k ingle con aining ansmemb ane p o ein 1 (KREMEN1) :
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
Add ess : 104-Madhu isha Heigh s Phase 1, Risali, Bhilai-490006, India
Co esponding au ho email : sinha.sh ip [email protected]
Abs ac
k ingle con aining ansmemb ane p o ein 1(KREMEN1), encodes a high-a ini y dick-
kop homolog 1 (DKK1) ansmemb ane ecep o ha unc ionally coope a es wi h
DKK1 o block wingless (WNT)/β-ca enin signaling. 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 e-
men s a e singula in na u e. He e, I •enume a e and ank all 2415 KREMEN1 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 KREMEN1-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 ning sea ch en-
gine (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 KREMEN1 comb. in WNT3A s imula ed cells
1Aspec s o unpublished wo k we e p esen ed in a pos e session a Cell Symposia: Technology.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 Ma ch 1, 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 KREMEN1 ela ed combina ions using indi idual gene exp essions
measu 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. k ingle con aining ansmemb ane p o ein 1 (KREMEN1)
P o h ombin, plasminogen, u okinase- and issue- ype plasminogen ac i a o s con ain
s uc u es known as k ingles. They co espond o au onomous s uc u al and old-
ing domains which media e he binding o hese mul idomain p o eins o o he p o-
eins. Pa hy e al. [4] show ha he amino acid sequences o he ype II s uc u es o
he gela in-binding egion o ib onec in a e homologous wi h hose o he p o ease-
k ingles. K ingle domain, a iple loop, 3-disul ide b idge s uc u e, is conse ed in
di e se p o eins which play impo an oles in a ious biological p ocesses.
Nakamu a e al. [5] cloned KREMEN, a no el membe o k ingle-con aining p o-
eins, which is likely o be a ype-I ansmemb ane p o ein composed o 473 amino
acid esidues. KREMEN has a k ingle domain, a WSC domain, and CUB domains
in he ex acellula egion, while he in acellula egion has no conse ed mo i in-
ol ed in signal ansduc ion. Inc eased KREMEN mRNA le els in mouse emb yo
and i s exp ession in he adul mouse in a a ie y o issues sugges ed a po en ial ole
o KREMEN in he egula ion o cellula esponses upon ex acellula s imulus o
cellcell in e ac ion in neu onal and/o muscle cells.
Canonical WNT signalling ia β-ca enin pa hway is ansduced by wo ecep o
amilies - F izzled (FZD) p o eins and lipop o ein- ecep o - ela ed p o eins 5 and 6
(LRP-5/6) which bind WNTs and ansmi hei signal by s abilizing in acellula β-
ca enin. Howe e , his pa hway is inhibi ed by he sec e ed p o ein Dickkop 1 (DKK1)
by binding o and an agonizing LRP-5/6. Mao e al. [6] show ha he ansmemb ane
p o eins KREMEN-1/2 a e high-a ini y DKK1 ecep o s ha coope a e wi h DKK1 o
block WNT/β-ca enin signalling.
Upon binding o DKK1, KREMEN p o eins (bo h KREMEN-1/2) a e ec ui ed
in o a complex wi h LRP-5/6, which leads o apid endocy osis and emo al o LRP-
5/6 om he plasma memb ane. This o ma ion o a e na y complex composed o
KREMEN, DKK, and LRP-5/6 ( he co ecep o o WNT) inhibi s WNT/β-ca enin sig-
nalling. The inhibi o y unc ion o DKKs depends on he p esence o app op ia e KRE-
MEN p o eins. Nakamu a e al. [7] p esen he iden i ica ion and s uc u e o KRE-
MEN, KREMEN as a nega i e egula o in WNT signalling, exp ession o KREMEN
and i s ole in de elopmen and i s in ol emen in WNT signalling and cance .
I p esen 3 d o de combina ions o KREMEN1 wi h o he genes, ha he machine
lea ning based sea ch engine poin s o, as possible syne gis ic combina ions ha migh
be wo king in ime.
3
3. 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.
4. 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 [8]. 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 [8].
5. Design o expe imen
5.1. 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.
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
4
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 SV MRank
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.
