN-WNT2B 795 49304 52661 53929 54016 DKK1-FGF4-WNT2B 797 14004 54579 50721 31962
FOSL1-SFRP1-WNT2B 802 20624 39428 24273 52148 SENP2-SFRP1-WNT2B 804 39477 39510 38291 12235
FBXW11-GSK3A-WNT2B 812 55736 14360 54703 35145 FZD8-JUN-WNT2B 814 45692 37162 26955 54126
DKK1-WNT1-WNT2B 829 33707 24814 9762 55167 DVL1-WNT1-WNT2B 850 7844 1434 7855 55450
FRZB-NKD1-WNT2B 861 8764 29474 26264 14733 DKK1-FOXN1-WNT2B 864 31296 16351 4633 30734
CCND2-WNT1-WNT2B 867 3849 5828 18983 29898 FZD1-T-WNT2B 868 18866 10080 50380 16044
FBXW11-RHOU-WNT2B 887 56605 51928 47819 44859 DAAM1-T-WNT2B 901 38916 30634 18661 34795
DKK1-NKD1-WNT2B 912 10412 49963 52787 8425 EP300-WNT1-WNT2B 940 30973 2609 12191 47783
CTBP2-CTNNB1-WNT2B 947 49967 49546 42990 40963 FZD6-WNT1-WNT2B 953 30498 22050 10632 41588
FBXW11-WIF1-WNT2B 980 2151 19852 53626 35239 FBXW11-FOXN1-WNT2B 989 38275 4532 5886 43707
DAAM1-WNT1-WNT2B 991 40641 19923 4873 55071 NLK-PORCN-WNT2B 1006 26349 37659 35498 4512
TCF7L1-WIF1-WNT2B 1008 31286 33213 39169 51635 CTBP2-T-WNT2B 1012 44271 1973 37802 4806
FBXW11-NKD1-WNT2B 1027 51970 24642 25865 43366 CSNK2A1-FOXN1-WNT2B 1037 3175 7624 2538 6838
DKK1-PYGO1-WNT2B 1041 14062 34049 32775 7169 FBXW11-PORCN-WNT2B 1048 54134 36167 45459 15114
CCND3-NKD1-WNT2B 1067 19542 49729 33902 7166 FBXW11-FZD2-WNT2B 1086 51272 31485 45352 31130
CSNK1G1-FZD2-WNT2B 1144 10281 11030 49965 37172 DAAM1-JUN-WNT2B 1152 51606 37010 32012 42370
DAAM1-DVL2-WNT2B 1174 32045 51094 41937 43272 FZD1-PORCN-WNT2B 1214 23191 49164 44140 14132
DKK1-MYC-WNT2B 1215 17325 49314 54587 40306 DKK1-PORCN-WNT2B 1222 26601 56978 25305 51044
FZD8-T-WNT2B 1251 32856 3216 26449 52860 DAAM1-LRP6-WNT2B 1282 52882 52168 19705 36790
FRZB-FZD2-WNT2B 1309 8669 14015 44385 26991 CSNK1D-FOXN1-WNT2B 1328 17615 2986 7052 5219
FZD1-WIF1-WNT2B 1329 23 38111 30027 18511 LRP5-PORCN-WNT2B 1349 12551 28905 56410 16845
FBXW11-SLC9A3R1-WNT2B 1355 52940 23862 29838 38478 CXXC4-DVL2-WNT2B 1361 15018 7269 31481 39016
FBXW11-FGF4-WNT2B 1372 54955 42859 53156 22936 FOSL1-WNT1-WNT2B 1381 1526 2254 11678 47870
BCL9-PORCN-WNT2B 1394 28608 33398 47599 21197 KREMEN1-NKD1-WNT2B 1400 34496 34759 43275 20181
KREMEN1-PORCN-WNT2B 1401 36444 47192 17886 28451 FOSL1-NLK-WNT2B 1425 3331 440 49507 31594
CTBP1-FGF4-WNT2B 1487 28989 34409 34222 14602 DAAM1-FOXN1-WNT2B 1503 50616 30398 2836 38247
FZD6-PITX2-WNT2B 1504 10725 14634 54318 17213 FBXW2-NKD1-WNT2B 1547 22973 29232 13160 53054
KREMEN1-PPP2CA-WNT2B 1585 14425 197 53141 37098 FZD1-JUN-WNT2B 1648 10746 47422 41725 9336
CSNK2A1-FSHB-WNT2B 1655 8809 48217 20614 27385 LRP5-NKD1-WNT2B 1686 21363 28403 16564 24813
LRP5-NKD1-WNT2B 1686 21363 28403 16564 24813 FZD8-GSK3A-WNT2B 1696 42493 8212 43675 53692
LRP5-NLK-WNT2B 1725 4903 8642 34617 54453 CSNK1D-WNT1-WNT2B 1760 3377 3805 17345 50447
FRZB-GSK3A-WNT2B 1779 9801 7248 51968 31318 FZD6-GSK3A-WNT2B 1794 11589 22435 52656 45662
FRAT1-PORCN-WNT2B 1796 26246 45830 36444 11708 DAAM1-FZD2-WNT2B 1809 48671 51601 34844 29258
CCND2-LRP6-WNT2B 1827 10665 28916 33276 6590 FRZB-T-WNT2B 1833 7114 4823 46312 4584
FZD1-NLK-WNT2B 1840 1616 1306 53698 22012 FZD7-PPP2CA-WNT2B 1854 16103 178 39687 33132
CCND3-WNT1-WNT2B 1871 43142 11213 19290 51620 FBXW11-PYGO1-WNT2B 1888 54480 51998 19913 52577
FZD7-PORCN-WNT2B 1892 48697 42677 33490 16364 BTRC-GSK3A-WNT2B 1933 56634 52638 55432 37508
JUN-PYGO1-WNT2B 1971 11759 22992 23296 32538 FBXW4-WNT1-WNT2B 2008 53679 7037 14699 52059
FBXW11-T-WNT2B 2020 55625 21630 50429 53482 DVL1-FOXN1-WNT2B 2025 34956 3080 2911 43071
KREMEN1-WNT1-WNT2B 2036 35623 4394 5538 18503 FZD8-NKD1-WNT2B 2038 34027 33288 19731 46263
EP300-GSK3B-WNT2B 2076 31297 1204 24013 16338 FZD5-DVL2-WNT2B 2087 17738 10392 23649 35917
Table 5: Rankings o WNT2B-X-X. A lis o app oxima ely i s 126 combina ions wi h ankings below
10,000 ou o 57,155. SA - HSIC; Ke nel - linea
7.4.2. Examining he beha iou o FZD-WNT2B-X combina ions
O iz-Masia e al. [43] obse ed ha ib osis and exp ession o epi helial-mesenchymal
ansi ion (EMT) ma ke s we e de ec ed in samples om C ohn’s disease (CD) pa ien s
16

RANKING @ iUSING HSIC - RBF
3 d o de comb. 1 3 6 12 24 3 d o de comb. 1 3 6 12 24
CTNNBIP1-WIF1-WNT2B 38092 3733 8392 37231 50461 AES-AXIN1-WNT2B 40966 43839 31440 26846 9969
LRP6-TCF7-WNT2B 8702 5235 40220 35007 4082 DKK1-JUN-WNT2B 23590 25652 38169 27335 22936
CXXC4-PORCN-WNT2B 11272 21120 2288 41634 56160 TLE1-WIF1-WNT2B 39953 13690 3178 37473 11178
CSNK1D-FGF4-WNT2B 2842 20288 7801 35728 43120 CCND1-WIF1-WNT2B 36761 20542 11221 38644 7317
APC-DIXDC1-WNT2B 33671 16882 4145 48106 51792 FZD7-NKD1-WNT2B 47917 26281 13366 54412 1630
TLE2-WIF1-WNT2B 39741 6829 13257 43555 31091 FOXN1-KREMEN1-WNT2B 20404 27973 36396 884 30778
CSNK2A1-T-WNT2B 38723 10644 19106 40549 37163 TLE2-WNT1-WNT2B 6950 27605 29445 9814 44123
FRAT1-FZD1-WNT2B 32803 42239 28688 52215 27867 CCND1-FGF4-WNT2B 21085 49383 9451 42420 11828
DVL1-EP300-WNT2B 53233 2104 15799 56735 2280 CSNK1D-SFRP1-WNT2B 7873 54928 11692 34070 52974
PPP2CA-SFRP4-WNT2B 55580 46429 27467 46270 1672 DVL2-JUN-WNT2B 35904 41234 30718 47010 18770
FGF4-SFRP1-WNT2B 39785 39441 5909 50353 52814 FZD6-PORCN-WNT2B 47 9685 16997 36922 48852
DKK1-DVL2-WNT2B 30054 11006 42662 15953 2499 AXIN1-FZD2-WNT2B 19640 10980 37938 11186 26435
TLE1-WNT1-WNT2B 13179 5610 13964 224 26765 TCF7L1-WNT1-WNT2B 2635 2641 24523 210 37831
LRP5-SFRP1-WNT2B 24362 31966 30181 37100 46651 FZD5-NKD1-WNT2B 18497 19475 22567 24649 24247
CXXC4-FZD7-WNT2B 3497 13030 1072 53710 54739 AES-DVL1-WNT2B 19399 35944 18278 22178 26836
CSNK1D-PORCN-WNT2B 8595 53305 9816 26691 42121 FBXW11-GSK3B-WNT2B 28340 54433 907 12470 3331
PITX2-PORCN-WNT2B 6802 25276 16938 13140 54357 DKK1-GSK3A-WNT2B 76 11011 47102 15898 19458
CSNK2A1-MYC-WNT2B 1714 9603 40200 31690 23030 FOSL1-PORCN-WNT2B 4296 5489 1279 29512 55035
FSHB-NKD1-WNT2B 24792 50507 25909 42911 36692 SENP2-WNT1-WNT2B 2021 43379 30860 2867 24069
PYGO1-WNT2-WNT2B 42713 30786 13433 45795 1718 FOSL1-WIF1-WNT2B 41773 13018 2276 54404 49689
LEF1-T-WNT2B 4043 15103 15608 21225 12447 FZD8-WNT1-WNT2B 1302 19 29799 354 19089
FBXW11-TCF7-WNT2B 35364 55673 1310 14191 3082 DAAM1-FGF4-WNT2B 1448 41378 13135 45446 17389
FBXW11-JUN-WNT2B 30736 52338 1286 29236 8641 DKK1-FGF4-WNT2B 2163 8554 28809 20482 48779
FOSL1-SFRP1-WNT2B 21116 7705 2123 56839 56883 SENP2-SFRP1-WNT2B 12477 36645 18903 52949 54446
FBXW11-GSK3A-WNT2B 3891 54907 19679 12118 3846 FZD8-JUN-WNT2B 30397 45061 16498 26458 9398
DKK1-WNT1-WNT2B 1427 29543 44949 34992 19834 DVL1-WNT1-WNT2B 15873 18998 26270 88 9209
FRZB-NKD1-WNT2B 26947 18964 19602 32120 37731 DKK1-FOXN1-WNT2B 1531 23991 43537 22407 32006
CCND2-WNT1-WNT2B 5263 5867 3189 15 13075 FZD1-T-WNT2B 38075 8619 20316 40538 36073
FBXW11-RHOU-WNT2B 34750 57120 1020 11008 24856 DAAM1-T-WNT2B 38077 48304 11694 47924 6436
DKK1-NKD1-WNT2B 33321 46336 43515 12948 3783 EP300-WNT1-WNT2B 2458 13992 29930 2629 26795
CTBP2-CTNNB1-WNT2B 36257 43633 7888 56627 41687 FZD6-WNT1-WNT2B 1547 39201 26442 188 15436
FBXW11-WIF1-WNT2B 38776 30910 903 8803 21329 FBXW11-FOXN1-WNT2B 3637 18134 11920 13018 6771
DAAM1-WNT1-WNT2B 14817 47333 17911 1242 1180 NLK-PORCN-WNT2B 30300 3466 8133 31316 44880
TCF7L1-WIF1-WNT2B 17438 28330 20158 41636 47785 CTBP2-T-WNT2B 12738 34451 25925 48123 42558
FBXW11-NKD1-WNT2B 42436 56089 5208 5851 6025 CSNK2A1-FOXN1-WNT2B 1203 7766 40805 5216 17738
DKK1-PYGO1-WNT2B 2010 10992 36338 13891 29481 FBXW11-PORCN-WNT2B 4588 54697 1382 3672 49591
CCND3-NKD1-WNT2B 31750 9905 43256 46510 4045 FBXW11-FZD2-WNT2B 18346 54018 1322 6284 1184
CSNK1G1-FZD2-WNT2B 31344 5642 34740 5475 23273 DAAM1-JUN-WNT2B 34628 49211 11090 56716 4721
DAAM1-DVL2-WNT2B 6942 14480 18352 38461 5669 FZD1-PORCN-WNT2B 12628 31292 8901 34846 55210
DKK1-MYC-WNT2B 2720 3916 32917 27454 26540 DKK1-PORCN-WNT2B 6263 7902 41853 840 49894
FZD8-T-WNT2B 15847 32806 8042 19815 9401 DAAM1-LRP6-WNT2B 19994 49638 18834 51013 3681
FRZB-FZD2-WNT2B 18182 6700 6577 13974 41022 CSNK1D-FOXN1-WNT2B 2477 5135 39962 11954 23525
FZD1-WIF1-WNT2B 46438 3992 11382 45997 45602 LRP5-PORCN-WNT2B 13427 8220 27519 32046 55939
FBXW11-SLC9A3R1-WNT2B 35442 56713 645 7849 1242 CXXC4-DVL2-WNT2B 14916 7821 10829 36605 32745
FBXW11-FGF4-WNT2B 7080 54386 714 19379 16509 FOSL1-WNT1-WNT2B 8040 5830 31727 31 46871
BCL9-PORCN-WNT2B 7648 28196 20793 10962 34371 KREMEN1-NKD1-WNT2B 10715 45017 15095 25349 17172
KREMEN1-PORCN-WNT2B 4060 34624 13586 33545 46659 FOSL1-NLK-WNT2B 20492 705 35136 30860 53018
CTBP1-FGF4-WNT2B 3838 22868 10303 52844 53469 DAAM1-FOXN1-WNT2B 1209 51245 29982 6041 1467
FZD6-PITX2-WNT2B 8135 7300 14987 7418 3456 FBXW2-NKD1-WNT2B 33781 33859 11109 13486 210
KREMEN1-PPP2CA-WNT2B 25164 28694 34566 35971 17687 FZD1-JUN-WNT2B 49546 6083 15156 54576 28886
CSNK2A1-FSHB-WNT2B 14373 4327 52378 10457 6308 LRP5-NKD1-WNT2B 32145 41013 38068 34089 24010
LRP5-NKD1-WNT2B 32145 41013 38068 34089 24010 FZD8-GSK3A-WNT2B 750 34363 43071 24851 7386
LRP5-NLK-WNT2B 28396 1960 19941 23600 55297 CSNK1D-WNT1-WNT2B 3674 5014 26127 3017 32922
FRZB-GSK3A-WNT2B 1619 7239 47111 39827 42272 FZD6-GSK3A-WNT2B 2435 10468 36364 50835 5185
FRAT1-PORCN-WNT2B 5506 22998 20346 48317 52835 DAAM1-FZD2-WNT2B 28698 41371 17118 4063 2227
CCND2-LRP6-WNT2B 11171 11125 4049 53108 11661 FRZB-T-WNT2B 17363 23133 2973 38410 49610
FZD1-NLK-WNT2B 28935 4414 27054 36546 52981 FZD7-PPP2CA-WNT2B 54842 24004 41817 52487 4145
CCND3-WNT1-WNT2B 5662 36122 43485 1250 11198 FBXW11-PYGO1-WNT2B 7490 53715 924 4743 16840
FZD7-PORCN-WNT2B 35742 42851 5084 32980 11716 BTRC-GSK3A-WNT2B 9987 55898 47839 49215 4144
JUN-PYGO1-WNT2B 2703 20164 23828 23294 38517 FBXW4-WNT1-WNT2B 3114 52426 37613 1129 42822
FBXW11-T-WNT2B 23753 56671 897 4228 17584 DVL1-FOXN1-WNT2B 14274 29565 47737 20496 2243
KREMEN1-WNT1-WNT2B 7206 28407 30386 2208 20264 FZD8-NKD1-WNT2B 49791 35392 25199 27885 3968
EP300-GSK3B-WNT2B 17031 3072 9839 9763 7695 FZD5-DVL2-WNT2B 11786 13958 21829 28234 6764
Table 6: Rankings o WNT2B-X-X. A lis o app oxima ely i s 126 combina ions wi h ankings below
10,000 ou o 57,155. SA - HSIC; Ke nel - b
i espec i e o he clinical beha iou . They show ha an inc eased EMT, associa ed
wi h inc eased WNT2B-FZD4 in e ac ion, was de ec ed in in es inal issue om CD
pa ien s wi h a pene a ing beha iou . No mal de elopmen o pe iphe al eye s uc u es
is also egula ed by Wn signaling, wi h WNT2B and FZD4 ac ing as he p ima y WNT
17
RANKING @ iUSING SOBOL - 2002
3 d o de comb. 1 3 6 12 24 3 d o de comb. 1 3 6 12 24
CTNNBIP1-WIF1-WNT2B 32269 9564 44982 43273 5808 AES-AXIN1-WNT2B 3629 31781 1126 27740 52489
LRP6-TCF7-WNT2B 9173 15520 2142 1846 43832 DKK1-JUN-WNT2B 55363 40120 46822 38204 3471
CXXC4-PORCN-WNT2B 39582 44080 51571 43634 12796 TLE1-WIF1-WNT2B 42718 23842 52893 55585 8492
CSNK1D-FGF4-WNT2B 28074 51541 15533 12033 30048 CCND1-WIF1-WNT2B 53452 50296 53198 44416 331
APC-DIXDC1-WNT2B 32686 46138 57032 49706 8604 FZD7-NKD1-WNT2B 56201 48723 45825 38106 22510
TLE2-WIF1-WNT2B 35013 18233 37906 28769 3346 FOXN1-KREMEN1-WNT2B 48078 14775 45903 47094 15768
CSNK2A1-T-WNT2B 14346 8714 2556 866 56003 TLE2-WNT1-WNT2B 40245 22669 37689 29819 30399
FRAT1-FZD1-WNT2B 43184 45767 55957 45461 9098 CCND1-FGF4-WNT2B 1271 16968 23159 21229 39055
DVL1-EP300-WNT2B 44498 7790 46717 29455 10013 CSNK1D-SFRP1-WNT2B 14464 28189 8702 8326 25216
PPP2CA-SFRP4-WNT2B 45917 16377 56750 51527 8872 DVL2-JUN-WNT2B 40463 48141 46668 43995 4463
FGF4-SFRP1-WNT2B 17695 38619 13360 27949 40245 FZD6-PORCN-WNT2B 31884 54376 34870 43757 175
DKK1-DVL2-WNT2B 11607 18789 19566 26257 36056 AXIN1-FZD2-WNT2B 13078 46421 9134 3535 56514
TLE1-WNT1-WNT2B 44201 2292 42877 38512 19669 TCF7L1-WNT1-WNT2B 49295 4478 33582 55669 18987
LRP5-SFRP1-WNT2B 2020 796 19380 20779 1060 FZD5-NKD1-WNT2B 1021 7682 6037 13559 34507