6. Resul s & Discussion
6.1. 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
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
5
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 .
6.2. Enume a ion and anking o 2415 KREMEN1-X-X combina-
ions om Guj al and MacBea h [1]
In he supplemen a y sec ion, I p esen ou iles, 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 esen 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 [9]) and Sobol indicies (wi h 2002 implemen a ion in Sal elli [10]
and ma inez implemen a ion in Ma inez [11] and Baudin e al. [12]).
6.3. Conse ed machine lea ning ankings o es ed KREMEN1-
X-X combina ions
A o al o 2415, 3 d o de combina ions in ol ing KREMEN1 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.
NOTE - I is impo an o no e ha KERMEN1 along wi h DKK1 and LRP-5/6
we e down egula ed (−i e alue) du ing he i s hal o he WNT3A s imula ion in
Guj al and MacBea h [1].
6.3.1. Examining he beha iou o DKK1-KREMEN1-X combina ions
Based on he abo e li e a u e, KREMEN1 is known o in e ac wi h DKK1 o inhibi
he WNT signaling pa hway. Looking a he ables abo e, one inds he ollowing com-
6
RANKING @ iUSING HSIC - LINEAR
3 d o de comb. 1 3 6 12 24 3 d o de comb. 1 3 6 12 24
FZD5-JUN-KREMEN1 96 24278 50801 44288 10781 AES-AXIN1-KREMEN1 127 47825 39191 53628 788
FOXN1-KREMEN1-WNT2B 170 28253 38493 15670 30910 DVL2-JUN-KREMEN1 178 24966 37758 33223 9256
FOXN1-KREMEN1-PPP2R1A 187 38390 45372 22596 7296 FOXN1-KREMEN1-WNT3 217 53012 56130 3088 18960
CCND1-CTBP1-KREMEN1 234 57106 44293 35945 33357 CTNNBIP1-JUN-KREMEN1 241 6571 55388 29592 14471
FOXN1-KREMEN1-LRP5 260 52346 51858 34049 42979 FSHB-FZD2-KREMEN1 286 34277 55693 24595 31187
FBXW11-FOXN1-KREMEN1 302 14589 4660 6330 19835 KREMEN1-PPP2CA-SFRP4 362 833 2893 48271 49787
CSNK1G1-FOXN1-KREMEN1 390 10815 10745 12917 12924 EP300-JUN-KREMEN1 445 18545 22047 46724 18178
DKK1-FOXN1-KREMEN1 480 13941 53110 3917 4043 CTNNB1-FOXN1-KREMEN1 484 1965 14838 7676 28339
FOXN1-KREMEN1-SFRP4 510 51802 54641 8830 39747 FZD5-FOXN1-KREMEN1 511 1786 8577 7989 16170
CSNK1D-FGF4-KREMEN1 529 10037 50110 50880 28493 FZD1-FZD7-KREMEN1 651 16749 42649 57051 9750
KREMEN1-PORCN-WNT4 693 6753 23243 1864 44869 FOSL1-FOXN1-KREMEN1 742 14009 6113 8523 21187
CTNNBIP1-FRAT1-KREMEN1 758 28255 42529 10768 13750 CSNK2A1-FOXN1-KREMEN1 775 7975 18477 6845 18012
FZD5-GSK3A-KREMEN1 798 32935 3687 34447 2546 CCND1-FGF4-KREMEN1 833 56773 18833 37224 15499
FZD8-GSK3A-KREMEN1 914 37178 3268 52107 6645 FSHB-GSK3A-KREMEN1 921 38254 26495 28443 3064
DIXDC1-FOXN1-KREMEN1 939 687 5376 7847 13303 FOXN1-KREMEN1-SFRP1 985 42401 54457 12806 414
DVL2-FGF4-KREMEN1 1025 11180 25345 35577 33719 FZD5-CCND2-KREMEN1 1049 44629 22542 28884 49843
KREMEN1-PORCN-SENP2 1055 20253 16697 487 37387 KREMEN1-PYGO1-WNT3A 1064 30070 1340 20277 52737
CSNK1D-FOXN1-KREMEN1 1122 3656 11331 13933 38262 DKK1-FGF4-KREMEN1 1129 19854 18903 14425 19943
CSNK1A1-CTBP2-KREMEN1 1221 5094 21366 17954 17531 FZD1-FZD2-KREMEN1 1236 35400 37152 3827 42898
CSNK1G1-FGF4-KREMEN1 1239 30116 44329 46230 30098 KREMEN1-WNT1-WNT4 1280 5994 3234 2746 2189
APC-GSK3A-KREMEN1 1292 17817 5446 51090 6601 KREMEN1-PORCN-WNT3A 1377 25809 2588 12830 26801
KREMEN1-PORCN-WNT3A 1377 25809 2588 12830 26801 KREMEN1-NKD1-WNT2B 1400 34496 34759 43275 20181
KREMEN1-PORCN-WNT2B 1401 36444 47192 17886 28451 KREMEN1-NKD1-SENP2 1463 18745 6060 20808 42111
FZD5-FZD2-KREMEN1 1552 30795 21588 5315 28264 CSNK1G1-JUN-KREMEN1 1571 14622 52390 27682 7035
KREMEN1-RHOU-TCF7 1573 55772 27141 223 46704 KREMEN1-PPP2CA-WNT2B 1585 14425 197 53141 37098
FRZB-FZD2-KREMEN1 1603 3863 36101 9766 48273 EP300-FOXN1-KREMEN1 1620 7884 6802 739 13419
CSNK1G1-CTNNB1-KREMEN1 1675 48319 35467 28250 6432 KREMEN1-NKD1-TCF7L1 1699 28241 2070 41242 30439
DIXDC1-FZD2-KREMEN1 1727 6226 28247 11263 35521 FZD1-GSK3A-KREMEN1 1738 40748 5530 55553 1476
KREMEN1-MYC-SENP2 1739 20338 4422 34221 40748 CTNNBIP1-FZD2-KREMEN1 1837 23176 37249 4014 33708
FBXW11-GSK3A-KREMEN1 1865 56429 31282 41254 1352 DAAM1-JUN-KREMEN1 1890 51281 41166 36350 16680
FOXN1-KREMEN1-WNT2 1894 42716 55280 13922 40195 KREMEN1-PORCN-TCF7L1 1902 38888 15726 2313 30252
FRAT1-JUN-KREMEN1 1937 45988 42307 30915 9629 CXXC4-FGF4-KREMEN1 1948 42829 14565 52294 56300
APC-FOXN1-KREMEN1 2000 4298 6205 6426 23498 DIXDC1-JUN-KREMEN1 2010 2457 38608 53030 25504
FZD5-FGF4-KREMEN1 2013 27018 21260 27088 23655 KREMEN1-WNT1-WNT2B 2036 35623 4394 5538 18503
KREMEN1-FBXW4-WNT3A 2114 13176 100 22815 19325 DAAM1-GSK3A-KREMEN1 2129 51563 36659 50263 21382
FZD6-GSK3A-KREMEN1 2225 27912 27936 52258 25906 FBXW2-FGF4-KREMEN1 2253 32946 50021 47804 26837
CTBP1-GSK3A-KREMEN1 2271 26478 2298 49251 1887 AES-DVL1-KREMEN1 2316 39410 26030 52356 23834
KREMEN1-T-WNT2B 2344 47077 5424 49942 15572 KREMEN1-PORCN-SFRP4 2368 33549 23605 2332 43954
CTBP1-FOXN1-KREMEN1 2451 10517 9466 7533 49640 KREMEN1-MYC-TLE2 2509 13737 10240 55345 25198
FBXW2-GSK3A-KREMEN1 2527 40868 10027 47061 40112 KREMEN1-LRP6-TCF7 2533 55286 41418 32082 2935
DAAM1-FGF4-KREMEN1 2579 47103 51872 50968 4413 KREMEN1-NKD1-TLE2 2619 18016 16139 44657 37610