CXXC4-FZD7-WNT2B 49726 31087 32815 31314 18255 AES-DVL1-WNT2B 24665 8966 13653 21215 2061
CSNK1D-PORCN-WNT2B 39627 20751 32331 36708 28715 FBXW11-GSK3B-WNT2B 26943 804 26801 1082 52742
PITX2-PORCN-WNT2B 9536 5794 12824 18961 17911 DKK1-GSK3A-WNT2B 533 30975 18469 11508 29654
CSNK2A1-MYC-WNT2B 40989 30656 53975 49615 2007 FOSL1-PORCN-WNT2B 9686 2290 2189 14059 39340
FSHB-NKD1-WNT2B 44401 54732 42873 52925 7821 SENP2-WNT1-WNT2B 31781 23905 56648 48582 12552
PYGO1-WNT2-WNT2B 35098 23545 34784 49087 46216 FOSL1-WIF1-WNT2B 25173 2114 24567 1335 44580
LEF1-T-WNT2B 14224 20300 7495 265 47970 FZD8-WNT1-WNT2B 51664 44478 38109 40380 35203
FBXW11-TCF7-WNT2B 30352 16888 44808 42493 7236 DAAM1-FGF4-WNT2B 23184 55519 15829 13855 31157
FBXW11-JUN-WNT2B 29211 26070 34684 38249 15818 DKK1-FGF4-WNT2B 5181 13583 19476 28501 11610
FOSL1-SFRP1-WNT2B 36889 18888 44464 53547 13962 SENP2-SFRP1-WNT2B 7482 33180 11485 14807 20446
FBXW11-GSK3A-WNT2B 22556 12928 3029 4009 52731 FZD8-JUN-WNT2B 53721 5288 39583 33282 9288
DKK1-WNT1-WNT2B 38884 6393 34240 30384 22894 DVL1-WNT1-WNT2B 30250 50468 45283 44194 6705
FRZB-NKD1-WNT2B 16138 5567 23173 23193 50096 DKK1-FOXN1-WNT2B 55818 51616 29843 30059 41899
CCND2-WNT1-WNT2B 26615 12983 5711 75 50116 FZD1-T-WNT2B 17356 15997 26197 2810 33591
FBXW11-RHOU-WNT2B 31931 54618 43300 44261 19228 DAAM1-T-WNT2B 23003 8949 18729 22669 44999
DKK1-NKD1-WNT2B 16505 52805 21482 25919 33616 EP300-WNT1-WNT2B 24766 7961 7149 6651 57039
CTBP2-CTNNB1-WNT2B 29939 31301 39087 52855 26416 FZD6-WNT1-WNT2B 50360 38778 41647 35013 7193
FBXW11-WIF1-WNT2B 29590 51803 34137 33592 22138 FBXW11-FOXN1-WNT2B 38643 50360 51216 56044 10628
DAAM1-WNT1-WNT2B 45462 20187 47757 48914 24934 NLK-PORCN-WNT2B 53778 43223 50000 50320 693
TCF7L1-WIF1-WNT2B 46419 20351 52066 55826 19213 CTBP2-T-WNT2B 6821 22296 6124 9606 43942
FBXW11-NKD1-WNT2B 2665 20622 20959 28247 43772 CSNK2A1-FOXN1-WNT2B 53238 9771 44983 35149 2439
DKK1-PYGO1-WNT2B 54188 35764 37921 46266 24833 FBXW11-PORCN-WNT2B 33797 43559 32346 51083 11772
CCND3-NKD1-WNT2B 27627 1999 24899 12345 29380 FBXW11-FZD2-WNT2B 23532 3530 10144 25174 49705
CSNK1G1-FZD2-WNT2B 43957 8905 55685 37469 3334 DAAM1-JUN-WNT2B 52248 43893 48230 50763 39740
DAAM1-DVL2-WNT2B 20771 46186 8841 3792 51630 FZD1-PORCN-WNT2B 53071 43558 43509 40293 16263
DKK1-MYC-WNT2B 41021 983 42832 50572 13552 DKK1-PORCN-WNT2B 41383 41457 40170 35729 7578
FZD8-T-WNT2B 11750 5176 23231 19560 52516 DAAM1-LRP6-WNT2B 45219 41641 34094 48928 25060
FRZB-FZD2-WNT2B 17755 36646 17037 1266 17860 CSNK1D-FOXN1-WNT2B 34971 36541 30580 44435 4295
FZD1-WIF1-WNT2B 41197 35896 29093 49255 31536 LRP5-PORCN-WNT2B 53023 48201 48575 48454 8907
FBXW11-SLC9A3R1-WNT2B 24284 33812 24367 891 20731 CXXC4-DVL2-WNT2B 6744 50339 17055 22295 46522
FBXW11-FGF4-WNT2B 25936 11195 20618 18729 32916 FOSL1-WNT1-WNT2B 27112 14023 16313 6628 52241
BCL9-PORCN-WNT2B 619 12023 16698 20050 36808 KREMEN1-NKD1-WNT2B 3720 31186 24394 8640 52443
KREMEN1-PORCN-WNT2B 52764 52181 54179 35890 32504 FOSL1-NLK-WNT2B 42013 9877 52887 52662 11462
CTBP1-FGF4-WNT2B 15907 2856 754 18068 33714 DAAM1-FOXN1-WNT2B 49677 19444 42826 45397 19848
FZD6-PITX2-WNT2B 42547 47083 32974 29428 5335 FBXW2-NKD1-WNT2B 6500 43410 325 13681 45117
KREMEN1-PPP2CA-WNT2B 2599 25978 4343 22180 25119 FZD1-JUN-WNT2B 34517 30754 39634 38168 4014
CSNK2A1-FSHB-WNT2B 56035 49999 49902 45966 16417 LRP5-NKD1-WNT2B 6733 21320 13120 11007 47150
LRP5-NKD1-WNT2B 6733 21320 13120 11007 47150 FZD8-GSK3A-WNT2B 16883 32110 17993 5422 40875
LRP5-NLK-WNT2B 5246 28793 23635 4377 51925 CSNK1D-WNT1-WNT2B 42719 30480 50555 50603 27505
FRZB-GSK3A-WNT2B 27783 13118 20027 17784 24093 FZD6-GSK3A-WNT2B 14460 51037 20362 6739 56613
FRAT1-PORCN-WNT2B 37208 46905 41078 48022 2109 DAAM1-FZD2-WNT2B 21589 11905 16194 15774 27169
CCND2-LRP6-WNT2B 6636 56088 3124 21004 48482 FRZB-T-WNT2B 24201 10815 17479 15334 45319
FZD1-NLK-WNT2B 26886 12820 19770 537 36921 FZD7-PPP2CA-WNT2B 49373 38171 36850 38963 35731
CCND3-WNT1-WNT2B 48160 29114 29530 31870 18669 FBXW11-PYGO1-WNT2B 33541 53563 42544 44866 11547
FZD7-PORCN-WNT2B 5088 17699 18559 1094 44896 BTRC-GSK3A-WNT2B 8517 28470 17221 9308 40220
JUN-PYGO1-WNT2B 784 29200 21789 1189 45268 FBXW4-WNT1-WNT2B 45929 18615 31454 47272 11773
FBXW11-T-WNT2B 19469 44633 26413 20803 44750 DVL1-FOXN1-WNT2B 42127 9502 36314 42347 27070
KREMEN1-WNT1-WNT2B 36576 35166 39887 54348 48410 FZD8-NKD1-WNT2B 7879 40127 24943 28578 45650
EP300-GSK3B-WNT2B 30525 47975 41708 29146 6959 FZD5-DVL2-WNT2B 21058 49799 6043 28547 35739
Table 7: Rankings o WNT2B-X-X. A lis o app oxima ely i s 125 combina ions wi h ankings below
10,000 ou o 57,155. SA - SOBOL; Implemen a ion - 2002
ligand and ecep o . Oh a e al. [44] show ha he sec e ed p o ein Tsukushi (TSK)
unc ioned as a WNT signaling inhibi o by binding di ec ly o he cys eine- ich domain
o FZD4 and compe ed wi h WNT2B. Con e sely, hei a ge ed inac i a ion o he
TSK gene in mice caused expansion o he cilia y body and up- egula ion o WNT2B
18
RANKING @ iUSING SOBOL - MARTINEZ
3 d o de comb. 1 3 6 12 24 3 d o de comb. 1 3 6 12 24
CTNNBIP1-WIF1-WNT2B 11399 24367 25017 23530 21484 AES-AXIN1-WNT2B 12663 8851 4385 30838 53104
LRP6-TCF7-WNT2B 3861 31924 15999 20260 1723 DKK1-JUN-WNT2B 16474 6155 31575 3599 21858
CXXC4-PORCN-WNT2B 14191 46734 705 50002 13918 TLE1-WIF1-WNT2B 22858 4824 44491 36814 47038
CSNK1D-FGF4-WNT2B 11099 33067 21662 18628 9514 CCND1-WIF1-WNT2B 41667 49854 1695 14733 9964
APC-DIXDC1-WNT2B 33667 9816 37410 33932 21947 FZD7-NKD1-WNT2B 56222 35279 4725 54614 43292
TLE2-WIF1-WNT2B 32197 2739 53514 46829 47415 FOXN1-KREMEN1-WNT2B 21687 4778 50738 46118 18804
CSNK2A1-T-WNT2B 5760 12660 53417 53139 1959 TLE2-WNT1-WNT2B 40200 2166 49574 41995 42003
FRAT1-FZD1-WNT2B 9353 10394 44162 36655 40931 CCND1-FGF4-WNT2B 27190 52288 44069 26037 33209
DVL1-EP300-WNT2B 8726 18065 22256 42886 36883 CSNK1D-SFRP1-WNT2B 45504 25704 37754 9982 35219
PPP2CA-SFRP4-WNT2B 13418 45868 44709 51672 55851 DVL2-JUN-WNT2B 50622 8656 8692 8248 41711
FGF4-SFRP1-WNT2B 2215 4984 42493 13876 33910 FZD6-PORCN-WNT2B 5774 40911 34822 40189 42079
DKK1-DVL2-WNT2B 6263 22609 16657 25832 34913 AXIN1-FZD2-WNT2B 37386 51493 15577 12660 1933
TLE1-WNT1-WNT2B 34900 4162 23677 15497 48629 TCF7L1-WNT1-WNT2B 32996 5243 28606 285 39952
LRP5-SFRP1-WNT2B 50657 25330 23317 7661 960 FZD5-NKD1-WNT2B 27769 32100 5018 27110 12151
CXXC4-FZD7-WNT2B 47761 31077 51924 46061 8191 AES-DVL1-WNT2B 9253 4149 13719 20634 42491
CSNK1D-PORCN-WNT2B 54547 33746 2831 17934 52535 FBXW11-GSK3B-WNT2B 6446 25466 48443 9756 981
PITX2-PORCN-WNT2B 32916 28214 19614 42831 17840 DKK1-GSK3A-WNT2B 46435 22075 14989 21647 18101
CSNK2A1-MYC-WNT2B 33055 55999 36655 287 9236 FOSL1-PORCN-WNT2B 51756 54848 26032 20042 1751
FSHB-NKD1-WNT2B 55721 42851 2627 5107 7553 SENP2-WNT1-WNT2B 16555 17079 41227 9388 56362
PYGO1-WNT2-WNT2B 23785 7527 40262 615 38247 FOSL1-WIF1-WNT2B 12903 16845 50910 16896 7421
LEF1-T-WNT2B 48424 50113 47991 1522 2960 FZD8-WNT1-WNT2B 31837 25698 25477 38489 25104
FBXW11-TCF7-WNT2B 41108 33848 28348 48942 26369 DAAM1-FGF4-WNT2B 16000 9089 55066 40863 27056
FBXW11-JUN-WNT2B 33659 37203 20213 9874 32143 DKK1-FGF4-WNT2B 103 10354 20410 29259 46133
FOSL1-SFRP1-WNT2B 6277 10803 37453 46689 25622 SENP2-SFRP1-WNT2B 40240 50851 56622 9242 9004
FBXW11-GSK3A-WNT2B 20409 22617 34216 48084 5873 FZD8-JUN-WNT2B 47390 29843 6652 5804 30618
DKK1-WNT1-WNT2B 5148 39741 99 25462 25379 DVL1-WNT1-WNT2B 44615 10931 27851 20224 47773
FRZB-NKD1-WNT2B 3508 55779 21413 56958 54884 DKK1-FOXN1-WNT2B 22219 29187 3624 37031 31136
CCND2-WNT1-WNT2B 8206 22475 56331 33393 19889 FZD1-T-WNT2B 10987 38809 11964 13374 51442
FBXW11-RHOU-WNT2B 40385 21306 912 54428 46020 DAAM1-T-WNT2B 23320 9302 18677 25820 50860
DKK1-NKD1-WNT2B 2 21468 4661 31962 47604 EP300-WNT1-WNT2B 40403 45788 6306 37531 53145
CTBP2-CTNNB1-WNT2B 7875 19830 34195 23465 32213 FZD6-WNT1-WNT2B 14865 55096 2854 19971 18190
FBXW11-WIF1-WNT2B 36968 5122 16875 36018 40185 FBXW11-FOXN1-WNT2B 55663 32223 6184 10160 38098
DAAM1-WNT1-WNT2B 8310 11548 37506 38188 47486 NLK-PORCN-WNT2B 23304 40640 40983 7483 30297
TCF7L1-WIF1-WNT2B 38177 34 28918 2665 24315 CTBP2-T-WNT2B 53395 8911 12910 8267 38289
FBXW11-NKD1-WNT2B 46316 49834 31463 34942 54972 CSNK2A1-FOXN1-WNT2B 56377 38665 54391 50687 12268
DKK1-PYGO1-WNT2B 9922 1845 49860 25488 36909 FBXW11-PORCN-WNT2B 35745 24457 1321 41380 44484
CCND3-NKD1-WNT2B 29468 17702 29050 41716 43213 FBXW11-FZD2-WNT2B 3308 32854 50919 52505 53174
CSNK1G1-FZD2-WNT2B 16988 38740 33148 19223 15749 DAAM1-JUN-WNT2B 54799 36164 2157 26110 26593
DAAM1-DVL2-WNT2B 15381 5625 50468 46525 49297 FZD1-PORCN-WNT2B 56201 55890 2978 45069 8402
DKK1-MYC-WNT2B 7585 27260 2699 34894 52083 DKK1-PORCN-WNT2B 13119 7914 33768 34345 53916
FZD8-T-WNT2B 828 38497 56911 52032 4429 DAAM1-LRP6-WNT2B 56089 47777 32504 8528 21823
FRZB-FZD2-WNT2B 6148 17323 30176 51069 4378 CSNK1D-FOXN1-WNT2B 40727 20657 11342 28759 54605
FZD1-WIF1-WNT2B 45148 33096 22965 3267 28017 LRP5-PORCN-WNT2B 18108 55585 52704 49602 30842
FBXW11-SLC9A3R1-WNT2B 32360 3783 53535 55838 5608 CXXC4-DVL2-WNT2B 35400 16086 45800 56946 44441
FBXW11-FGF4-WNT2B 39346 16482 33435 8074 1498 FOSL1-WNT1-WNT2B 16777 24758 43097 23275 38302
BCL9-PORCN-WNT2B 31320 49751 15858 56923 5674 KREMEN1-NKD1-WNT2B 41860 50698 42188 13420 1100
KREMEN1-PORCN-WNT2B 25373 52290 22610 2903 12826 FOSL1-NLK-WNT2B 14329 18478 43731 32209 46898
CTBP1-FGF4-WNT2B 301 21245 14872 56780 43226 DAAM1-FOXN1-WNT2B 29721 26744 32942 6037 9724
FZD6-PITX2-WNT2B 10663 27608 9003 33499 56550 FBXW2-NKD1-WNT2B 51198 7198 8275 25665 44537
KREMEN1-PPP2CA-WNT2B 36014 45601 55143 6929 4063 FZD1-JUN-WNT2B 40470 56406 19457 34145 8292
CSNK2A1-FSHB-WNT2B 57093 25886 24846 4769 8081 LRP5-NKD1-WNT2B 6506 56675 30108 35596 51172
LRP5-NKD1-WNT2B 6506 56675 30108 35596 51172 FZD8-GSK3A-WNT2B 9103 8669 15155 42693 27422
LRP5-NLK-WNT2B 12533 30603 27930 42546 28598 CSNK1D-WNT1-WNT2B 31537 11063 42528 38828 9460
FRZB-GSK3A-WNT2B 2610 26089 53894 55872 38044 FZD6-GSK3A-WNT2B 4557 22541 14486 35375 21117
FRAT1-PORCN-WNT2B 20944 46462 334 27557 17691 DAAM1-FZD2-WNT2B 17163 7944 13520 39457 4542
CCND2-LRP6-WNT2B 33693 21023 53000 51329 28570 FRZB-T-WNT2B 923 43383 42589 7043 21178
FZD1-NLK-WNT2B 3078 19116 35164 4311 41638 FZD7-PPP2CA-WNT2B 16737 33330 1637 33682 42332
CCND3-WNT1-WNT2B 56781 48641 12692 21153 53121 FBXW11-PYGO1-WNT2B 38516 3021 34825 23473 34676
FZD7-PORCN-WNT2B 22739 11163 28241 3088 23003 BTRC-GSK3A-WNT2B 3582 20261 29185 8102 27659
JUN-PYGO1-WNT2B 8806 9304 56999 30033 36730 FBXW4-WNT1-WNT2B 49985 4684 49002 50868 27871
FBXW11-T-WNT2B 8167 5125 56206 52284 24972 DVL1-FOXN1-WNT2B 8379 36905 17227 46425 37614
KREMEN1-WNT1-WNT2B 9185 50045 47503 42420 14152 FZD8-NKD1-WNT2B 9631 7680 43019 11274 51358
EP300-GSK3B-WNT2B 39896 34405 6246 29749 20434 FZD5-DVL2-WNT2B 812 9099 50058 12589 49298
Table 8: Rankings o WNT2B-X-X. A lis o app oxima ely i s 125 combina ions wi h ankings below
10,000 ou o 57,155. SA - SOBOL; Implemen a ion - ma inez
and FZD4 exp ession in he de eloping pe iphe al eye. Looking a he ables abo e,
one inds he ollowing combina ions o membe s o FZD maily along wi h WNT2B,
o be p ominen a 3 d o de le el - FRAT1-FZD1-WNT2B, CXXC4-FZD7-WNT2B,
CSNK1G1-FZD2-WNT2B, FZD8-T-WNT2B, FRZB-FZD2-WNT2B, FZD1-WIF1-WNT2B,
19
FZD6-PITX2-WNT2B, FZD1-NLK-WNT2B, FZD7-PORCN-WNT2B, FZD7-NKD1-
WNT2B, FZD6-PORCN-WNT2B, AXIN1-FZD2-WNT2B, TCF7L1-WNT1-WNT2B,
FZD5-NKD1-WNT2B, FZD8-WNT1-WNT2B, FZD8-JUN-WNT2B, FZD1-T-WNT2B,
FZD6-WNT1-WNT2B, FBXW11-FZD2-WNT2B, FZD1-PORCN-WNT2B, FZD1-JUN-
WNT2B, FZD8-GSK3A-WNT2B, FZD6-GSK3A-WNT2B, DAAM1-FZD2-WNT2B,
FZD7-PPP2CA-WNT2B, FZD8-NKD1-WNT2B and FZD5-DVL2-WNT2B. All hese
combina ions indica e possible exis ence o a syne gy when hey ake a highe ank in
he lis o combina ions.