APC-BTRC-KREMEN1 2657 22730 7427 25126 52825 FZD5-CCND1-KREMEN1 2661 25140 10521 9081 26597
KREMEN1-NKD1-WNT3A 2675 23678 2816 47552 40285 CCND3-FOXN1-KREMEN1 2685 41560 9399 7692 43041
BTRC-FOXN1-KREMEN1 2723 18292 12669 9692 56435 FBXW2-FOXN1-KREMEN1 2728 8404 19667 17910 51326
KREMEN1-WIF1-WNT3A 2762 721 11586 56871 31145 KREMEN1-WNT3-WNT3A 2788 47193 12084 27016 19027
FZD1-JUN-KREMEN1 2822 32928 46013 50199 15289 DKK1-FZD2-KREMEN1 2860 30210 53732 5383 20250
CXXC4-FZD7-KREMEN1 2872 42910 42232 51357 48270 CSNK1G1-CTBP2-KREMEN1 2889 6171 37322 13856 5323
KREMEN1-PYGO1-WNT2B 2904 37451 19332 29917 48436 FZD7-JUN-KREMEN1 2975 27209 49555 48377 22318
AXIN1-DVL1-KREMEN1 3005 6666 41605 52750 7478 BTRC-GSK3A-KREMEN1 3010 54393 56679 45265 52103
FOSL1-GSK3A-KREMEN1 3017 11044 1525 53908 3915 KREMEN1-NKD1-FBXW4 3108 22301 16832 29059 23025
KREMEN1-LRP6-SENP2 3111 32111 14514 33645 6872 FOXN1-KREMEN1-SLC9A3R1 3159 39744 45905 6948 40383
FRAT1-GSK3A-KREMEN1 3217 49686 3676 49905 14302 FBXW11-FGF4-KREMEN1 3258 55985 54859 34318 13486
FZD8-JUN-KREMEN1 3275 44731 52219 20333 8524 FBXW11-JUN-KREMEN1 3339 52289 38426 40741 34907
DIXDC1-GSK3A-KREMEN1 3347 13841 2607 50326 30275 CCND2-FOXN1-KREMEN1 3355 3908 6975 5408 46170
DVL1-EP300-KREMEN1 3366 29392 28100 54892 20990 KREMEN1-MYC-WNT3A 3433 19129 6220 28682 38858
CXXC4-FRAT1-KREMEN1 3542 41044 29584 5685 51990 KREMEN1-SLC9A3R1-WNT3A 3580 17181 25435 54188 25643
KREMEN1-PORCN-FBXW4 3663 26907 15869 622 32460 FBXW2-JUN-KREMEN1 3735 35906 54609 50369 55231
KREMEN1-PORCN-TCF7 3746 56109 39312 3880 34922 CSNK1G1-CTNNBIP1-KREMEN1 3759 25578 23550 7886 28116
KREMEN1-LRP6-FBXW4 3766 33137 25609 45562 1844 AES-EP300-KREMEN1 3796 45394 51834 52960 6499
KREMEN1-MYC-TCF7L1 3819 32963 15399 45595 28737 KREMEN1-NKD1-WNT4 3871 11426 4535 41285 47213
CTNNB1-FGF4-KREMEN1 3963 19788 15003 22803 26132 CTBP2-GSK3A-KREMEN1 3981 56103 1110 40270 1391
KREMEN1-PORCN-TLE2 4003 29172 18083 3949 32896 KREMEN1-T-TCF7L1 4058 45731 11965 33080 25646
KREMEN1-WNT1-WNT5A 4086 1014 15715 19712 13437 KREMEN1-PORCN-TLE1 4111 17653 11096 399 32135
Table 1: Rankings o KREMEN1-X-X. A lis o app oxima ely i s 125 combina ions wi h ankings below
10,000 ou o 57,155. SA - HSIC; Ke nel - linea
bina ions o DKK1 along wi h KREMEN1, o be p ominen a 3 d o de le el - DKK1-
FOXN1-KREMEN1, DKK1-FGF4-KREMEN1 and DKK1-FZD2-KREMEN1. All
hese combina ions indica e he exis ence o a possible syne gy when hey ake a highe
ank in he lis o combina ions.
7
RANKING @ iUSING HSIC - RBF
3 d o de comb. 1 3 6 12 24 3 d o de comb. 1 3 6 12 24
FZD5-JUN-KREMEN1 14265 7847 49848 50707 31671 AES-AXIN1-KREMEN1 37703 35313 40516 18682 15851
FOXN1-KREMEN1-WNT2B 20404 27973 36396 884 30778 DVL2-JUN-KREMEN1 13103 30709 32743 48017 27397
FOXN1-KREMEN1-PPP2R1A 21547 15130 581 7154 55001 FOXN1-KREMEN1-WNT3 13156 54946 25548 2636 21279
CCND1-CTBP1-KREMEN1 28942 57047 8671 40620 6175 CTNNBIP1-JUN-KREMEN1 49360 1571 43983 55548 30690
FOXN1-KREMEN1-LRP5 11126 50667 3123 17750 44144 FSHB-FZD2-KREMEN1 5444 42081 8565 25988 38407
FBXW11-FOXN1-KREMEN1 332 11091 39492 5306 3719 KREMEN1-PPP2CA-SFRP4 19893 13395 43502 13961 6353
CSNK1G1-FOXN1-KREMEN1 7103 1710 43024 36832 31611 EP300-JUN-KREMEN1 4639 142 27356 54948 19911
DKK1-FOXN1-KREMEN1 881 21837 24344 36049 9457 CTNNB1-FOXN1-KREMEN1 3133 5700 50426 39968 6394
FOXN1-KREMEN1-SFRP4 21541 47835 13452 25040 38289 FZD5-FOXN1-KREMEN1 2473 6345 54537 47495 8093
CSNK1D-FGF4-KREMEN1 2147 22653 25065 18882 43497 FZD1-FZD7-KREMEN1 40446 14016 820 47659 32313
KREMEN1-PORCN-WNT4 4572 591 18551 4045 46258 FOSL1-FOXN1-KREMEN1 2901 4767 41791 45598 13163
CTNNBIP1-FRAT1-KREMEN1 23718 42906 43026 55168 47523 CSNK2A1-FOXN1-KREMEN1 393 11453 41930 49554 21564
FZD5-GSK3A-KREMEN1 3906 30061 53828 42745 53934 CCND1-FGF4-KREMEN1 22424 56825 8471 20861 15165
FZD8-GSK3A-KREMEN1 1348 36579 51609 22398 40701 FSHB-GSK3A-KREMEN1 9218 45608 28535 37479 51895
DIXDC1-FOXN1-KREMEN1 3184 5794 52693 37317 689 FOXN1-KREMEN1-SFRP1 27973 46263 7809 24618 51572
DVL2-FGF4-KREMEN1 6004 6605 12570 48822 49957 FZD5-CCND2-KREMEN1 8697 44124 49389 52728 52529
KREMEN1-PORCN-SENP2 2897 40815 14540 5841 26554 KREMEN1-PYGO1-WNT3A 7864 26771 50128 43544 15239
CSNK1D-FOXN1-KREMEN1 3060 1922 41865 30003 8137 DKK1-FGF4-KREMEN1 1554 26908 3678 42614 56156
CSNK1A1-CTBP2-KREMEN1 10123 4733 30223 55392 43989 FZD1-FZD2-KREMEN1 10931 27613 9671 42642 45433
CSNK1G1-FGF4-KREMEN1 12312 33122 8653 27029 51700 KREMEN1-WNT1-WNT4 2412 6480 36977 30144 18633
APC-GSK3A-KREMEN1 127 26706 52155 45367 53973 KREMEN1-PORCN-WNT3A 8946 29482 33980 6745 37128
KREMEN1-PORCN-WNT3A 8946 29482 33980 6745 37128 KREMEN1-NKD1-WNT2B 10715 45017 15095 25349 17172