7.4.3. Examining he beha iou o CCND-WNT2B-X combina ions
WNT2B is a key egula o o downs eam a ge β-ca enin and cyclin D1 (CCND1)
in Wn signaling pa hway. Zhu e al. [45] checked he exp ession o WNT2B, β-
ca enin and CCND1, and ound ha a e high glucose ea men , he exp ession o
all h ee we e signi ican ly up egula ed ( hus enhancing cell p oli e a ion and in lam-
ma ion, and inc ease ib osis- ela ed p o ein exp ession), bu Ho ip silencing could
inhibi hei exp ession which could be e e sed by miR-455-3p inhibi o . These da a
indica ed ha WNT2B was a a ge o miR-455-3p and Wn pa hway was in ol ed in
diabe ic neph opa hy (DN). Looking a he ables abo e, one inds he ollowing combi-
na ions o membe s o CCND maily along wi h WNT2B, o be p ominen a 3 d o de
le el - CCND2-WNT1-WNT2B, CCND3-NKD1-WNT2B, CCND2-LRP6-WNT2B,
CCND3-WNT1-WNT2B, CCND1-WIF1-WNT2B, and CCND1-FGF4-WNT2B. All
hese combina ions indica e possible exis ence o a syne gy when hey ake a highe
ank in he lis o combina ions.
7.4.4. Examining he beha iou o FBXW11-WNT2B-X combina ions
Nodula and supe icial a e he mos common sub ypes o basal cell ca cinoma (BCC)
and WNT signaling is associa ed wi h BCC pheno ypic a ia ion. Do Ca mo e al. [46]
obse ed ha nodula BCC p esen ed up- egula ion o CSNK1D, RAB23, PRKACB,
PRKX, WNT5A, BMP6, FBXW11, IFT52, and SIAH1; and down- egula ion o PRKACA,
WIF1, WNT2B, WNT3, WNT10A, WNT10B, WNT16, FKBP8, NPC1, and MAPK1.
In conclusion hey ound ha PRKX (up- egula ed), WNT3 (down- egula ed) and WNT16
(down- egula ed) genes, belonging o he WNT signaling pa hway, a e in ol ed in he
umo igenic p ocess o nodula BCC.
Dalle Ca bona e e al. [47] show ha FBXW11 is highly modula ed du ing di e -
en ia ion and ha inc eased le els o FBXW11 cause a dec ease in he a ge β-ca enin
le els unde no mal condi ions. Unde pa hological condi ions such as cleidoc anial
dysplasia (CCD) he ela ionship be ween FBXW11 and RUNX2 o β-ca enin changes
om no mal condi ions, sugges ing he lack o β-ca enin deg ada ion by FBXW11.
I has been epo ed in Dalle Ca bona e e al. [47] ha WNT signalling and RUNX2
mu ually egula e hei exp ession. In his disease model, FBXW11 le els migh be el-
e a ed o coun e ac he dys egula ed le els o β-ca enin. Con e sely, in os eosa coma
cells, he educ ion o FBXW11 p o ein le els inc eases β-ca enin. Since β-ca enin
p omo es umou o ma ion and p og ession, educed FBXW11 le els in os eosa coma
may be conside ed a nega i e p ognos ic ac o .
20
Looking a he ables abo e, one inds he ollowing combina ions o FBXW11
along wi h WNT2B, o be p ominen a 3 d o de le el - FBXW11-TCF7-WNT2B,
FBXW11-JUN-WNT2B, FBXW11-GSK3A-WNT2B, FBXW11-RHOU-WNT2B, FBXW11-
WIF1-WNT2B, FBXW11-NKD1-WNT2B, FBXW11-SLC9A3R1-WNT2B, FBXW11-
FGF4-WNT2B, FBXW11-T-WNT2B, FBXW11-GSK3B-WNT2B, FBXW11-FOXN1-
WNT2B, FBXW11-PORCN-WNT2B, FBXW11-FZD2-WNT2B and FBXW11-PYGO1-
WNT2B. All hese combina ions indica e possible exis ence o a syne gy when hey
ake a highe ank in he lis o combina ions.
7.4.5. Examining he beha iou o LRP-WNT2B-X combina ions
To assess he po en ial ole o WNT/TCF signaling in in asi e ophoblas di e en ia-
ion, Pollheime e al. [48] in es iga ed he ole o selec ed WNT ligands and izzled
ecep o s. WNT2B, WNT7B, FZD3, FZD6, and LRP6 mRNAs we e exp essed in all
issues and cell ypes analyzed, sugges ing ha unc ional WNT ecep o s (FZD/LRP6)
could be o med in human ophoblas s. As pa o hei s udy, Pollheime e al. [48]
demons a ed mRNA exp ession o WNT2B, WNT7B, FZD3, FZD6, and LRP6 in
all ophoblas cell ypes s eng hening he idea ha hese and o he WNT/FZD ac o s
could play a ole in au oc ine WNT signaling. Looking a he ables abo e, one inds he
ollowing combina ions o membe s o LRP amily along wi h WNT2B, o be p omi-
nen a 3 d o de le el - LRP6-TCF7-WNT2B, LRP5-SFRP1-WNT2B, LRP5-NKD1-
WNT2B, LRP5-NLK-WNT2B, CCND2-LRP6-WNT2B, DAAM1-LRP6-WNT2B, LRP5-
PORCN-WNT2B and LRP5-NKD1-WNT2B. All hese combina ions indica e possible
exis ence o a syne gy when hey ake a highe ank in he lis o combina ions.
7.4.6. Examining he beha iou o FOSL1-WNT2B-X combina ions
Bonci e al. [49] epo down egula ion o miRs in B-cell ch onic lymphocy ic leukemia
(CLL) as well as p os a e ca cinoma whe e addi ional WNT- ela ed a ge s included
SMAD7, SOX5, WNT2B and FOSL1. FOSL1 is known as a β-ca enin/WNT signaling
a ge gene, ansc ibed when WNT signaling is ac i a ed. Hachim e al. [50] decided
o deciphe he ole o WNT signaling on b onchial ib oblas biology and hei an-
sc ip omics p o iling o ib oblas s om as hma ic pa ien s compa ed o heal hy ones
con i med hei in silico analysis, as membe s o canonical WNT signaling (WNT1,
FOSL1, WNT2B, LRP5, WNT2, WNT16, and CCND2) we e signi ican ly up egula ed
in ib oblas s om as hma ic pa ien s. Looking a he ables abo e, one inds he ollow-
ing combina ions o FOSL1 along wi h WNT2B, o be p ominen a 3 d o de le el -
FOSL1-SFRP1-WNT2B, FOSL1-PORCN-WNT2B, FOSL1-WIF1-WNT2B, FOSL1-
WNT1-WNT2B and FOSL1-NLK-WNT2B. All hese combina ions indica e possible
exis ence o a syne gy when hey ake a highe ank in he lis o combina ions.
21

7.5. Conse ed machine lea ning ankings o es ed WNT3A-X-X
combina ions
A o al o 2415, 3 d o de combina ions in ol ing WNT3A we e ob ained om a ull
se o 71C3= 57155 combina ions. Fu he , om his selec ed se , using he abo e c i-
e ia o conse ed ankings, I epo / abula e he meaning ul combina ions ha migh
be wo king syne gis ically. Tables 10, 11 and 12 show he ankings o he same com-
bina ions as in able 9, bu using b ke nel o HSIC, 2002 implemen a ion o SOBOL
and ma inez implemen a ion o SOBOL, espec i ely. As one allies he ankings o
ac oss hese ables o a pa icula combina ion, one inds ha he ole o he combina-
ion o in e es is conse ed. This conse a ion poin s o he exis ence o he biological
syne gy, whe he he combina ion has been es ed o unexplo ed/un es ed.
7.5.1. Examining he beha iou o JUN-WNT3A-X combina ions
Sa o e al. [51] ound ha he exp ession le els o AXIN2 and c-JUN ac i a ed by
WNT3A s imula ion in HEK293T cells we e also inhibi ed in he p esence o STOCKS2S-
26016 (inhibi o s o he WNK signalling pa hway as epo ed in Mo i e al. [52]).
Looking a he ables abo e, one inds he ollowing combina ions o JUN along
wi h WNT3A, o be p ominen a 3 d o de le el - DKK1-JUN-WNT3A, DVL2-JUN-
WNT3A, FOSL1-JUN-WNT3A, CSNK1D-JUN-WNT3A, DIXDC1-JUN-WNT3A, CSNK1G1-
JUN-WNT3A, JUN-PYGO1-WNT3A, CTNNBIP1-JUN-WNT3A, FZD7-JUN-WNT3A,
BCL9-JUN-WNT3A and FBXW11-JUN-WNT3A. Addi ionally, one also inds he ol-
lowing combina ions o AXIN1 along wi h WNT3A, o be p ominen a 3 d o de
le el - AXIN1-DVL1-WNT3A, AES-AXIN1-WNT3A and AXIN1-MYC-WNT3A.
All hese combina ions indica e possible exis ence o a syne gy when hey ake a highe
ank in he lis o combina ions.
7.5.2. Examining he beha iou o DVL-WNT3A-X combina ions
Zhan e al. [53] s a e ha he WNT canonical pa hway is ac i a ed upon binding o
sec e ed WNT ligands ( o example, WNT3A and WNT1) o FZD ecep o s and LRP
co- ecep o s. LRP ecep o s a e hen phospho yla ed by CK1αand GSK3β, which
ec ui s Dishe elled (DVL) p o eins o he plasma memb ane whe e hey polyme ize
and a e ac i a ed as obse ed in Me cal e e al. [54]. Looking a he ables abo e, one
inds he ollowing combina ions o membe s o DVL amily along wi h WNT3A, o
be p ominen a 3 d o de le el - DVL2-JUN-WNT3A, AES-DVL1-WNT3A, AXIN1-
DVL1-WNT3A, DVL2-PYGO1-WNT3A, CXXC4-DVL2-WNT3A, DVL2-FGF4-WNT3A
and DVL1-FOXN1-WNT3A. All hese combina ions indica e possible exis ence o a
syne gy when hey ake a highe ank in he lis o combina ions.
7.5.3. Examining he beha iou o TCF-WNT3A-X combina ions
The TCF/Le amily o ansc ip ion ac o s u ilise β-ca enin as a ansc ip ional co-
ac i a o , and ins iga e a ge gene exp ession in WNT signaling pa hway. In o de o
assess whe he a lis o 90 di e en ially exp essed genes (DEGs) had been p e iously
iden i ied as di ec a ge s o β-ca enin/TCF-/Le in o he cell ypes, Szemes e al.
22
RANKING @ iUSING HSIC - LINEAR
3 d o de comb. 1 3 6 12 24 3 d o de comb. 1 3 6 12 24
FZD8-FBXW4-WNT3A 145 14722 464 49602 17899 SENP2-FBXW4-WNT3A 274 39131 29 44525 46327
DKK1-JUN-WNT3A 289 6120 44241 52638 12402 AES-AXIN1-WNT3A 300 53570 33402 33493 7041
DVL2-JUN-WNT3A 322 31939 32028 29113 4760 TLE1-WIF1-WNT3A 449 13164 8253 51282 7381
AES-DVL1-WNT3A 454 42413 16222 33799 31908 CCND1-FGF4-WNT3A 513 52076 47881 31710 26148
FBXW2-WNT3A-WNT4 532 33676 31112 1276 53531 JUN-PYGO1-WNT3A 570 14118 6423 19469 36536
CTNNBIP1-WIF1-WNT3A 603 57 12000 57039 19928 DAAM1-FBXW4-WNT3A 715 40167 9213 50253 45515
PPP2CA-WNT1-WNT3A 732 6546 10800 53535 9982 FZD7-PORCN-WNT3A 780 35610 948 25632 12174
FZD7-WNT1-WNT3A 796 6819 613 46978 36231 CCND1-PYGO1-WNT3A 859 46424 26699 23831 49470
TLE1-WNT1-WNT3A 862 11066 907 29504 42805 CXXC4-FGF4-WNT3A 905 28520 52397 52668 30693
AXIN1-DVL1-WNT3A 931 6900 28087 51866 19748 SFRP4-WNT1-WNT3A 994 7835 823 32443 11457
FBXW11-FBXW4-WNT3A 995 33770 89 41396 23538 FRAT1-NLK-WNT3A 1005 19771 7884 9479 10249
KREMEN1-PYGO1-WNT3A 1064 30070 1340 20277 52737 CTNNBIP1-JUN-WNT3A 1110 7698 46119 54862 31125
DKK1-FGF4-WNT3A 1181 38076 34967 42717 15527 CCND2-WNT1-WNT3A 1238 24529 3203 46942 8642
FBXW2-PYGO1-WNT3A 1243 46844 41378 10348 56667 FZD7-JUN-WNT3A 1250 17078 32637 21100 43381
FBXW11-LRP6-WNT3A 1267 46922 30660 12401 30214 EP300-WNT1-WNT3A 1360 30527 695 53063 7375
KREMEN1-PORCN-WNT3A 1377 25809 2588 12830 26801 CXXC4-FRAT1-WNT3A 1421 24998 29856 17406 1342
PPP2CA-T-WNT3A 1435 46308 13460 20855 21652 FZD5-WNT1-WNT3A 1443 14058 943 50372 9921
TCF7L1-WNT1-WNT3A 1465 4078 1392 49037 48926 FOSL1-NLK-WNT3A 1512 2335 4160 3374 12963
FOSL1-JUN-WNT3A 1542 4890 20754 29478 5342 BCL9-FGF4-WNT3A 1545 4871 55810 38541 37087
CCND3-FOXN1-WNT3A 1640 42647 14999 19304 19369 TLE2-WIF1-WNT3A 1645 195 4085 52703 19685
AES-SLC9A3R1-WNT3A 1649 50445 53711 29727 31801 FZD7-NKD1-WNT3A 1664 5491 2056 28279 37124
CCND3-FGF4-WNT3A 1666 48541 24627 42342 22550 DKK1-PYGO1-WNT3A 1670 37660 30663 36831 4685
FZD5-FGF4-WNT3A 1678 10370 56144 43866 11767 DVL2-FGF4-WNT3A 1706 31123 51974 39714 28294
FBXW4-WNT3A-WNT4 1716 50053 13154 14680 40891 CXXC4-WIF1-WNT3A 1745 353 12465 51440 34488
FZD6-WNT1-WNT3A 1761 55679 36296 46569 31443 PPP2R1A-WNT3-WNT3A 1817 55448 5096 45267 43648