KREMEN1-PORCN-WNT2B 4060 34624 13586 33545 46659 KREMEN1-NKD1-SENP2 730 3287 51067 20876 22424
FZD5-FZD2-KREMEN1 17381 29667 40888 35883 46791 CSNK1G1-JUN-KREMEN1 6491 2240 25073 41585 18357
KREMEN1-RHOU-TCF7 13632 56061 32578 2640 36177 KREMEN1-PPP2CA-WNT2B 25164 28694 34566 35971 17687
FRZB-FZD2-KREMEN1 9733 3875 18132 24675 50396 EP300-FOXN1-KREMEN1 2486 110 54841 38583 4454
CSNK1G1-CTNNB1-KREMEN1 12259 40883 18405 45871 37363 KREMEN1-NKD1-TCF7L1 6544 33167 55781 7544 9258
DIXDC1-FZD2-KREMEN1 14683 17223 32337 21120 1723 FZD1-GSK3A-KREMEN1 1383 26847 53461 44646 50340
KREMEN1-MYC-SENP2 7375 12701 49420 6987 13204 CTNNBIP1-FZD2-KREMEN1 10840 35951 31211 40651 41730
FBXW11-GSK3A-KREMEN1 2846 54984 50753 24803 36268 DAAM1-JUN-KREMEN1 12541 51560 9266 55905 3551
FOXN1-KREMEN1-WNT2 14202 42807 982 1807 50203 KREMEN1-PORCN-TCF7L1 5105 42564 13754 28956 27851
FRAT1-JUN-KREMEN1 5995 44498 42143 51675 21496 CXXC4-FGF4-KREMEN1 1514 40573 41207 46205 49688
APC-FOXN1-KREMEN1 1997 6943 51297 49623 30810 DIXDC1-JUN-KREMEN1 28857 3 41815 56574 3054
FZD5-FGF4-KREMEN1 1921 28429 50401 52865 52795 KREMEN1-WNT1-WNT2B 7206 28407 30386 2208 20264
KREMEN1-FBXW4-WNT3A 49105 7228 49337 28152 8690 DAAM1-GSK3A-KREMEN1 2003 53652 54181 54441 24386
FZD6-GSK3A-KREMEN1 2997 31223 53428 45556 33165 FBXW2-FGF4-KREMEN1 2821 26088 13154 23517 16921
CTBP1-GSK3A-KREMEN1 1319 10146 55450 49855 53098 AES-DVL1-KREMEN1 23959 30765 28010 19926 10756
KREMEN1-T-WNT2B 5079 45857 6720 48287 28414 KREMEN1-PORCN-SFRP4 1803 22519 801 35021 39778
CTBP1-FOXN1-KREMEN1 5743 17110 49946 41629 26263 KREMEN1-MYC-TLE2 15234 1306 52625 36242 22622
FBXW2-GSK3A-KREMEN1 852 35836 33828 33146 22194 KREMEN1-LRP6-TCF7 3639 53069 30894 20591 19675
DAAM1-FGF4-KREMEN1 870 48494 7124 51889 10006 KREMEN1-NKD1-TLE2 2919 14915 47965 33551 33612
APC-BTRC-KREMEN1 8265 27604 37492 52851 54717 FZD5-CCND1-KREMEN1 9857 36236 47155 44679 56118
KREMEN1-NKD1-WNT3A 9700 7837 52991 45907 10853 CCND3-FOXN1-KREMEN1 1171 34063 53094 50272 4611
BTRC-FOXN1-KREMEN1 2135 23342 46688 49929 2379 FBXW2-FOXN1-KREMEN1 1595 364 52793 37705 895
KREMEN1-WIF1-WNT3A 38760 4243 33739 39807 7207 KREMEN1-WNT3-WNT3A 13113 51425 51324 32502 6247