CTBP1-FGF4-WNT3A 1841 5230 55626 51583 10691 CCND3-SFRP1-WNT3A 1848 50249 51613 12702 11723
BTRC-GSK3A-WNT3A 1946 45085 56552 39291 36207 FZD7-NLK-WNT3A 1957 2219 4173 15212 30086
CCND3-NKD1-WNT3A 1995 32953 30709 40159 23393 TCF7L1-WIF1-WNT3A 2015 7414 38348 38153 24687
NKD1-WIF1-WNT3A 2028 3129 43733 48011 30914 KREMEN1-FBXW4-WNT3A 2114 13176 100 22815 19325
FZD7-T-WNT3A 2142 42066 4203 1701 36597 PITX2-WNT3-WNT3A 2155 50776 27010 46543 38273
CCND1-WIF1-WNT3A 2203 19821 39265 34450 38713 DVL1-FOXN1-WNT3A 2232 41159 6747 12944 33691
FSHB-T-WNT3A 2242 34175 56516 9226 7363 FSHB-FZD2-WNT3A 2298 5294 54044 44316 3638
CCND3-FZD2-WNT3A 2329 41088 38338 37278 1771 FZD6-PORCN-WNT3A 2394 56979 41510 33895 6602
FBXW11-FOXN1-WNT3A 2396 2939 7434 18375 6211 AXIN1-MYC-WNT3A 2439 8891 14689 6272 37521
CTNNB1-FOXN1-WNT3A 2450 2310 9829 19274 20611 BCL9-JUN-WNT3A 2492 808 53814 42860 28316
FOSL1-WNT1-WNT3A 2512 4481 499 34674 10423 FOSL1-FBXW4-WNT3A 2570 6332 206 39656 6459
DKK1-GSK3A-WNT3A 2600 35402 42900 54934 30633 FBXW11-FGF4-WNT3A 2605 40212 42342 53886 2588
LRP5-WNT1-WNT3A 2674 6803 1423 45127 28226 KREMEN1-NKD1-WNT3A 2675 23678 2816 47552 40285
CSNK1D-WNT3-WNT3A 2727 49625 22336 55596 44252 CXXC4-WNT1-WNT3A 2734 34306 282 36977 4488
CSNK1D-JUN-WNT3A 2740 3878 56083 44551 46162 CCND2-LRP6-WNT3A 2746 39921 17378 19134 17966
KREMEN1-WIF1-WNT3A 2762 721 11586 56871 31145 KREMEN1-WNT3-WNT3A 2788 47193 12084 27016 19027
CXXC4-FOXN1-WNT3A 2796 53 5860 22254 12575 CCND3-LRP6-WNT3A 2824 48608 19945 32728 25411
DKK1-FOXN1-WNT3A 2859 5191 36256 16450 1748 CCND3-CSNK1A1-WNT3A 2882 32791 9744 16123 5109
DVL2-PYGO1-WNT3A 2944 11528 11111 13103 36306 FRAT1-FBXW4-WNT3A 2950 1626 150 55124 17849
CCND3-GSK3A-WNT3A 2984 45295 31574 8988 26511 PPP2R1A-WNT1-WNT3A 2989 13277 15619 27990 53390
DKK1-PORCN-WNT3A 3027 51411 42480 14175 39772 FZD5-CCND2-WNT3A 3096 41702 14175 37261 53046
DKK1-FBXW4-WNT3A 3172 11326 10275 19536 18392 FZD5-GSK3A-WNT3A 3176 26274 10429 35512 33685
CXXC4-DVL2-WNT3A 3186 7341 5733 24584 2313 FRZB-WNT1-WNT3A 3221 19926 900 52289 15551
FZD7-WIF1-WNT3A 3300 22512 13048 31811 10684 FRAT1-WIF1-WNT3A 3328 15377 26382 55074 7682
LEF1-PYGO1-WNT3A 3330 4637 9706 492 45999 PPP2CA-TCF7-WNT3A 3403 35126 15557 53522 39901
KREMEN1-MYC-WNT3A 3433 19129 6220 28682 38858 FBXW11-JUN-WNT3A 3438 21481 29928 50261 15749
CCND3-PYGO1-WNT3A 3454 44362 41213 28500 14947 NKD1-WNT2B-WNT3A 3477 51633 33941 7298 45111
CCND3-PITX2-WNT3A 3484 43666 17937 5868 27350 CCND3-T-WNT3A 3489 45724 10406 23614 102
CTBP2-T-WNT3A 3498 50012 4697 8661 6051 SFRP1-WNT3-WNT3A 3510 39054 12426 27569 44656
DIXDC1-JUN-WNT3A 3551 836 21850 41587 6942 CCND3-MYC-WNT3A 3563 41874 14702 4017 36721
KREMEN1-SLC9A3R1-WNT3A 3580 17181 25435 54188 25643 FZD6-GSK3A-WNT3A 3594 53588 35897 18833 55286
FZD7-PYGO1-WNT3A 3597 13080 6229 10048 9938 LRP5-WNT3-WNT3A 3611 25911 30682 26320 29360
CSNK1G1-FOXN1-WNT3A 3634 7199 9792 30313 10861 BTRC-WNT2-WNT3A 3667 53111 52839 51977 37208
CSNK1D-NLK-WNT3A 3672 3466 7618 26301 5357 CSNK1G1-WNT1-WNT3A 3690 42269 1886 38618 12595
BCL9-WNT3-WNT3A 3715 24411 28195 43748 28562 DAAM1-FGF4-WNT3A 3756 49690 53434 53503 17500
CSNK1G1-JUN-WNT3A 3774 3727 52028 22145 682 APC-GSK3A-WNT3A 3849 6781 15492 26625 29835
FOSL1-PORCN-WNT3A 3900 15019 1518 39920 12124 SENP2-WNT1-WNT3A 3925 51191 778 45722 31784
FBXW11-PYGO1-WNT3A 3985 37584 56193 14716 37160 FOSL1-FRAT1-WNT3A 4035 2654 13405 47524 18665
Table 9: Rankings o WNT3A-X-X. A lis o app oxima ely i s 126 combina ions wi h ankings below
10,000 ou o 57,155. SA - HSIC; Ke nel - linea
[55] compa ed he gene lis wi h published a ge genes o canonical WNT signalling,
based on using ChIPseq in U87 glioma cells in Zhang e al. [56], HEK293, and he
colo ec al cance cell line LS174T in Schuije s e al. [57]. 53 ou o he 90 DEGs we e
iden i ied as ha ing β-ca enin and/o TCF7L2/TCF4 bound o hei p omo e s in one
23
RANKING @ iUSING HSIC - RBF
3 d o de comb. 1 3 6 12 24 3 d o de comb. 1 3 6 12 24
FZD8-FBXW4-WNT3A 20619 3629 53249 29648 303 SENP2-FBXW4-WNT3A 27065 27541 40533 55578 8502
DKK1-JUN-WNT3A 10634 402 10397 46299 3270 AES-AXIN1-WNT3A 44301 49473 26232 27600 11298
DVL2-JUN-WNT3A 25797 23440 31750 21568 1485 TLE1-WIF1-WNT3A 50523 24823 48636 56307 10235
AES-DVL1-WNT3A 29401 45255 5093 37036 20749 CCND1-FGF4-WNT3A 20339 51659 33176 36373 2796
FBXW2-WNT3A-WNT4 41397 25061 14067 24192 5301 JUN-PYGO1-WNT3A 10181 579 35737 33610 43746
CTNNBIP1-WIF1-WNT3A 28101 8157 26911 47091 41515 DAAM1-FBXW4-WNT3A 17278 46399 38042 50218 2460
PPP2CA-WNT1-WNT3A 4487 6874 35552 24125 19493 FZD7-PORCN-WNT3A 7046 46922 42358 23913 36667
FZD7-WNT1-WNT3A 2224 19292 34884 35013 23800 CCND1-PYGO1-WNT3A 2014 38925 42108 33199 4343
TLE1-WNT1-WNT3A 21715 17829 32814 37959 6447 CXXC4-FGF4-WNT3A 376 11041 597 49220 57138
AXIN1-DVL1-WNT3A 11069 4918 11450 55352 33473 SFRP4-WNT1-WNT3A 11755 16260 28669 23387 22304
FBXW11-FBXW4-WNT3A 26939 26457 29630 45627 2113 FRAT1-NLK-WNT3A 51049 30143 52377 44271 42168
KREMEN1-PYGO1-WNT3A 7864 26771 50128 43544 15239 CTNNBIP1-JUN-WNT3A 24780 5944 45858 50803 13854
DKK1-FGF4-WNT3A 4166 17858 5679 30944 57050 CCND2-WNT1-WNT3A 4465 36473 38095 30987 12981
FBXW2-PYGO1-WNT3A 7391 48320 9248 34651 2524 FZD7-JUN-WNT3A 6578 3907 45657 38691 15081
FBXW11-LRP6-WNT3A 4398 36975 26538 31998 11795 EP300-WNT1-WNT3A 1327 24404 26980 31626 25194
KREMEN1-PORCN-WNT3A 8946 29482 33980 6745 37128 CXXC4-FRAT1-WNT3A 5682 22392 33504 50525 42228
PPP2CA-T-WNT3A 5197 44818 17755 38317 4985 FZD5-WNT1-WNT3A 1830 18724 34025 38182 14214
TCF7L1-WNT1-WNT3A 795 7154 34307 17085 15742 FOSL1-NLK-WNT3A 51755 5242 44005 49978 52983
FOSL1-JUN-WNT3A 37744 27522 48171 53533 24924 BCL9-FGF4-WNT3A 21656 7138 34183 51050 57004
CCND3-FOXN1-WNT3A 1170 42424 49947 36625 9095 TLE2-WIF1-WNT3A 40072 5491 24360 49488 34844
AES-SLC9A3R1-WNT3A 27911 53364 5344 27251 24128 FZD7-NKD1-WNT3A 16651 467 45031 55399 13378
CCND3-FGF4-WNT3A 263 53391 5905 50246 9076 DKK1-PYGO1-WNT3A 1315 30284 30530 24495 19085
FZD5-FGF4-WNT3A 3473 4265 35669 53993 57079 DVL2-FGF4-WNT3A 9868 16034 8886 17654 56545
FBXW4-WNT3A-WNT4 12835 41912 3061 4307 23428 CXXC4-WIF1-WNT3A 11746 12153 2343 56809 35373
FZD6-WNT1-WNT3A 5732 56781 23090 25529 3318 PPP2R1A-WNT3-WNT3A 9441 54192 34392 53766 7535
CTBP1-FGF4-WNT3A 8308 4009 36169 55681 56958 CCND3-SFRP1-WNT3A 9608 51246 2223 54986 19086
BTRC-GSK3A-WNT3A 12858 35286 25253 43232 19671 FZD7-NLK-WNT3A 23365 3018 51679 44843 19133
CCND3-NKD1-WNT3A 19177 14820 26493 56175 64 TCF7L1-WIF1-WNT3A 2909 25918 43790 53902 35000
NKD1-WIF1-WNT3A 48793 3970 17300 56778 21427 KREMEN1-FBXW4-WNT3A 49105 7228 49337 28152 8690
FZD7-T-WNT3A 3884 36637 47776 31821 37282 PITX2-WNT3-WNT3A 36927 41437 49172 9526 14468
CCND1-WIF1-WNT3A 22745 5551 30083 51087 4790 DVL1-FOXN1-WNT3A 4248 43920 50848 47064 9942
FSHB-T-WNT3A 37189 29725 873 25128 8181 FSHB-FZD2-WNT3A 10002 6702 2404 44003 56141
CCND3-FZD2-WNT3A 8329 31657 13384 30632 4736 FZD6-PORCN-WNT3A 75 57089 15014 7701 45470
FBXW11-FOXN1-WNT3A 1436 1677 40456 28639 873 AXIN1-MYC-WNT3A 28398 5982 50308 53667 3744
CTNNB1-FOXN1-WNT3A 15788 5414 49911 40803 23438 BCL9-JUN-WNT3A 34709 926 55356 53174 7223
FOSL1-WNT1-WNT3A 9692 5532 35479 30879 13078 FOSL1-FBXW4-WNT3A 40808 8862 52958 56668 7351
DKK1-GSK3A-WNT3A 60 28159 48806 35302 44957 FBXW11-FGF4-WNT3A 8897 26541 9766 20101 47787
LRP5-WNT1-WNT3A 14614 22492 43733 37764 22905 KREMEN1-NKD1-WNT3A 9700 7837 52991 45907 10853
CSNK1D-WNT3-WNT3A 4832 51374 56476 26830 11649 CXXC4-WNT1-WNT3A 1236 41816 5972 30693 33822
CSNK1D-JUN-WNT3A 3991 7790 52423 12387 1862 CCND2-LRP6-WNT3A 8184 44311 52569 51142 13842
KREMEN1-WIF1-WNT3A 38760 4243 33739 39807 7207 KREMEN1-WNT3-WNT3A 13113 51425 51324 32502 6247
CXXC4-FOXN1-WNT3A 2235 1906 54317 41438 43489 CCND3-LRP6-WNT3A 3531 48100 27710 44059 3100
DKK1-FOXN1-WNT3A 1472 17560 29991 26863 22001 CCND3-CSNK1A1-WNT3A 17118 24899 2478 56125 79
DVL2-PYGO1-WNT3A 18087 2223 36690 1889 26351 FRAT1-FBXW4-WNT3A 9047 7060 50667 48783 9181
CCND3-GSK3A-WNT3A 1094 43778 55604 51021 6348 PPP2R1A-WNT1-WNT3A 2644 9345 37570 29489 17577
DKK1-PORCN-WNT3A 3656 53268 6994 22200 48539 FZD5-CCND2-WNT3A 6120 47234 56065 55258 35257
DKK1-FBXW4-WNT3A 12647 753 39108 46782 2266 FZD5-GSK3A-WNT3A 6043 40468 54992 52291 56281
CXXC4-DVL2-WNT3A 5548 8944 24906 33696 42805 FRZB-WNT1-WNT3A 6977 20832 38003 35393 38215
FZD7-WIF1-WNT3A 3521 32340 43606 53450 22727 FRAT1-WIF1-WNT3A 9771 4923 24250 54851 24596
LEF1-PYGO1-WNT3A 7948 34410 45811 27590 17447 PPP2CA-TCF7-WNT3A 36467 12019 36560 49458 39632
KREMEN1-MYC-WNT3A 10637 5567 56637 35572 1429 FBXW11-JUN-WNT3A 12922 7009 24204 32352 1608
CCND3-PYGO1-WNT3A 782 47470 16204 30209 9636 NKD1-WNT2B-WNT3A 50905 55634 51652 46273 6139
CCND3-PITX2-WNT3A 14471 39233 2731 800 1147 CCND3-T-WNT3A 16919 45958 10525 46128 1089
CTBP2-T-WNT3A 2552 43203 27518 36551 13398 SFRP1-WNT3-WNT3A 26158 40876 48765 52296 6149
DIXDC1-JUN-WNT3A 26524 53 54094 51456 1811 CCND3-MYC-WNT3A 4583 44095 29482 55800 1173
KREMEN1-SLC9A3R1-WNT3A 5894 4234 35325 31271 14229 FZD6-GSK3A-WNT3A 8511 55686 50518 43306 37494
FZD7-PYGO1-WNT3A 2200 3030 44689 22869 39525 LRP5-WNT3-WNT3A 31453 12512 52372 44108 34882
CSNK1G1-FOXN1-WNT3A 7916 4786 40233 7694 33821 BTRC-WNT2-WNT3A 31077 52852 5122 22613 1175
CSNK1D-NLK-WNT3A 12770 9632 43802 42949 37641 CSNK1G1-WNT1-WNT3A 10871 47854 9882 20452 14786
BCL9-WNT3-WNT3A 12754 19725 38705 53029 6499 DAAM1-FGF4-WNT3A 2588 48679 1464 46798 25162
CSNK1G1-JUN-WNT3A 8236 643 17222 17109 5337 APC-GSK3A-WNT3A 5761 38390 52609 49492 54574
FOSL1-PORCN-WNT3A 1761 8657 47396 12988 53731 SENP2-WNT1-WNT3A 1571 55369 22016 26046 17241
FBXW11-PYGO1-WNT3A 5958 23716 24819 17645 5707 FOSL1-FRAT1-WNT3A 41058 173 49766 43236 36519
Table 10: Rankings o WNT3A-X-X. A lis o app oxima ely i s 126 combina ions wi h ankings below
10,000 ou o 57,155. SA - HSIC; Ke nel - b
o mo e o hese h ee da a se s. Looking a he ables abo e, one inds he ollowing
combina ions o membe s o TCF amily along wi h WNT3A, o be p ominen a 3 d
o de le el - TCF7L1-WNT1-WNT3A, TCF7L1-WIF1-WNT3A and PPP2CA-TCF7-
WNT3A . All hese combina ions indica e possible exis ence o a syne gy when hey
ake a highe ank in he lis o combina ions.
24
RANKING @ iUSING SOBOL - 2002
3 d o de comb. 1 3 6 12 24 3 d o de comb. 1 3 6 12 24
FZD8-FBXW4-WNT3A 37163 14519 40451 32936 12343 SENP2-FBXW4-WNT3A 32061 15253 50111 35264 22955
DKK1-JUN-WNT3A 51531 12300 46409 53700 3796 AES-AXIN1-WNT3A 7792 24132 1607 25930 54940
DVL2-JUN-WNT3A 35727 49416 40820 44967 1537 TLE1-WIF1-WNT3A 50693 6752 56468 57096 11947
AES-DVL1-WNT3A 25130 20756 22584 26521 48898 CCND1-FGF4-WNT3A 12635 24029 16295 7779 50619
FBXW2-WNT3A-WNT4 645 48140 5748 27685 37510 JUN-PYGO1-WNT3A 1610 17601 24757 13846 37085
CTNNBIP1-WIF1-WNT3A 41974 54167 46904 51223 14244 DAAM1-FBXW4-WNT3A 46983 16004 31724 37539 28514
PPP2CA-WNT1-WNT3A 40524 9682 46210 50633 28358 FZD7-PORCN-WNT3A 20917 23923 24750 6039 49403
FZD7-WNT1-WNT3A 1438 7881 25103 25538 10719 CCND1-PYGO1-WNT3A 39080 19013 56205 51729 13572
TLE1-WNT1-WNT3A 45532 17196 56383 56904 289 CXXC4-FGF4-WNT3A 7493 411 15315 24389 48926
AXIN1-DVL1-WNT3A 17158 2599 23950 24990 26879 SFRP4-WNT1-WNT3A 19672 39835 4609 14591 47471
FBXW11-FBXW4-WNT3A 42391 26218 31369 55873 4622 FRAT1-NLK-WNT3A 21933 31321 12151 6237 52766
KREMEN1-PYGO1-WNT3A 52932 56977 53771 37472 14726 CTNNBIP1-JUN-WNT3A 47078 14611 51686 48296 5008
DKK1-FGF4-WNT3A 3178 11584 22425 8017 10360 CCND2-WNT1-WNT3A 19781 51583 73 4270 44933
FBXW2-PYGO1-WNT3A 52031 31884 46340 31823 2792 FZD7-JUN-WNT3A 1386 53880 25449 20632 45908
FBXW11-LRP6-WNT3A 34355 56789 38495 44740 5646 EP300-WNT1-WNT3A 23045 8793 21877 20602 35795
KREMEN1-PORCN-WNT3A 36088 42706 41171 37942 19003 CXXC4-FRAT1-WNT3A 7869 2751 20454 26029 9961
PPP2CA-T-WNT3A 8306 15391 15440 22058 43691 FZD5-WNT1-WNT3A 46539 42443 44834 49091 30828
TCF7L1-WNT1-WNT3A 47046 10502 49803 53053 33064 FOSL1-NLK-WNT3A 43309 33771 50006 38500 4467
FOSL1-JUN-WNT3A 10579 5753 10670 19639 21636 BCL9-FGF4-WNT3A 48960 21173 56013 55763 6132
CCND3-FOXN1-WNT3A 53912 11334 52192 32549 47236 TLE2-WIF1-WNT3A 33475 13433 36234 29978 9382
AES-SLC9A3R1-WNT3A 25865 22510 7109 28361 27321 FZD7-NKD1-WNT3A 56393 1785 42882 38968 851
CCND3-FGF4-WNT3A 2964 34278 17730 11836 49760 DKK1-PYGO1-WNT3A 49429 22863 28934 47297 24196
FZD5-FGF4-WNT3A 4616 7975 9759 18730 22965 DVL2-FGF4-WNT3A 28299 7239 25133 17514 55735
FBXW4-WNT3A-WNT4 17016 30005 5680 6177 53510 CXXC4-WIF1-WNT3A 54553 44801 48557 52030 1570
FZD6-WNT1-WNT3A 56029 34810 37658 39310 933 PPP2R1A-WNT3-WNT3A 36443 18940 41310 53135 2959
CTBP1-FGF4-WNT3A 8200 460 13684 26877 18621 CCND3-SFRP1-WNT3A 14356 25266 26873 23467 26717
BTRC-GSK3A-WNT3A 5197 2769 4826 638 44313 FZD7-NLK-WNT3A 56722 52305 45867 39848 966
CCND3-NKD1-WNT3A 17921 19886 26294 22858 34282 TCF7L1-WIF1-WNT3A 50706 10131 45130 48883 856
NKD1-WIF1-WNT3A 37352 21808 33337 55217 6162 KREMEN1-FBXW4-WNT3A 45167 47280 56590 48968 2663
FZD7-T-WNT3A 57116 45706 31412 38082 48517 PITX2-WNT3-WNT3A 1072 29636 4611 11649 49643
CCND1-WIF1-WNT3A 30286 43921 47521 55757 2241 DVL1-FOXN1-WNT3A 47581 4764 35882 37697 32002
FSHB-T-WNT3A 38613 13069 34339 29636 16201 FSHB-FZD2-WNT3A 39818 41432 46903 36007 7232
CCND3-FZD2-WNT3A 21930 38957 21806 22322 45824 FZD6-PORCN-WNT3A 56095 49583 38183 45187 10584
FBXW11-FOXN1-WNT3A 37771 37458 34204 47681 8870 AXIN1-MYC-WNT3A 55143 55018 52203 52922 5932
CTNNB1-FOXN1-WNT3A 14432 17654 10067 1699 34508 BCL9-JUN-WNT3A 1664 30352 8333 8059 41645
FOSL1-WNT1-WNT3A 15630 39992 11099 5546 48850 FOSL1-FBXW4-WNT3A 14577 48454 4103 4489 48405
DKK1-GSK3A-WNT3A 4570 55680 19251 18539 47694 FBXW11-FGF4-WNT3A 22277 1832 26256 5894 41316
LRP5-WNT1-WNT3A 51115 46900 55604 39495 9121 KREMEN1-NKD1-WNT3A 3850 55089 612 11917 55918
CSNK1D-WNT3-WNT3A 36262 46174 50463 43303 12247 CXXC4-WNT1-WNT3A 46602 51045 38468 51607 4562
CSNK1D-JUN-WNT3A 41685 14518 29055 33675 22133 CCND2-LRP6-WNT3A 4596 45720 404 249 56846
KREMEN1-WIF1-WNT3A 36608 31863 33558 56397 51574 KREMEN1-WNT3-WNT3A 46697 24784 33813 55605 41537
CXXC4-FOXN1-WNT3A 51263 50390 30984 42574 46666 CCND3-LRP6-WNT3A 34677 8954 29468 44307 23310
DKK1-FOXN1-WNT3A 50685 32463 50243 48254 12211 CCND3-CSNK1A1-WNT3A 2952 56510 305 26398 49052
DVL2-PYGO1-WNT3A 35451 32587 46161 49351 14826 FRAT1-FBXW4-WNT3A 42074 26045 31970 33331 9797
CCND3-GSK3A-WNT3A 24268 44070 28374 18849 40260 PPP2R1A-WNT1-WNT3A 44486 25983 55160 38768 876
DKK1-PORCN-WNT3A 50877 8870 41126 42802 14055 FZD5-CCND2-WNT3A 44151 8669 39209 29947 3499
DKK1-FBXW4-WNT3A 43840 46055 39740 42266 18236 FZD5-GSK3A-WNT3A 4921 4098 4925 5427 49194
CXXC4-DVL2-WNT3A 17336 51748 14847 23229 36228 FRZB-WNT1-WNT3A 47750 57036 42232 37002 55623
FZD7-WIF1-WNT3A 462 1898 24495 17586 7553 FRAT1-WIF1-WNT3A 38203 56268 35949 38506 8834
LEF1-PYGO1-WNT3A 40621 17131 45161 29919 31440 PPP2CA-TCF7-WNT3A 53743 13986 53761 54445 6921
KREMEN1-MYC-WNT3A 53432 44377 45039 45412 2524 FBXW11-JUN-WNT3A 29118 54401 45309 57041 2430
CCND3-PYGO1-WNT3A 51433 27320 30354 36390 39641 NKD1-WNT2B-WNT3A 4519 50837 9924 21240 36721
CCND3-PITX2-WNT3A 34394 29164 30661 48295 16862 CCND3-T-WNT3A 20183 39370 25828 26415 52435
CTBP2-T-WNT3A 15847 17322 7068 4880 31616 SFRP1-WNT3-WNT3A 44625 19927 40999 39830 7659
DIXDC1-JUN-WNT3A 642 31777 12679 15634 45593 CCND3-MYC-WNT3A 36632 24224 28942 30557 27130
KREMEN1-SLC9A3R1-WNT3A 7391 2325 5102 8894 56781 FZD6-GSK3A-WNT3A 26209 37042 19572 17832 42767
FZD7-PYGO1-WNT3A 1165 50482 26897 25768 53340 LRP5-WNT3-WNT3A 50760 41203 55018 45994 3924
CSNK1G1-FOXN1-WNT3A 18175 14967 2698 926 50456 BTRC-WNT2-WNT3A 7977 19933 27864 6975 11980
CSNK1D-NLK-WNT3A 15647 31281 25207 25693 26652 CSNK1G1-WNT1-WNT3A 10811 5687 16886 21507 41231
BCL9-WNT3-WNT3A 5547 41916 2456 22916 32645 DAAM1-FGF4-WNT3A 20174 3824 15389 9232 44937
CSNK1G1-JUN-WNT3A 23983 11639 7142 6023 49316 APC-GSK3A-WNT3A 9483 20303 24414 16874 26548
FOSL1-PORCN-WNT3A 9807 26119 20412 9520 38142 SENP2-WNT1-WNT3A 34690 19702 55187 53391 16705
FBXW11-PYGO1-WNT3A 39947 53781 36004 52889 15695 FOSL1-FRAT1-WNT3A 46128 6025 54699 53346 1957
Table 11: Rankings o WNT3A-X-X. A lis o app oxima ely i s 125 combina ions wi h ankings below
10,000 ou o 57,155. SA - SOBOL; Implemen a ion - 2002
7.5.4. Examining he beha iou o FZD / LRP/ CCND / FOSL1 / PITX2 -WNT3A-
X combina ions
Amyo ophic la e al scle osis (ALS) is a ch onic neu odegene a i e disease cha ac e -
ized by p og essi e degene a ion o he mo o neu ons in he co ex, b ains em, and
25
RANKING @ iUSING SOBOL - MARTINEZ
3 d o de comb. 1 3 6 12 24 3 d o de comb. 1 3 6 12 24
CXXC4-PORCN-WNT4 4276 14596 42774 57022 45130 FZD5-JUN-WNT4 19865 9292 48700 121386 52601
CCND3-PORCN-WNT4 26806 19860 18309 28843 27352 CSNK1D-FGF4-WNT4 30931 24624 1645 40905 44453
LRP5-NLK-WNT4 11875 29409 39497 6717 14614 PITX2-PORCN-WNT4 9395 23474 32883 37297 24846
FSHB-FZD2-WNT4 2021 57140 14789 29295 53443 AXIN1-WNT1-WNT4 2778 38952 44497 24969 214
DVL2-JUN-WNT4 12922 5091 28902 26178 19271 FZD7-PORCN-WNT4 5819 17955 1724 40196 33807
DVL1-EP300-WNT4 25389 12501 1599 51389 44362 FSHB-T-WNT4 40510 47251 23497 18487 55763
APC-PORCN-WNT4 22457 14933 19953 27502 33252 DKK1-JUN-WNT4 292 3863 10616 27487 47309
CSNK1G1-NLK-WNT4 9882 34667 14911 20141 31237 CCND2-WNT1-WNT4 56311 32819 51920 32545 37821
FOSL1-FRAT1-WNT4 40993 13521 5723 19915 17592 FOSL1-NLK-WNT4 45098 10285 6164 24489 8061
FZD6-PORCN-WNT4 199 7166 3089 14140 1367 CTBP2-CTNNB1-WNT4 34634 28678 15747 18697 28122
CSNK2A1-MYC-WNT4 19871 31001 13262 3506 6248 CCND1-WIF1-WNT4 19090 34087 44892 9619 637
FOSL1-PORCN-WNT4 7917 37593 48481 35640 51574 CXXC4-NLK-WNT4 55944 14516 7372 46062 23888
FBXW2-PORCN-WNT4 46672 28991 8289 11846 43257 FBXW2-WNT3A-WNT4 6270 53231 8071 37859 6097
FRAT1-NLK-WNT4 25990 49738 661 19315 9889 DAAM1-FBXW4-WNT4 9541 3985 22660 40797 34016
APC-PITX2-WNT4 33809 3550 4717 20161 40028 CCND2-LRP6-WNT4 37728 13104 27207 45558 52678
FZD5-PORCN-WNT4 8507 37632 48747 30800 4942 TCF7L1-WNT1-WNT4 32094 40529 21150 6996 1659
TLE1-WNT1-WNT4 36555 15670 21408 7024 45023 DIXDC1-PORCN-WNT4 12247 40184 4921 27175 55522
KREMEN1-PORCN-WNT4 25014 55908 56360 6264 40529 DKK1-PORCN-WNT4 25947 40656 8698 44050 26641
FZD5-WNT1-WNT4 47089 43274 11221 47423 52439 FBXW11-FBXW4-WNT4 11236 5133 55151 49822 27142
CSNK1A1-FBXW4-WNT4 21502 52930 8543 32700 10282 FBXW2-JUN-WNT4 35429 42647 44788 43088 49776
6 DKK1-FGF4-WNT4 15805 32746 7014 37963 19923 FBXW2-WNT1-WNT4 12354 12266 47167 24853 6316
SENP2-WNT1-WNT4 23302 15994 3637 19774 7442 FBXW2-PYGO1-WNT4 52436 10894 44161 20796 21790
DKK1-WNT1-WNT4 4150 8692 11857 26791 3627 SENP2-FBXW4-WNT4 30943 9589 56816 22982 2735
FBXW2-FGF4-WNT4 35089 12142 7048 18433 30806 TLE1-WIF1-WNT4 13417 53175 11985 6640 5468
CCND1-FGF4-WNT4 45423 56248 37480 20853 10917 RHOU-WNT1-WNT4 14697 29770 55730 10370 1690
DVL1-WNT1-WNT4 17136 51482 9987 16743 1726 DIXDC1-WNT3-WNT4 7590 21662 40072 54760 19415
KREMEN1-WNT1-WNT4 2199 38104 48857 13973 4782 BTRC-FOXN1-WNT4 46136 7354 21239 41736 23521
PPP2R1A-WNT1-WNT4 37092 5843 25053 14666 48915 FBXW11-FOXN1-WNT4 15807 8100 17793 26530 5575
LRP6-SLC9A3R1-WNT4 36806 29083 35933 3613 8254 FZD8-PORCN-WNT4 16866 18194 19414 12569 12962
FBXW11-PORCN-WNT4 20159 34969 20626 54364 6425 FBXW11-WNT1-WNT4 11180 25231 49052 48653 18382
DIXDC1-NKD1-WNT4 46229 42232 4694 26610 37481 FRZB-WNT1-WNT4 6698 54817 3429 48430 7937
DIXDC1-FZD2-WNT4 50281 20232 28903 8355 45251 CTNNBIP1-JUN-WNT4 8571 16635 1790 9191 55418
BTRC-PPP2CA-WNT4 18544 53592 12219 41275 6887 PPP2CA-WNT1-WNT4 45922 51703 31831 5639 9
FZD5-FOXN1-WNT4 396 43921 5362 42075 4967 FBXW4-WNT3A-WNT4 17207 4496 54748 47713 9359
NLK-PORCN-WNT4 839 35865 37133 52537 3763 CXXC4-FGF4-WNT4 53473 50248 53015 47741 53510
FRZB-PORCN-WNT4 36039 40997 30705 7328 55361 CTBP1-PYGO1-WNT4 31272 3069 22436 8609 40251
DAAM1-FOXN1-WNT4 42073 49218 33120 29009 300 FZD6-WNT1-WNT4 7233 45016 15516 10015 3188
AES-WNT1-WNT4 35587 7864 26131 9828 43837 FZD5-CTNNBIP1-WNT4 37790 17996 35360 13627 69
FZD8-FBXW4-WNT4 15999 27058 54943 26395 226 GSK3B-PORCN-WNT4 30196 41020 21974 56816 40470
CSNK1G1-FZD2-WNT4 10410 34283 49819 8764 3839 APC-FZD6-WNT4 37397 53670 39026 39666 36556
FRAT1-PORCN-WNT4 1204 15349 9265 36000 46519 APC-WNT1-WNT4 917 11941 13711 9897 48253
FGF4-NLK-WNT4 7085 8398 45782 12210 41629 FBXW2-FOXN1-WNT4 39561 25779 15329 28673 6746
DIXDC1-FOXN1-WNT4 32682 1731 13063 29733 30817 FSHB-LEF1-WNT4 15442 25307 14632 33427 52184
DIXDC1-LRP5-WNT4 1097 14539 41487 34988 44516 BCL9-FGF4-WNT4 4313 55037 11369 13920 5299
SFRP4-WNT1-WNT4 27168 3150 38903 887 56174 DIXDC1-NLK-WNT4 1935 7729 30708 20858 4426
DIXDC1-WNT1-WNT4 31540 9049 855 15412 43794 DIXDC1-GSK3A-WNT4 33583 29470 10959 48219 48401
TCF7L1-WIF1-WNT4 16671 56895 12326 3087 5863 LRP5-WNT1-WNT4 38582 11835 11954 12770 51873
DVL1-JUN-WNT4 37828 11537 12122 28401 10081 FBXW11-JUN-WNT4 37910 15788 21334 3785 16647
CTBP1-FOXN1-WNT4 43275 38868 21797 19991 39467 CCND1-CTNNBIP1-WNT4 33341 37082 32687 33491 887
DAAM1-FZD8-WNT4 834 52586 22406 43223 34981 PPP2R1A-WNT3-WNT4 38925 6831 8673 22959 7896
CSNK2A1-CTNNB1-WNT4 1302 27956 45071 49285 9763 FRZB-GSK3A-WNT4 51688 50258 8762 4281 16089
SFRP4-T-WNT4 37649 20378 3687 1979 51544 DVL2-FZD1-WNT4 17536 52315 14707 9854 19061
RHOU-SLC9A3R1-WNT4 52925 62 40274 23424 10431 FRZB-NLK-WNT4 20535 24126 28511 55751 12292
CSNK1G1-WIF1-WNT4 56789 43140 52845 54585 19132 FOSL1-WNT1-WNT4 40112 4912 51361 40583 39621
FBXW11-FGF4-WNT4 44736 39342 39578 319 36586 FZD5-NKD1-WNT4 50883 36657 40818 51578 32742
RHOU-SFRP1-WNT4 37322 9276 39470 33165 21606 CXXC4-JUN-WNT4 8214 33327 19909 4326 55524
DVL1-MYC-WNT4 39413 5460 14296 33480 49353 BTRC-CCND3-WNT4 40306 33905 50218 23253 472
APC-FZD2-WNT4 55887 29000 17998 44736 23788 CSNK1D-NLK-WNT4 55088 4562 19617 29935 54873
CTBP1-FRAT1-WNT4 42916 92 41662 39172 18130 DIXDC1-SFRP1-WNT4 5295 28151 32604 54855 40585
FBXW2-WIF1-WNT4 29533 55498 12217 29219 42911 DVL2-FGF4-WNT4 18376 48270 11104 49246 35704
LEF1-WNT1-WNT4 2712 26579 51004 53571 711 PPP2R1A-TLE1-WNT4 51244 380 10001 46733 50906
FOSL1-FOXN1-WNT4 20287 2448 37360 25562 16564 CSNK1G1-JUN-WNT4 7327 52583 35808 38813 18150
FZD5-PYGO1-WNT4 33763 36551 23826 53334 40907 NKD1-WIF1-WNT4 29254 43808 28256 8965 5464
Table 16: Rankings o WNT4-X-X. A lis o app oxima ely i s 125 combina ions wi h ankings below
10,000 ou o 57,155. SA - SOBOL; Implemen a ion - ma inez
Looking a he ables abo e, one inds he ollowing combina ions o FOSL1 along
wi h WNT4, o be p ominen a 3 d o de le el - FOSL1-FRAT1-WNT4, FOSL1-
PORCN-WNT4, FOSL1-FOXN1-WNT4, FOSL1-NLK-WNT4 and FOSL1-WNT1-
WNT4. All hese combina ions indica e possible exis ence o a syne gy when hey
ake a highe ank in he lis o combina ions.
32

7.6.4. Examining he beha iou o NLK-WNT4-X combina ions
Nemo-like kinase (NLK) is an e olu iona ily conse ed p o ein kinase in ol ed in
WNT/β-ca enin signalling. O a e al. [65] demons a e ha NLK unc ions down-
s eam o Dishe elled (DVL) in he WNT/β-ca enin signalling pa hway. Swann e al.
[66] obse e ha NLK has p e iously been demons a ed o ei he enhance o sup-
p ess Wn signaling in a con ex -dependen manne ; howe e , he de ec i e mig a-
ion o he hymic lobes, pa a hy oids o hy oid was p ese ed in NLK-de icien ,
WNT4- ansgenic emb yos, indica ing ha NLK is no equi ed o media e he WNT4-
induced signaling pa hway ha dis up s o gan mo phogenesis. Yu e al. [67] ob-
se ed ha ecombinan WNT4 p o eins ( WNT4) s imula ion induced he o ma ion
o he TAK1-TAB2-NLK complex. Looking a he ables abo e, one inds he ol-
lowing combina ions o NLK along wi h WNT4, o be p ominen a 3 d o de le el
- LRP5-NLK-WNT4, CSNK1G1-NLK-WNT4, FRAT1-NLK-WNT4, NLK-PORCN-
WNT4, FGF4-NLK-WNT4, FOSL1-NLK-WNT4, CXXC4-NLK-WNT4, DIXDC1-
NLK-WNT4, FRZB-NLK-WNT4 and CSNK1D-NLK-WNT4. All hese combina ions
indica e possible exis ence o a syne gy when hey ake a highe ank in he lis o com-
bina ions.
7.6.5. Examining he beha iou o DVL-WNT4-X combina ions
Siko a e al. [68] obse ed ha WNT4 did no ac i a e β-ca enin-dependen ansc ip-
ion in HT1080 cells despi e inducing phospho yla ion o he DVL-2/3 WNT signal-
ing molecules in HT1080. Emodin, an an h aquinone wi h mul iple physiological
ac i i ies, has been epo ed o inhibi p oli e a ion o ascula smoo h muscle cells
(VSMCs) ha migh cause in imal a e ial hickening. Emodin elie ed inju y-induced
a e y in imal hickness. To assess he downs eam signal o WNT4 ha media es
emodin-induced p e en ion o a e y s enosis, Hua e al. [69] examined le els o DVL-
1 and β-ca enin in inju ed a e ies and ound ha exp ession o bo h p o eins was ac i-
a ed by ascula balloon inju y, bu was inhibi ed in a s adminis e ed emodin. Look-
ing a he ables abo e, one inds he ollowing combina ions o membe s o DVL am-
ily along wi h WNT4, o be p ominen a 3 d o de le el - DVL2-JUN-WNT4, DVL1-
EP300-WNT4, DVL1-WNT1-WNT4, DVL1-JUN-WNT4, DVL1-MYC-WNT4, DVL2-
FZD1-WNT4 and DVL2-FGF4-WNT4. All hese combina ions indica e possible exis-
ence o a syne gy when hey ake a highe ank in he lis o combina ions.
33
7.7. Conse ed machine lea ning ankings o es ed WNT5A-X-X
combina ions
A o al o 2415, 3 d o de combina ions in ol ing WNT5A we e ob ained om a ull
se o 71C3= 57155 combina ions. Fu he , om his selec ed se , using he abo e c i e-
ia o conse ed ankings, I epo / abula e he meaning ul combina ions ha migh be
wo king syne gis ically. Tables 18, 19 and 20 show he ankings o he same combi-
na ions as in able 17, bu using b ke nel o HSIC, 2002 implemen a ion o SOBOL
and ma inez implemen a ion o SOBOL, espec i ely. As one allies he ankings o
ac oss hese ables o a pa icula combina ion, one inds ha he ole o he combina-
ion o in e es is conse ed. This conse a ion poin s o he exis ence o he biological
syne gy, whe he he combina ion has been es ed o unexplo ed/un es ed.