FZD1-JUN-KREMEN1 15931 13787 9034 41845 30091 DKK1-FZD2-KREMEN1 6261 35724 3154 16366 45481
CXXC4-FZD7-KREMEN1 3201 51583 32100 52166 52493 CSNK1G1-CTBP2-KREMEN1 16581 39296 9396 40247 34672
KREMEN1-PYGO1-WNT2B 2480 27771 5674 47549 30280 FZD7-JUN-KREMEN1 6606 12101 29205 53157 12973
AXIN1-DVL1-KREMEN1 6881 8114 22985 56273 14578 BTRC-GSK3A-KREMEN1 5140 53781 54895 53606 19024
FOSL1-GSK3A-KREMEN1 5655 3612 51883 54394 46466 KREMEN1-NKD1-FBXW4 16975 10848 31634 30290 26950
KREMEN1-LRP6-SENP2 2434 29765 40575 33866 40506 FOXN1-KREMEN1-SLC9A3R1 14501 25331 8315 26659 34832
FRAT1-GSK3A-KREMEN1 1014 49731 56438 48125 38195 FBXW11-FGF4-KREMEN1 3698 53770 4230 517 36721
FZD8-JUN-KREMEN1 8991 45182 43032 29768 21965 FBXW11-JUN-KREMEN1 8267 48029 13598 24626 10882
DIXDC1-GSK3A-KREMEN1 962 5165 52201 49330 13895 CCND2-FOXN1-KREMEN1 8379 10719 51570 46577 14647
DVL1-EP300-KREMEN1 54034 12200 13668 57031 15029 KREMEN1-MYC-WNT3A 10637 5567 56637 35572 1429
CXXC4-FRAT1-KREMEN1 9306 45373 50696 51816 46911 KREMEN1-SLC9A3R1-WNT3A 5894 4234 35325 31271 14229
KREMEN1-PORCN-FBXW4 2024 24361 7927 6273 32503 FBXW2-JUN-KREMEN1 45460 39448 22654 30792 5213
KREMEN1-PORCN-TCF7 4135 52520 18227 7012 25650 CSNK1G1-CTNNBIP1-KREMEN1 44820 20207 8775 44692 55891
KREMEN1-LRP6-FBXW4 4459 21512 25267 25628 35821 AES-EP300-KREMEN1 46085 42522 27876 8199 46619
KREMEN1-MYC-TCF7L1 11844 48709 41046 17332 2258 KREMEN1-NKD1-WNT4 1146 12492 44039 43786 11253
CTNNB1-FGF4-KREMEN1 1779 13542 31545 43294 49835 CTBP2-GSK3A-KREMEN1 2929 53064 51746 47070 37417
KREMEN1-PORCN-TLE2 18984 25116 9384 24961 48839 KREMEN1-T-TCF7L1 1217 40415 35163 33451 5680
KREMEN1-WNT1-WNT5A 4362 35794 22223 40251 36925 KREMEN1-PORCN-TLE1 12519 13926 4026 25562 26223
Table 2: Rankings o KREMEN1-X-X. A lis o app oxima ely i s 125 combina ions wi h ankings below
10,000 ou o 57,155. SA - HSIC; Ke nel - b
6.3.2. Examining he beha iou o LRP-5/6-KREMEN1-X combina ions
Since KREMEN p o eins combine wi h DKK1 along wi h LRP-5/6, looking a he a-
bles abo e, one inds he ollowing combina ions o membe s o LRP amily along
wi h KREMEN1, o be p ominen a 3 d o de le el - FOXN1-KREMEN1-LRP5,
KREMEN1-LRP6-SENP2, KREMEN1-LRP6-FBXW4 and KREMEN1-LRP6-TCF7.