7.7.1. Examining he beha iou o WIF1-WNT5A-X combina ions
Su mann-Schmi e al. [70] epo ha WIF1 is highly exp essed a ca ilage-mesenchyme
in e aces o he ea ly de eloping skele on andin e al and pos na al skele al de elop-
men , WIF1 is exp essed in a sha ply es ic ed zone in he uppe hyaline laye o
epiphyseal and a icula ca ilage and in abecula bone. They ound ha ecombi-
nan WIF1 and WNT ac o s show speci ic binding o he o me o WNT3A, WNT4,
WNT5A, WNT7A, WNT9A and WNT11. Chond osa coma (CS) is a a e cance and
Liu e al. [71] in hei s udy, ound p omo e me hyla ed WIF1 in bo h CS cell lines
(CS-1 and SW1353) and umo issues. They con i med loss o WIF1 exp ession
and ac i a ion o Wn pa hway p o eins (WNT5-A/B, LRP6, and DVL2) and an in-
e se co ela ion be ween he exp ession o WNT5-A/B and WIF1. Taken oge he ,
hei esul s suppo he hypo hesis ha WIF1 es o a ion could a enua e he ac i i y
o WNT pa hway and impedes he ansmission o WNT signal. Ska ia e al. [72]
in es iga ed he an agonis ic e ec o he RYK speci ic sec e ed WIF1 on WNT5A-
media ed ac i a ion/inac i a ion o LIMK/CFL, and adhe ens junc ion dis up ion in
human ascula endo helial cells (VECs). They ound ha in human co ona y a e y
endo helial cells (HCAEC), ea men wi h WNT5A enhanced he phospho yla ion o
LIMK and CFL ha was signi ican ly p e en ed by WIF1. The p esence o WIF1 sup-
p essed WNT5A-media ed dis up ion o β-ca enin and VE-cadhe in adhe ens junc-
ions in HCAEC, he eby p e en ing ba ie dys unc ion caused by WNT5A. Vassallo
e al. [73] show ha loss o WIF1 enhanced he mig a o y po en ial o glioblas oma
h ough WNT5A ha ac i a ed he WNT/Ca2+pa hway and me as asis-associa ed lung
adenoca cinoma ansc ip 1 (MALAT1). Guj al and MacBea h [1] eco d he ac i i y
o WIF1 and WNT5A and i shows ha in ime, he exp ession le els o WIF1 a e much
highe han WNT5A, indica ing ha WIF1 migh be a enua ing WNT5A exp ession.
Looking a he ables abo e, one inds he ollowing combina ions o WIF1 along
wi h WNT5A, o be p ominen a 3 d o de le el - CTNNBIP1-WIF1-WNT5A, TLE1-
WIF1-WNT5A, JUN-WIF1-WNT5A, CCND1-WIF1-WNT5A, TCF7L1-WIF1-WNT5A
and PYGO1-WIF1-WNT5A. All hese combina ions indica e possible exis ence o a
syne gy when hey ake a highe ank in he lis o combina ions.
34
7.7.2. Examining he beha iou o FZD-WNT5A-X combina ions
Ku ayoshi e al. [74] show ha he binding o WNT5A o he ex acellula domain o
FZD5 equi ed palmi oyla ion o WNT5A bu no equi ed o i s sec e ion. Kumawa
e al. [75] show ha silencing o he noncanonical WNT5A ecep o s FZD8 and RYK
a enua ed TGF-β-induced ex acellula ma ix (ECM) exp ession. T auma ic b ain
inju y (TBI) can d ama ically inc ease le els o in acellula calcium (Ca2+). In mam-
malian ne e cells, Niu e al. [76] s udy he associa ion be ween WNT5A-FZD2 signal-
ing and Ca2+cellula homeos asis and demons a ed ha he WNT5A-FZD2 signaling
pa hway con ibu ed o inc easing in acellula Ca2+in ne e cells unde physiologi-
cal and pa hological condi ions. Chen e al. [77] obse e ha endocy osis o FZD4 in
human emb yonic kidney 293 cells was dependen on added WNT5A p o ein and was
accomplished by he mul i unc ional adap o p o ein be a-a es in 2 (be aa 2), which
was ec ui ed o FZD4 by binding o phospho yla ed DVL2. Kawasaki e al. [78] con-
cluded ha WNT5A is a na u al ligand o FZD3 ha igge s he PI3K/AKT signal and
p omo es adhesion o human de mal ib oblas s. Abou hal o all melanomas ha bo
a mu a ion ha esul s in a cons i u i ely ac i e BRAF kinase mu an (BRAFV600E/K)
ha can be selec i ely inhibi ed by a ge ed BRAF inhibi o s (BRAFis). Anas as e al.
[79] sugges ha ch onic BRAF inhibi ion ele a es WNT5A exp ession, which p o-
mo es AKT signaling h ough FZD7 and RYK, leading o inc eased g ow h and he -
apeu ic esis ance. Looking a he ables abo e, one inds he ollowing combina-
ions o membe s o FZD amily along wi h WNT5A, o be p ominen a 3 d o de
le el - FZD5-JUN-WNT5A, APC-FZD6-WNT5A, FZD6-PORCN-WNT5A, FZD5-
PPP2R1A-WNT5A, CSNK1G1-FZD2-WNT5A, APC-FZD2-WNT5A, FRZB-FZD2-
WNT5A, FZD1-SFRP1-WNT5A, FZD2-WNT1-WNT5A, FZD5-FGF4-WNT5A, FSHB-
FZD2-WNT5A, FZD5-FOXN1-WNT5A, FZD6-WNT1-WNT5A, FZD6-PORCN-WNT5A,
FZD5-SFRP1-WNT5A, FZD8-WNT1-WNT5A, FZD5-NKD1-WNT5A, FZD1-NLK-
WNT5A, FZD7-NKD1-WNT5A, FZD5-FZD2-WNT5A, FZD5-CSNK1D-WNT5A, FZD8-
GSK3A-WNT5A, FZD1-T-WNT5A, AXIN1-FZD2-WNT5A and EP300-FZD2-WNT5A.
All hese combina ions indica e possible exis ence o a syne gy when hey ake a highe
ank in he lis o combina ions.
7.7.3. Examining he beha iou o FGF4-WNT5A-X combina ions
The apical ec ode mal idge (AER) has a i al ole in di ec ing emb yonic limb de el-
opmen . Allen [80] demons a e ha FGF4 om he AER ac i a es a dis al g adien o
WNT5A exp ession in he limb. They obse e ha when he FGF4 bead is implan ed
close o he limb bud, endogenous WNT5A is exp essed mo e s ongly, indica ing ha
ele a ed le els o WNT5A a e exp essed wi h inc easing FGF4 concen a ion. Look-
ing a he ables abo e, one inds he ollowing combina ions o FGF4 along wi h
WNT5A, o be p ominen a 3 d o de le el - CSNK1D-FGF4-WNT5A, DIXDC1-
FGF4-WNT5A, CCND1-FGF4-WNT5A, DKK1-FGF4-WNT5A, DVL2-FGF4-WNT5A,
CTBP1-FGF4-WNT5A, CXXC4-FGF4-WNT5A, FZD5-FGF4-WNT5A, FBXW2-FGF4-
WNT5A, CSNK1A1-FGF4-WNT5A, FBXW11-FGF4-WNT5A and CTNNBIP1-FGF4-
WNT5A. All hese combina ions indica e possible exis ence o a syne gy when hey
ake a highe ank in he lis o combina ions.
35
7.7.4. Examining he beha iou o FOXN1-WNT5A-X combina ions
Epi helialmesenchymal in e ac ions a e key o skin mo phogenesis and homeos asis.
Th ough unc ional escue expe imen s Hu e al. [81] es ablish WNT5A as an essen-
ial downs eam media o o No chCSL signaling, impinging on exp ession in he ke -
a inocy e compa men o FOXN1, a gene wi h a key hai ollicle egula o y unc ion.
Thei immuno luo escence analysis con i med ha WNT5A ea men caused a sig-
ni ican inc ease o FOXN1 exp ession in hai ollicles o cul u ed (ColI-C e * RBP-
JloxP/loxP
K) skin. Looking a he ables abo e, one inds he ollowing combina ions
o FOXN1 along wi h WNT5A, o be p ominen a 3 d o de le el - DVL1-FOXN1-
WNT5A, DIXDC1-FOXN1-WNT5A, DKK1-FOXN1-WNT5A, FZD5-FOXN1-WNT5A,
FOSL1-FOXN1-WNT5A, FBXW11-FOXN1-WNT5A, CXXC4-FOXN1-WNT5A, BTRC-
FOXN1-WNT5A, CSNK1G1-FOXN1-WNT5A, APC-FOXN1-WNT5A, and FBXW2-
FOXN1-WNT5A. All hese combina ions indica e possible exis ence o a syne gy
when hey ake a highe ank in he lis o combina ions.
8. Conclusion
This manusc ip s udies he ime beha iou o 3 d o de combina ions o WNT amily
membe s in WNT3A s imula ed HEK 293 cells. Based on he ex ablished 2nd o de
combina ions o he WNT membe s, 3 d o de combina ions eme ge using he machine
lea ning based sea ch engine. These 3 d o de combina ions migh be o in e es o
u he we lab in es iga ions.
Compe ing in e es s
No compe ing in e es is decla ed.
Au ho con ibu ions s a emen
SS concei ed and designed he expe imen s; w o e he code; pe o med he expe i-
men s; analyzed he da a; w o e he manusc ip .
A ailabili y o code
Code o ime se ies da a a ailable a CERN based Zenodo on h ps://zenodo.o g/
eco ds/14637456.
Acknowledgmen s
Special hanks o M s. Ri a Sinha and la e M . P abha Sinha o suppo ing he au ho
inancially, wi hou which his wo k could no ha e been made possible.
36
RANKING @ iUSING HSIC - LINEAR
3 d o de comb. 1 3 6 12 24 3 d o de comb. 1 3 6 12 24
CSNK1D-FGF4-WNT5A 59 12095 43366 47094 42796 FSHB-T-WNT5A 122 29061 57139 24091 2613
CTNNBIP1-WIF1-WNT5A 128 2117 50325 55816 30661 CCND1-FGF4-WNT5A 165 47269 47793 37145 12904
FZD5-JUN-WNT5A 284 6962 43259 53869 10481 CCND2-LRP6-WNT5A 407 16539 8597 20565 13858
PITX2-PORCN-WNT5A 460 36097 17787 53210 23094 CXXC4-PORCN-WNT5A 535 15961 16253 55679 46631
LEF1-T-WNT5A 536 18912 30178 32688 1901 DKK1-FGF4-WNT5A 647 20327 35056 40689 45318
CCND2-WNT1-WNT5A 649 4100 17754 49943 24216 DVL2-FGF4-WNT5A 704 40017 53884 26198 56433
CTNNBIP1-FRAT1-WNT5A 734 14176 29898 41568 9680 CTBP1-FGF4-WNT5A 828 15379 39203 43512 39680
CTNNBIP1-NLK-WNT5A 840 10869 21909 56571 16909 DVL2-JUN-WNT5A 871 37929 52159 30056 48277
TCF7L1-WNT1-WNT5A 951 10419 14748 50321 56416 CXXC4-FGF4-WNT5A 957 4552 41511 51712 55041
CSNK1D-PPP2R1A-WNT5A 992 931 1207 30631 56811 FZD5-FGF4-WNT5A 1112 9925 43559 46683 36390
CCND3-WNT1-WNT5A 1130 34700 23749 48106 39841 FSHB-NKD1-WNT5A 1146 8921 29165 19619 2206
TLE1-WIF1-WNT5A 1188 23457 43932 51409 21021 FSHB-FZD2-WNT5A 1190 10906 56570 47332 4072
LRP6-TCF7-WNT5A 1209 36573 40965 49762 7878 FBXW2-FGF4-WNT5A 1216 14837 41991 48331 9404
AES-EP300-WNT5A 1232 50236 54302 23216 39305 DKK1-FOXN1-WNT5A 1346 18310 46663 16625 23963
APC-FZD6-WNT5A 1498 16910 1630 41699 21038 FZD5-FOXN1-WNT5A 1560 2664 23846 23386 12164
LRP6-SLC9A3R1-WNT5A 1593 9653 35688 33506 34192 CSNK1A1-FGF4-WNT5A 1597 15092 35949 31672 40613
DVL1-FOXN1-WNT5A 1611 44292 19025 17511 32923 LEF1-MYC-WNT5A 1622 11652 19069 1638 12533
FBXW11-LRP6-WNT5A 1633 9564 30602 20103 19149 EP300-WNT1-WNT5A 1667 20162 16144 44114 26527
PITX2-WNT3-WNT5A 1726 32979 5136 41370 17012 CCND2-TCF7-WNT5A 1728 3936 34730 44523 52026
CXXC4-FOSL1-WNT5A 1800 15338 42242 52718 32578 FBXW11-FGF4-WNT5A 1812 8275 53849 49534 26193
DIXDC1-NKD1-WNT5A 1830 5103 33835 49403 2232 CSNK2A1-MYC-WNT5A 1924 52368 38656 2374 28977
BCL9-PORCN-WNT5A 1929 7488 5825 56273 34499 LRP5-SFRP1-WNT5A 1931 37754 47154 35962 19209
TLE2-WNT1-WNT5A 1934 1735 16448 40349 48415 FZD6-WNT1-WNT5A 2012 42767 35693 43649 25350
NLK-SFRP1-WNT5A 2032 55480 32725 47613 26430 FOSL1-FOXN1-WNT5A 2034 6923 6744 9847 23516
LEF1-WNT1-WNT5A 2164 2916 24333 52522 19459 FZD6-PORCN-WNT5A 2165 41983 26329 43017 27185
FZD6-PORCN-WNT5A 2165 41983 26329 43017 27185 CCND1-WIF1-WNT5A 2206 17920 56231 50097 15244
CCND1-CTBP1-WNT5A 2219 47772 29829 51047 3738 FBXW11-FOXN1-WNT5A 2226 594 18962 23786 9557
FZD5-PPP2R1A-WNT5A 2239 9275 9172 22179 32268 CTNNBIP1-FGF4-WNT5A 2261 20092 46938 34699 41410
CCND3-PORCN-WNT5A 2270 38617 15634 39601 37699 JUN-PYGO1-WNT5A 2273 30941 1607 4887 6388
LRP6-RHOU-WNT5A 2371 52871 42173 56381 27277 FZD5-SFRP1-WNT5A 2397 37105 25747 56833 14943
DVL2-SFRP1-WNT5A 2494 52098 6476 40859 55468 FBXW11-SLC9A3R1-WNT5A 2545 22242 54164 19587 2861
PITX2-WNT1-WNT5A 2609 5926 14837 51671 5692 FZD8-WNT1-WNT5A 2653 3688 15335 41914 55425
BCL9-WNT3-WNT5A 2722 18035 5750 39690 6184 CSNK1G1-PORCN-WNT5A 2747 5935 22657 45224 29673
CTNNBIP1-WNT1-WNT5A 2892 2340 17541 31012 32743 CSNK1D-PORCN-WNT5A 2899 17376 34214 55252 32946
DVL1-EP300-WNT5A 2981 45215 32109 50904 36947 FZD5-NKD1-WNT5A 3021 6206 35575 52940 2092
CSNK2A1-CTNNB1-WNT5A 3035 55445 26243 38266 23130 LRP5-PORCN-WNT5A 3051 25077 6874 53519 30711
CSNK1G1-JUN-WNT5A 3068 8191 56989 38952 10438 CXXC4-FOXN1-WNT5A 3109 8816 13105 18798 36097
PPP2CA-WNT1-WNT5A 3127 17958 20275 50785 22700 FZD1-NLK-WNT5A 3220 14961 17555 36449 16975
APC-WNT1-WNT5A 3260 5882 29068 48459 44398 LRP5-NLK-WNT5A 3296 15243 30086 6594 47805
CSNK1G1-FZD2-WNT5A 3333 14640 38705 56952 5899 FZD7-NKD1-WNT5A 3371 2073 37837 34079 40424
DIXDC1-FGF4-WNT5A 3402 30477 40511 46509 49117 FZD5-FZD2-WNT5A 3441 11100 36263 56497 6341
CSNK1A1-CTBP2-WNT5A 3469 3917 28636 35088 16423 FOSL1-PORCN-WNT5A 3631 16428 9587 43895 35656
CSNK2A1-T-WNT5A 3660 45233 45887 26671 1396 BTRC-FOXN1-WNT5A 3687 8784 26520 30828 49695
DKK1-GSK3A-WNT5A 3713 18916 49874 56725 48396 CSNK1G1-FOXN1-WNT5A 3844 2053 5432 27959 8766
DIXDC1-FOXN1-WNT5A 3863 7743 18318 21775 11741 FOSL1-SFRP1-WNT5A 3880 20546 15812 56341 45565
DIXDC1-PORCN-WNT5A 3885 26867 8379 47688 52084 DVL1-SLC9A3R1-WNT5A 3901 42878 40021 40175 11848
FOSL1-WNT1-WNT5A 3911 934 9883 39216 24538 FZD5-CSNK1D-WNT5A 3923 32577 23307 47873 6444
CXXC4-NLK-WNT5A 3932 2627 16679 25816 15722 FZD8-GSK3A-WNT5A 3951 39522 29545 46470 37762
CSNK1D-SFRP1-WNT5A 3998 16473 29590 51130 13720 TCF7L1-WIF1-WNT5A 4007 25712 49240 53231 50932
LRP5-WNT1-WNT5A 4047 7108 21074 49106 36111 DAAM1-GSK3A-WNT5A 4051 49629 42474 35216 41411
DKK1-WNT1-WNT5A 4068 35503 45563 48503 45432 APC-FOXN1-WNT5A 4076 5465 27067 17582 33273
APC-FZD2-WNT5A 4079 13021 38909 56003 5306 KREMEN1-WNT1-WNT5A 4086 1014 15715 19712 13437
AXIN1-EP300-WNT5A 4180 9970 29920 45061 25015 FZD1-T-WNT5A 4216 53465 32743 41156 8347
APC-GSK3A-WNT5A 4225 14825 31576 32622 52407 AXIN1-FZD2-WNT5A 4330 36177 46404 56433 4476
SFRP4-T-WNT5A 4355 4858 31246 35810 3883 LRP5-WNT3-WNT5A 4490 38334 13435 16356 15034
CXXC4-SFRP1-WNT5A 4494 13816 11726 55305 20868 DKK1-PPP2R1A-WNT5A 4534 3478 36759 50853 55700
FBXW4-WNT1-WNT5A 4581 30084 19370 45293 28364 FSHB-GSK3A-WNT5A 4722 7262 52632 23091 38927
JUN-WIF1-WNT5A 4730 23210 50885 51206 36664 EP300-FZD2-WNT5A 4742 6196 44889 55869 24808
CCND3-CSNK1D-WNT5A 4753 43030 22446 46977 51854 FBXW2-FOXN1-WNT5A 4762 1838 37770 29635 12817
FRZB-FZD2-WNT5A 4769 13108 38666 56335 37688 LEF1-NKD1-WNT5A 4811 14924 45796 29502 2694
BTRC-GSK3A-WNT5A 4818 34238 56433 32265 47742 PYGO1-WIF1-WNT5A 4948 8911 30428 21376 24898
FZD1-SFRP1-WNT5A 4968 39398 12863 44772 6780 DIXDC1-GSK3A-WNT5A 4971 24828 27305 38034 51261
FZD2-WNT1-WNT5A 4992 34448 12933 13131 24695 CCND1-FRAT1-WNT5A 5062 46569 3187 54041 12710
Table 17: Rankings o WNT5A-X-X. A lis o app oxima ely i s 126 combina ions wi h ankings below
10,000 ou o 57,155. SA - HSIC; Ke nel - linea
Supplemen a y
The ollowing iles (ending wi h . x and can be opened in R o in simple ex p ocessing
p og am) wi h hese names a e made a ailable wi h his manusc ip . Fo e e y WNT
37

RANKING @ iUSING HSIC - RBF
3 d o de comb. 1 3 6 12 24 3 d o de comb. 1 3 6 12 24
CSNK1D-FGF4-WNT5A 16991 26760 1497 11585 17580 FSHB-T-WNT5A 38699 15943 1093 25527 28563
CTNNBIP1-WIF1-WNT5A 23143 5998 4289 37385 52573 CCND1-FGF4-WNT5A 19418 46790 4933 16199 11823
FZD5-JUN-WNT5A 8780 13834 37545 56636 50500 CCND2-LRP6-WNT5A 10166 22129 20505 51209 15333
PITX2-PORCN-WNT5A 11335 32674 6548 15458 54809 CXXC4-PORCN-WNT5A 24704 5412 10695 26556 50085
LEF1-T-WNT5A 8574 24318 38907 16551 20657 DKK1-FGF4-WNT5A 9621 8732 17015 38900 28750
CCND2-WNT1-WNT5A 2628 30300 41874 37956 39959 DVL2-FGF4-WNT5A 5059 21998 33434 16256 19267
CTNNBIP1-FRAT1-WNT5A 14700 16677 7050 19562 51259 CTBP1-FGF4-WNT5A 12798 10433 7187 48929 22701
CTNNBIP1-NLK-WNT5A 43965 11033 40662 17048 49376 DVL2-JUN-WNT5A 16054 35608 35930 17120 44512
TCF7L1-WNT1-WNT5A 4746 24167 45178 15067 34701 CXXC4-FGF4-WNT5A 6438 9457 13415 42775 42269
CSNK1D-PPP2R1A-WNT5A 27528 4279 14277 4265 42405 FZD5-FGF4-WNT5A 6337 27591 19612 53409 31870
CCND3-WNT1-WNT5A 3522 45126 4446 40031 11792 FSHB-NKD1-WNT5A 45339 3228 1592 43013 28219
TLE1-WIF1-WNT5A 40747 33211 3589 52410 46132 FSHB-FZD2-WNT5A 4908 10915 532 36402 27866
LRP6-TCF7-WNT5A 3378 28609 32749 45029 28221 FBXW2-FGF4-WNT5A 5739 17796 19310 37639 2729
AES-EP300-WNT5A 40140 51612 23938 4009 35408 DKK1-FOXN1-WNT5A 6288 34859 41852 39340 54131
APC-FZD6-WNT5A 9031 23346 51525 51644 24946 FZD5-FOXN1-WNT5A 3489 12125 37214 51686 53948
LRP6-SLC9A3R1-WNT5A 50636 8388 7361 48711 37589 CSNK1A1-FGF4-WNT5A 8952 17873 1108 36340 28004
DVL1-FOXN1-WNT5A 4912 51197 23796 43594 44907 LEF1-MYC-WNT5A 9292 1889 50136 33084 16897
FBXW11-LRP6-WNT5A 5244 4673 9444 17231 20722 EP300-WNT1-WNT5A 2374 24154 16830 20295 34795
PITX2-WNT3-WNT5A 50071 36976 3198 23809 43096 CCND2-TCF7-WNT5A 36497 1031 22725 50349 37229
CXXC4-FOSL1-WNT5A 53822 4385 5771 55698 30961 FBXW11-FGF4-WNT5A 6302 7098 2714 7045 9820
DIXDC1-NKD1-WNT5A 50477 15744 20410 52735 35648 CSNK2A1-MYC-WNT5A 4208 45258 25000 47595 27580
BCL9-PORCN-WNT5A 8717 4136 14582 10861 40557 LRP5-SFRP1-WNT5A 3834 45289 12470 27179 43165
TLE2-WNT1-WNT5A 6864 5968 35981 23184 14484 FZD6-WNT1-WNT5A 4137 47371 40981 23375 28715
NLK-SFRP1-WNT5A 22263 52123 16817 33554 46452 FOSL1-FOXN1-WNT5A 5307 14590 45152 44826 55367
LEF1-WNT1-WNT5A 9745 8583 36041 23307 26376 FZD6-PORCN-WNT5A 88 50478 30280 17366 51000
FZD6-PORCN-WNT5A 88 50478 30280 17366 51000 CCND1-WIF1-WNT5A 37414 8236 3639 32526 9840
CCND1-CTBP1-WNT5A 45138 36969 4022 32791 11604 FBXW11-FOXN1-WNT5A 1244 5232 21083 25289 44693
FZD5-PPP2R1A-WNT5A 17060 9682 37942 54060 54700 CTNNBIP1-FGF4-WNT5A 8234 24257 4204 17646 42626
CCND3-PORCN-WNT5A 12281 45137 3555 19433 30263 JUN-PYGO1-WNT5A 9776 20912 9445 6655 56641
LRP6-RHOU-WNT5A 25925 53449 10404 18899 8677 FZD5-SFRP1-WNT5A 5145 42699 20854 57127 43347
DVL2-SFRP1-WNT5A 12899 47430 34465 28971 49671 FBXW11-SLC9A3R1-WNT5A 17699 12088 3043 28403 36673
PITX2-WNT1-WNT5A 29674 16693 38632 17220 34621 FZD8-WNT1-WNT5A 759 20769 42200 32929 23343
BCL9-WNT3-WNT5A 9435 28043 21541 40962 35192 CSNK1G1-PORCN-WNT5A 8541 17540 20517 6560 46815
CTNNBIP1-WNT1-WNT5A 2110 11579 40080 21974 43169 CSNK1D-PORCN-WNT5A 17071 12074 1312 10487 50936
DVL1-EP300-WNT5A 45556 27855 659 56344 29253 FZD5-NKD1-WNT5A 33749 1909 44565 56409 39882
CSNK2A1-CTNNB1-WNT5A 34875 52148 5403 46302 46674 LRP5-PORCN-WNT5A 4664 27857 8039 7363 54523
CSNK1G1-JUN-WNT5A 1627 9471 37716 21278 33763 CXXC4-FOXN1-WNT5A 6575 17827 51655 52301 55304
PPP2CA-WNT1-WNT5A 1188 16609 32224 18050 32772 FZD1-NLK-WNT5A 28100 15641 23012 14962 49066
APC-WNT1-WNT5A 4247 4366 51707 29496 46072 LRP5-NLK-WNT5A 33250 14809 24503 18293 46276
CSNK1G1-FZD2-WNT5A 20419 29433 26502 7708 18760 FZD7-NKD1-WNT5A 53120 6594 44749 54824 2305
DIXDC1-FGF4-WNT5A 4107 43702 11521 38540 15389 FZD5-FZD2-WNT5A 3403 12239 17878 32444 43130
CSNK1A1-CTBP2-WNT5A 17747 9071 3307 44304 37334 FOSL1-PORCN-WNT5A 684 10157 3538 9803 48095
CSNK2A1-T-WNT5A 18871 49162 6434 9546 14718 BTRC-FOXN1-WNT5A 4629 21553 49380 16835 38205
DKK1-GSK3A-WNT5A 43 19654 49919 41864 44606 CSNK1G1-FOXN1-WNT5A 3727 8535 45722 16807 52197
DIXDC1-FOXN1-WNT5A 5575 34443 41139 40268 26945 FOSL1-SFRP1-WNT5A 10825 7619 8773 53939 44771
DIXDC1-PORCN-WNT5A 17412 29192 9192 10144 42283 DVL1-SLC9A3R1-WNT5A 24289 20621 1348 45986 19657
FOSL1-WNT1-WNT5A 5033 6402 35717 26574 39026 FZD5-CSNK1D-WNT5A 10782 25515 25535 29067 55122
CXXC4-NLK-WNT5A 46697 2350 52931 39870 42513 FZD8-GSK3A-WNT5A 792 39203 53965 12834 30863
CSNK1D-SFRP1-WNT5A 7931 18053 3281 19001 33260 TCF7L1-WIF1-WNT5A 19561 51039 4589 44974 51657
LRP5-WNT1-WNT5A 8985 6457 18102 28743 39412 DAAM1-GSK3A-WNT5A 993 52299 45640 48410 22898
DKK1-WNT1-WNT5A 7312 29238 24298 21731 36669 APC-FOXN1-WNT5A 4028 22788 53731 48438 52873
APC-FZD2-WNT5A 4650 34812 32837 41537 24627 KREMEN1-WNT1-WNT5A 4362 35794 22223 40251 36925
AXIN1-EP300-WNT5A 45393 1954 35430 55047 50435 FZD1-T-WNT5A 23654 53150 5001 19952 35892
APC-GSK3A-WNT5A 177 33763 56807 53251 34234 AXIN1-FZD2-WNT5A 15305 45673 36309 22018 30853
SFRP4-T-WNT5A 15711 24455 18874 6541 25978 LRP5-WNT3-WNT5A 28843 53692 4853 26810 40037
CXXC4-SFRP1-WNT5A 13274 4885 7023 55279 47701 DKK1-PPP2R1A-WNT5A 17268 5548 34963 48461 43857
FBXW4-WNT1-WNT5A 2762 44748 28649 28672 28184 FSHB-GSK3A-WNT5A 3423 15383 30952 30779 42858
JUN-WIF1-WNT5A 17879 25683 7574 50125 47128 EP300-FZD2-WNT5A 15423 4753 16468 24781 37279
CCND3-CSNK1D-WNT5A 26184 41606 8103 12634 19595 FBXW2-FOXN1-WNT5A 1059 14872 50798 40842 34023
FRZB-FZD2-WNT5A 17706 25689 4179 20867 43661 LEF1-NKD1-WNT5A 19218 16256 39358 48742 17741
BTRC-GSK3A-WNT5A 1331 34656 55842 14294 39235 PYGO1-WIF1-WNT5A 42194 2788 21830 11541 35248
FZD1-SFRP1-WNT5A 14778 32523 5788 42552 34576 DIXDC1-GSK3A-WNT5A 1711 34055 53310 43993 38089
FZD2-WNT1-WNT5A 4025 22760 45461 15274 35474 CCND1-FRAT1-WNT5A 7720 35707 9195 34088 9499
Table 18: Rankings o WNT5A-X-X. A lis o app oxima ely i s 126 combina ions wi h ankings below
10,000 ou o 57,155. SA - HSIC; Ke nel - b
amily membe , (1) -3-od -TP- anking-linea . x , (2) -3-od -TP- anking- b . x , (3)
-3-od -TP- anking-2002. x , and (4) -3-od -TP- anking-ma inez. x , con ain ank-
ings o 3 d o de combina ions ac oss each ime poin o , HSIC (linea ke nel), HSIC
( b ke nel), SOBOL (2002 implemen a ion) and SOBOL (ma inez implemen a ion),
espec i ely.
38
RANKING @ iUSING SOBOL - 2002
3 d o de comb. 1 3 6 12 24 3 d o de comb. 1 3 6 12 24
CSNK1D-FGF4-WNT5A 27276 41074 28302 22360 34593 FSHB-T-WNT5A 45606 52982 44145 47718 206
CTNNBIP1-WIF1-WNT5A 37517 8726 47830 33901 17853 CCND1-FGF4-WNT5A 11036 43537 12003 4568 37363
FZD5-JUN-WNT5A 46652 4870 31639 33192 2907 CCND2-LRP6-WNT5A 4772 13576 13447 14907 37434
PITX2-PORCN-WNT5A 4366 18564 14041 19978 22471 CXXC4-PORCN-WNT5A 47497 52019 55859 50726 19154
LEF1-T-WNT5A 13770 32123 1321 829 46232 DKK1-FGF4-WNT5A 3774 41348 22112 15337 7096
CCND2-WNT1-WNT5A 26348 908 6977 2060 37746 DVL2-FGF4-WNT5A 25909 3076 24938 11478 55213
CTNNBIP1-FRAT1-WNT5A 11059 21534 9005 4048 52412 CTBP1-FGF4-WNT5A 7713 2474 7138 10246 21735
CTNNBIP1-NLK-WNT5A 20035 789 8556 6531 46843 DVL2-JUN-WNT5A 40789 46792 43770 36077 2170
TCF7L1-WNT1-WNT5A 50375 3147 51646 41475 20572 CXXC4-FGF4-WNT5A 4008 46378 14592 16580 56090
CSNK1D-PPP2R1A-WNT5A 26135 44357 28294 20860 36948 FZD5-FGF4-WNT5A 18127 25149 13713 14643 40340
CCND3-WNT1-WNT5A 33845 7291 36752 42568 20426 FSHB-NKD1-WNT5A 37314 18350 48369 53041 3700
TLE1-WIF1-WNT5A 32505 9057 54581 55409 2636 FSHB-FZD2-WNT5A 31407 32496 45697 55367 3033
LRP6-TCF7-WNT5A 867 275 15437 481 42453 FBXW2-FGF4-WNT5A 22402 43589 10843 23182 50271
AES-EP300-WNT5A 29197 43023 38116 41964 4843 DKK1-FOXN1-WNT5A 36811 44788 36126 29818 15014
APC-FZD6-WNT5A 14108 30582 22634 26168 31875 FZD5-FOXN1-WNT5A 42864 15694 46968 56449 26791
LRP6-SLC9A3R1-WNT5A 56177 2075 49249 44624 2897 CSNK1A1-FGF4-WNT5A 19234 7567 25442 12975 45195
DVL1-FOXN1-WNT5A 39198 8747 31422 43031 24076 LEF1-MYC-WNT5A 52016 50835 55336 49992 7038
FBXW11-LRP6-WNT5A 35469 4159 38803 31715 5198 EP300-WNT1-WNT5A 26125 33898 12493 14926 56427
PITX2-WNT3-WNT5A 3631 37403 19670 4320 50237 CCND2-TCF7-WNT5A 22744 2466 10207 4582 38232
CXXC4-FOSL1-WNT5A 45823 54747 52368 41434 48001 FBXW11-FGF4-WNT5A 27801 7146 14256 13536 21447
DIXDC1-NKD1-WNT5A 52842 853 34383 35927 975 CSNK2A1-MYC-WNT5A 35456 22735 56665 49988 33664
BCL9-PORCN-WNT5A 10987 16048 15283 11849 27280 LRP5-SFRP1-WNT5A 2477 17688 15662 22754 16525
TLE2-WNT1-WNT5A 39711 21605 38989 30871 11764 FZD6-WNT1-WNT5A 54919 15489 31019 44772 9818
NLK-SFRP1-WNT5A 7723 23039 14415 17477 48341 FOSL1-FOXN1-WNT5A 8341 10381 8155 9375 49603
LEF1-WNT1-WNT5A 54167 7134 32380 34672 21919 FZD6-PORCN-WNT5A 44224 38925 32092 51688 14427
FZD6-PORCN-WNT5A 44224 38925 32092 51688 14427 CCND1-WIF1-WNT5A 52311 43612 54645 45673 6949
CCND1-CTBP1-WNT5A 4347 14757 26231 13484 42235 FBXW11-FOXN1-WNT5A 39827 21653 53284 49894 14306
FZD5-PPP2R1A-WNT5A 13161 3675 15841 13079 29407 CTNNBIP1-FGF4-WNT5A 19330 4795 13940 11390 41432
CCND3-PORCN-WNT5A 38273 8403 32926 50822 31855 JUN-PYGO1-WNT5A 2460 21997 22687 2953 49677
LRP6-RHOU-WNT5A 1674 54809 6843 11880 53337 FZD5-SFRP1-WNT5A 3648 6975 12983 2806 46950
DVL2-SFRP1-WNT5A 27290 8838 10832 13550 48661 FBXW11-SLC9A3R1-WNT5A 26559 43402 28324 24578 29359
PITX2-WNT1-WNT5A 34 29476 27919 8439 25717 FZD8-WNT1-WNT5A 55340 46156 39368 53203 20930
BCL9-WNT3-WNT5A 3109 27442 229 162 32612 CSNK1G1-PORCN-WNT5A 10356 8876 25975 28454 18185
CTNNBIP1-WNT1-WNT5A 39178 36630 45107 49287 14044 CSNK1D-PORCN-WNT5A 33173 15133 30807 39641 18354
DVL1-EP300-WNT5A 50248 16218 30548 30959 5678 FZD5-NKD1-WNT5A 7463 43025 2190 5552 51516
CSNK2A1-CTNNB1-WNT5A 49018 50110 52351 40046 7587 LRP5-PORCN-WNT5A 52695 9213 43304 43600 2584
CSNK1G1-JUN-WNT5A 21479 39247 6333 24156 52648 CXXC4-FOXN1-WNT5A 45779 49880 48086 39298 56659
PPP2CA-WNT1-WNT5A 48329 11938 40478 41705 4471 FZD1-NLK-WNT5A 26056 2877 20780 17408 38034
APC-WNT1-WNT5A 35340 14411 42165 39241 29207 LRP5-NLK-WNT5A 7424 17108 1077 11334 46700
CSNK1G1-FZD2-WNT5A 50135 56267 44911 41731 22635 FZD7-NKD1-WNT5A 44945 5271 38820 34295 16856
DIXDC1-FGF4-WNT5A 54426 18498 38052 43829 24212 FZD5-FZD2-WNT5A 9680 33164 12121 24460 14076
CSNK1A1-CTBP2-WNT5A 11628 24885 28394 9281 35281 FOSL1-PORCN-WNT5A 17862 53252 383 11834 29054
CSNK2A1-T-WNT5A 23799 14174 1661 753 51344 BTRC-FOXN1-WNT5A 47737 862 51520 47865 16688
DKK1-GSK3A-WNT5A 3254 56641 8807 7141 43235 CSNK1G1-FOXN1-WNT5A 21617 15364 15938 25477 56058
DIXDC1-FOXN1-WNT5A 7919 48369 15784 27764 27632 FOSL1-SFRP1-WNT5A 50217 49176 47672 56091 8412
DIXDC1-PORCN-WNT5A 952 7968 6431 9090 46718 DVL1-SLC9A3R1-WNT5A 13958 50206 15689 28528 49687
FOSL1-WNT1-WNT5A 25484 1744 15300 2521 38727 FZD5-CSNK1D-WNT5A 21298 15129 1430 366 40105
CXXC4-NLK-WNT5A 12448 41748 17765 12599 37639 FZD8-GSK3A-WNT5A 20110 8208 19050 4417 52624
CSNK1D-SFRP1-WNT5A 11269 25479 3686 15976 27188 TCF7L1-WIF1-WNT5A 45712 19992 50710 52827 3045
LRP5-WNT1-WNT5A 50803 3849 56592 53600 4056 DAAM1-GSK3A-WNT5A 25487 825 7891 11618 44798
DKK1-WNT1-WNT5A 43200 9393 41473 28806 20289 APC-FOXN1-WNT5A 29633 44234 48820 31227 29427
APC-FZD2-WNT5A 19978 21918 10502 24010 51341 KREMEN1-WNT1-WNT5A 41161 34326 39043 56585 47900
AXIN1-EP300-WNT5A 47677 47620 52664 49981 17016 FZD1-T-WNT5A 24581 37777 8879 6834 26206
APC-GSK3A-WNT5A 18761 23736 20548 24504 33419 AXIN1-FZD2-WNT5A 4423 32881 5507 12376 25610
SFRP4-T-WNT5A 43270 6351 52763 49463 14811 LRP5-WNT3-WNT5A 40845 31021 41202 39346 3252
CXXC4-SFRP1-WNT5A 14084 3064 9093 9911 43525 DKK1-PPP2R1A-WNT5A 4917 40830 24393 22265 31089
FBXW4-WNT1-WNT5A 36308 26390 55507 53187 11273 FSHB-GSK3A-WNT5A 34115 22730 34862 34229 6583
JUN-WIF1-WNT5A 11573 40788 5006 2485 37662 EP300-FZD2-WNT5A 37476 54071 35212 38568 52547
CCND3-CSNK1D-WNT5A 26753 51792 5466 20864 48578 FBXW2-FOXN1-WNT5A 33411 48436 51071 56698 8436
FRZB-FZD2-WNT5A 17628 21945 16123 924 9969 LEF1-NKD1-WNT5A 22558 37161 4282 14655 50963
BTRC-GSK3A-WNT5A 10037 4468 5019 1007 49446 PYGO1-WIF1-WNT5A 9422 32695 26276 12872 6210
FZD1-SFRP1-WNT5A 5325 3946 27019 13433 49902 DIXDC1-GSK3A-WNT5A 55995 46273 39418 47962 20481
FZD2-WNT1-WNT5A 55233 54207 42446 47868 26353 CCND1-FRAT1-WNT5A 427 45796 15844 19380 29008
Table 19: Rankings o WNT5A-X-X. A lis o app oxima ely i s 125 combina ions wi h ankings below
10,000 ou o 57,155. SA - SOBOL; Implemen a ion - 2002
Re e ences
[1] T. S. Guj al, G. MacBea h, A sys em-wide in es iga ion o he dynamics o wn signaling e eals no el phases o
ansc ip ional egula ion, PloS one 5 (2010) e10024.
[2] S. Sinha, Machine lea ning anking o plausible (un) explo ed syne gis ic gene combina ions using sensi i i y indices
39
RANKING @ iUSING SOBOL - MARTINEZ
3 d o de comb. 1 3 6 12 24 3 d o de comb. 1 3 6 12 24
CSNK1D-FGF4-WNT5A 39875 34325 26022 14242 1408 FSHB-T-WNT5A 56577 45398 1560 25202 8403
CTNNBIP1-WIF1-WNT5A 28881 38782 26985 15415 14875 CCND1-FGF4-WNT5A 6297 37930 14914 5118 3140
FZD5-JUN-WNT5A 37922 45149 3248 18094 8459 CCND2-LRP6-WNT5A 23928 33565 7728 24952 7424
PITX2-PORCN-WNT5A 23589 48950 34402 37236 3755 CXXC4-PORCN-WNT5A 30469 36642 4574 55370 14476
LEF1-T-WNT5A 49428 14633 28678 580 7231 DKK1-FGF4-WNT5A 38877 17476 11090 25677 46913
CCND2-WNT1-WNT5A 8935 56664 50350 50391 11278 DVL2-FGF4-WNT5A 37579 21122 32279 30959 6003
CTNNBIP1-FRAT1-WNT5A 9313 54626 33929 10670 26211 CTBP1-FGF4-WNT5A 2069 20005 8782 7871 28177
CTNNBIP1-NLK-WNT5A 10769 10715 43199 6383 43941 DVL2-JUN-WNT5A 56096 6903 2980 44469 43199
TCF7L1-WNT1-WNT5A 44025 2425 32527 20064 38205 CXXC4-FGF4-WNT5A 14261 23219 50216 56128 9682
CSNK1D-PPP2R1A-WNT5A 34799 46397 27927 38367 6548 FZD5-FGF4-WNT5A 1891 8102 55477 53665 49905
CCND3-WNT1-WNT5A 43181 44716 14441 14980 34724 FSHB-NKD1-WNT5A 54779 40235 14719 3551 9105
TLE1-WIF1-WNT5A 13523 477 24572 24146 33247 FSHB-FZD2-WNT5A 22760 56612 24534 7272 7730
LRP6-TCF7-WNT5A 35245 42533 12463 3947 884 FBXW2-FGF4-WNT5A 27493 53623 25626 34239 3074
AES-EP300-WNT5A 29498 5467 36624 45146 8858 DKK1-FOXN1-WNT5A 11041 32783 5504 28116 20846
APC-FZD6-WNT5A 40404 10209 8884 48406 4407 FZD5-FOXN1-WNT5A 14770 8419 1940 49556 36803
LRP6-SLC9A3R1-WNT5A 53761 48694 17528 9747 26436 CSNK1A1-FGF4-WNT5A 17317 3438 16557 42025 30659
DVL1-FOXN1-WNT5A 7913 15374 11779 43135 49515 LEF1-MYC-WNT5A 15675 51861 35637 1042 9483
FBXW11-LRP6-WNT5A 44516 5058 17175 31059 17540 EP300-WNT1-WNT5A 18070 53885 18563 56960 314
PITX2-WNT3-WNT5A 11058 51240 29498 43821 8108 CCND2-TCF7-WNT5A 5759 24765 29731 14697 7213
CXXC4-FOSL1-WNT5A 44523 32024 5826 41353 32438 FBXW11-FGF4-WNT5A 34769 3709 29680 9258 5901
DIXDC1-NKD1-WNT5A 15090 51048 5734 37831 37533 CSNK2A1-MYC-WNT5A 37394 36968 36088 1047 19004
BCL9-PORCN-WNT5A 34440 9539 51956 35220 5319 LRP5-SFRP1-WNT5A 46626 53919 15587 3017 5879
TLE2-WNT1-WNT5A 46888 6306 53838 23255 34200 FZD6-WNT1-WNT5A 27585 47847 15634 4486 22587
NLK-SFRP1-WNT5A 1980 50539 36522 25586 2949 FOSL1-FOXN1-WNT5A 52174 12235 9794 10821 15555
LEF1-WNT1-WNT5A 24144 51166 47464 53981 30498 FZD6-PORCN-WNT5A 8901 16659 3797 41382 31216
FZD6-PORCN-WNT5A 8901 16659 3797 41382 31216 CCND1-WIF1-WNT5A 44698 46968 24492 10707 12993
CCND1-CTBP1-WNT5A 42105 14132 21995 16199 43575 FBXW11-FOXN1-WNT5A 50898 34299 23183 838 55601
FZD5-PPP2R1A-WNT5A 24265 52942 6115 49206 3338 CTNNBIP1-FGF4-WNT5A 4792 23078 54974 38853 49989
CCND3-PORCN-WNT5A 39066 29570 4018 3443 56436 JUN-PYGO1-WNT5A 5773 12825 7216 47792 6321
LRP6-RHOU-WNT5A 29804 56580 34206 18715 801 FZD5-SFRP1-WNT5A 16282 22947 54746 32208 20217
DVL2-SFRP1-WNT5A 25363 22509 18513 9807 6761 FBXW11-SLC9A3R1-WNT5A 275 14652 20579 7195 42710
PITX2-WNT1-WNT5A 34426 18511 22931 30346 5013 FZD8-WNT1-WNT5A 55382 28883 536 42970 27045
BCL9-WNT3-WNT5A 6367 13057 20467 21997 48148 CSNK1G1-PORCN-WNT5A 46413 14655 30449 49521 13435
CTNNBIP1-WNT1-WNT5A 52693 11674 3169 39076 16576 CSNK1D-PORCN-WNT5A 22402 4216 2288 18135 42734
DVL1-EP300-WNT5A 18933 25983 3336 33670 35252 FZD5-NKD1-WNT5A 40730 52111 18455 48698 51553
CSNK2A1-CTNNB1-WNT5A 15912 32149 48221 26938 16715 LRP5-PORCN-WNT5A 14554 31962 47440 55611 32184
CSNK1G1-JUN-WNT5A 90 18823 34308 8819 39419 CXXC4-FOXN1-WNT5A 55262 11570 2649 39122 29365
PPP2CA-WNT1-WNT5A 51641 38045 26358 31132 12482 FZD1-NLK-WNT5A 5156 51064 50988 8427 47484
APC-WNT1-WNT5A 37251 37308 4578 24642 44801 LRP5-NLK-WNT5A 45036 52213 6262 10225 16127
CSNK1G1-FZD2-WNT5A 47509 40249 19979 4150 23159 FZD7-NKD1-WNT5A 10258 28094 47222 55721 8269
DIXDC1-FGF4-WNT5A 21879 5576 19569 19900 43009 FZD5-FZD2-WNT5A 30203 8433 36831 1215 1675
CSNK1A1-CTBP2-WNT5A 9289 37103 7483 11014 25436 FOSL1-PORCN-WNT5A 51271 54488 32643 20512 3950
CSNK2A1-T-WNT5A 3889 52194 41219 43938 2464 BTRC-FOXN1-WNT5A 19210 37398 35493 33336 33577
DKK1-GSK3A-WNT5A 11537 9948 15513 25241 48610 CSNK1G1-FOXN1-WNT5A 6387 29278 22354 7557 5856
DIXDC1-FOXN1-WNT5A 1445 8496 13536 21503 49118 FOSL1-SFRP1-WNT5A 8800 21398 39607 27982 22951
DIXDC1-PORCN-WNT5A 16164 11219 7718 36336 22820 DVL1-SLC9A3R1-WNT5A 1145 13814 29450 54395 45479
FOSL1-WNT1-WNT5A 2153 54808 25487 36688 13369 FZD5-CSNK1D-WNT5A 22240 8729 8905 8361 14874
CXXC4-NLK-WNT5A 32823 7902 18426 32670 44201 FZD8-GSK3A-WNT5A 4848 28129 11376 48039 45929
CSNK1D-SFRP1-WNT5A 46232 40726 39677 8395 43436 TCF7L1-WIF1-WNT5A 47869 53134 38896 13270 55762
LRP5-WNT1-WNT5A 30334 45784 31282 41567 9655 DAAM1-GSK3A-WNT5A 24549 7238 51091 46401 45304
DKK1-WNT1-WNT5A 7853 29582 28794 6214 37984 APC-FOXN1-WNT5A 36047 8945 28253 35882 15215
APC-FZD2-WNT5A 14567 9359 10073 34001 26305 KREMEN1-WNT1-WNT5A 8580 19453 28068 44618 42482
AXIN1-EP300-WNT5A 14220 28915 40087 2321 27392 FZD1-T-WNT5A 22751 44215 45584 36502 24158
APC-GSK3A-WNT5A 42704 16681 10575 28232 1709 AXIN1-FZD2-WNT5A 32050 29613 22164 9626 30464
SFRP4-T-WNT5A 29815 18586 46013 35505 49789 LRP5-WNT3-WNT5A 12616 49962 10697 21498 12328
CXXC4-SFRP1-WNT5A 28284 25901 39210 34131 39373 DKK1-PPP2R1A-WNT5A 50575 2419 39679 15768 20655
FBXW4-WNT1-WNT5A 39385 854 53445 15372 35604 FSHB-GSK3A-WNT5A 36948 46381 47772 40630 8149
JUN-WIF1-WNT5A 32685 30228 10807 3557 2870 EP300-FZD2-WNT5A 50365 30389 578 35504 29268
CCND3-CSNK1D-WNT5A 36336 364 51360 31612 43178 FBXW2-FOXN1-WNT5A 44200 598 33241 28485 56446
FRZB-FZD2-WNT5A 23085 30981 22715 44817 55133 LEF1-NKD1-WNT5A 10158 48832 41731 2925 35572
BTRC-GSK3A-WNT5A 30595 22112 8606 29405 28103 PYGO1-WIF1-WNT5A 23700 55503 49268 17706 33207
FZD1-SFRP1-WNT5A 21330 16151 30093 43189 54496 DIXDC1-GSK3A-WNT5A 35337 25363 3235 35511 45938
FZD2-WNT1-WNT5A 48674 41210 577 33184 38986 CCND1-FRAT1-WNT5A 29157 12146 55984 49883 9815
Table 20: Rankings o WNT5A-X-X. A lis o app oxima ely i s 125 combina ions wi h ankings below
10,000 ou o 57,155. SA - SOBOL; Implemen a ion - ma inez
o ime se ies measu emen s o wn signaling pa hway, In eg a i e Biology 16 (2024) zyae020.
[3] T. Joachims, T aining linea s ms in linea ime, in: P oceedings o he 12 h ACM SIGKDD in e na ional con e ence
on Knowledge disco e y and da a mining, ACM, 2006, pp. 217–226.
[4] R. Sha ma, Wingless a new mu an in d osophila melanogas e , D osophila in o ma ion se ice 50 (1973) 134–134.
40
[5] L. Tho s ensen, G. E. Lind, T. Lø ig, C. B. Diep, G. I. Meling, T. O. Rognum, R. A. Lo he, Gene ic and epigene ic
changes o componen s a ec ing he wn pa hway in colo ec al ca cinomas s a i ied by mic osa elli e ins abili y,
Neoplasia 7 (2005) 99–108.
[6] R. Ba on, M. Kneissel, Wn signaling in bone homeos asis and disease: om human mu a ions o ea men s, Na u e
medicine 19 (2013) 179–192.
[7] H. Cle e s, Wn /[β]-ca enin signaling in de elopmen and disease, Cell 127 (2006) 469–480.
[8] S. Sokol, Wn Signaling in Emb yonic De elopmen , olume 17, Else ie , 2011.
[9] D. Pin o, A. G ego ie , H. Beg hel, H. Cle e s, Canonical wn signals a e essen ial o homeos asis o he in es inal
epi helium, Genes & de elopmen 17 (2003) 1709–1713.
[10] Z. Zhong, N. J. E hen, B. O. Williams, Wn signaling in bone de elopmen and homeos asis, Wiley In e disciplina y
Re iews: De elopmen al Biology 3 (2014) 489–500.
[11] N. Pe´
cina-ˇ
Slaus, Wn signal ansduc ion pa hway and apop osis: a e iew, Cance Cell In e na ional 10 (2010) 1–5.
[12] M. Kahn, Can we sa ely a ge he wn pa hway?, Na u e Re iews D ug Disco e y 13 (2014) 513–532.
[13] K. Ga be , D ugging he wn pa hway: p oblems and p og ess, Jou nal o he Na ional Cance Ins i u e 101 (2009)
548–550.
[14] A. Vo onko , S. K auss, Wn /be a-ca enin signaling and small molecule inhibi o s, Cu en pha maceu ical design
19 (2012) 634.
[15] A. Blagoda ski, D. Po e yae , V. Ka anae , Ta ge ing he wn pa hways o he apies, Mol Cell The 2 (2014) 28.
[16] J. C. Cu in, M. V. Lo enzi, D ug disco e y app oaches o a ge wn signaling in cance s em cells, Onco a ge 1
(2010) 552.
[17] C. B¨
anzige , D. Soldini, C. Sch¨
u , P. Zippe len, G. Hausmann, K. Basle , Wn less, a conse ed memb ane p o ein
dedica ed o he sec e ion o wn p o eins om signaling cells, Cell 125 (2006) 509–522.
[18] K. Ba sche e , N. Pel e, D. Ingel inge , M. Bou os, Sec e ion o wn ligands equi es e i, a conse ed ansmem-
b ane p o ein, Cell 125 (2006) 523–533.
[19] M. Ku ayoshi, H. Yamamo o, S. Izumi, A. Kikuchi, Pos - ansla ional palmi oyla ion and glycosyla ion o wn -5a
a e necessa y o i s signalling, Biochemical Jou nal 402 (2007) 515–523.
[20] X. Gao, R. N. Hannoush, Single-cell imaging o wn palmi oyla ion by he acyl ans e ase po cupine, Na u e
chemical biology 10 (2014) 61–68.
[21] F. Aulicino, I. Theka, L. Omb a o, F. Lluis, M. P. Cosma, Tempo al pe u ba ion o he wn signaling pa hway in he
con ol o cell ep og amming is modula ed by c 1, S em cell epo s 2 (2014) 707–720.
[22] C. W. Tan, B. S. Ga dine , Y. Hi okawa, D. W. Smi h, A. W. Bu gess, Analysis o wn signaling β-ca enin spa ial
dynamics in hek293 cells, BMC sys ems biology 8 (2014) 1–18.
[23] C. T.-L. Huang, Y. Tao, J. Lu, J. R. Jones, L. Fowle , J. P. Weick, S.-C. Zhang, Time-cou se gene exp ession p o iling
e eals a no el ole o non-canonical wn signaling du ing neu al induc ion, Scien i ic epo s 6 (2016) 32600.
[24] P. Ka i, S. E. Hasenson, I. Kan e , J. Sheinbe ge , N. Kino , S. Yunge , Y. Sha -Tal, Quan i ying β-ca enin subcel-
lula dynamics and cyclin d1 m na ansc ip ion du ing wn signaling in single li ing cells, Eli e 5 (2016) e16748.
[25] B. Madan, N. Ha ms on, G. Nallan, A. Mon oya, P. Faull, E. Pe e o, D. M. Vi shup, e al., Tempo al dynamics o
wn -dependen ansc ip ome e eal an oncogenic wn /myc/ ibosome axis, The Jou nal o clinical in es iga ion 128
(2019) 5620–5633.
[26] P. Pagella, S. Sode holm, A. No din, G. Zambanini, V. Ghezzi, A. Jau egi-Miguel, C. Can u, The ime- esol ed
genomic impac o wn /β-ca enin signaling, Cell Sys ems (2023).
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