All hese combina ions indica e he exis ence o a possible syne gy when hey ake a
8
RANKING @ iUSING SOBOL - 2002
3 d o de comb. 1 3 6 12 24 3 d o de comb. 1 3 6 12 24
FZD5-JUN-KREMEN1 40950 45002 28772 48247 9854 AES-AXIN1-KREMEN1 15129 20699 60 19492 50134
FOXN1-KREMEN1-WNT2B 48078 14775 45903 47094 15768 DVL2-JUN-KREMEN1 30808 34898 33501 52840 6443
FOXN1-KREMEN1-PPP2R1A 42868 43393 35692 37283 25597 FOXN1-KREMEN1-WNT3 22912 27457 7524 8198 32025
CCND1-CTBP1-KREMEN1 2059 53588 1909 4100 53006 CTNNBIP1-JUN-KREMEN1 42377 46499 47863 48423 9908
FOXN1-KREMEN1-LRP5 48531 10599 34009 31625 7563 FSHB-FZD2-KREMEN1 36466 29558 45780 49639 2209
FBXW11-FOXN1-KREMEN1 36681 54148 38407 41684 18205 KREMEN1-PPP2CA-SFRP4 47389 38291 46157 33295 21478
CSNK1G1-FOXN1-KREMEN1 12568 9848 1206 5693 56612 EP300-JUN-KREMEN1 11605 22398 6349 16123 55238
DKK1-FOXN1-KREMEN1 49863 2268 35179 34070 52801 CTNNB1-FOXN1-KREMEN1 28350 28602 22304 4596 30984
FOXN1-KREMEN1-SFRP4 7110 32958 11953 11793 25861 FZD5-FOXN1-KREMEN1 40550 9655 41021 31346 25618
CSNK1D-FGF4-KREMEN1 21369 16424 25622 19556 47905 FZD1-FZD7-KREMEN1 51823 19533 33033 29848 22214
KREMEN1-PORCN-WNT4 2994 1634 5445 11732 52786 FOSL1-FOXN1-KREMEN1 5566 2122 4725 4323 49299
CTNNBIP1-FRAT1-KREMEN1 2163 4891 11842 2940 40557 CSNK2A1-FOXN1-KREMEN1 57030 55282 44745 35369 8120
FZD5-GSK3A-KREMEN1 16434 54131 7576 208 46476 CCND1-FGF4-KREMEN1 6300 54164 19681 18160 46828
FZD8-GSK3A-KREMEN1 1673 51151 25679 27789 20543 FSHB-GSK3A-KREMEN1 49626 22553 37390 51741 6459
DIXDC1-FOXN1-KREMEN1 21482 50446 17603 1664 40258 FOXN1-KREMEN1-SFRP1 46908 27207 43387 43980 36486
DVL2-FGF4-KREMEN1 28296 6083 20156 19941 55458 FZD5-CCND2-KREMEN1 48984 49394 53174 47456 2995
KREMEN1-PORCN-SENP2 1460 11304 1074 20122 52679 KREMEN1-PYGO1-WNT3A 52932 56977 53771 37472 14726
CSNK1D-FOXN1-KREMEN1 31821 16389 28671 30403 11306 DKK1-FGF4-KREMEN1 3925 2235 12144 2997 40109
CSNK1A1-CTBP2-KREMEN1 22944 41262 26386 13278 43474 FZD1-FZD2-KREMEN1 15110 16794 24118 25653 14942
CSNK1G1-FGF4-KREMEN1 49711 51438 57107 44900 43052 KREMEN1-WNT1-WNT4 15955 22656 18139 572 9093
APC-GSK3A-KREMEN1 22161 34336 12787 23677 7226 KREMEN1-PORCN-WNT3A 36088 42706 41171 37942 19003
KREMEN1-PORCN-WNT3A 36088 42706 41171 37942 19003 KREMEN1-NKD1-WNT2B 3720 31186 24394 8640 52443
KREMEN1-PORCN-WNT2B 52764 52181 54179 35890 32504 KREMEN1-NKD1-SENP2 56836 50251 32521 51554 1744
FZD5-FZD2-KREMEN1 18555 33011 7751 196 40221 CSNK1G1-JUN-KREMEN1 6923 4884 26325 13483 55790
KREMEN1-RHOU-TCF7 4926 18206 668 7937 52639 KREMEN1-PPP2CA-WNT2B 2599 25978 4343 22180 25119
FRZB-FZD2-KREMEN1 15195 18589 16392 489 7409 EP300-FOXN1-KREMEN1 23162 5450 14335 12286 51032
CSNK1G1-CTNNB1-KREMEN1 8399 6622 8923 3958 38591 KREMEN1-NKD1-TCF7L1 584 45730 97 3743 56440
DIXDC1-FZD2-KREMEN1 37975 14894 44042 43100 25518 FZD1-GSK3A-KREMEN1 7660 43808 24295 26443 39968
KREMEN1-MYC-SENP2 17023 9287 11185 185 42065 CTNNBIP1-FZD2-KREMEN1 10794 9878 11545 460 10405
FBXW11-GSK3A-KREMEN1 21461 3002 26958 4138 47620 DAAM1-JUN-KREMEN1 52625 28542 37711 31692 4937
FOXN1-KREMEN1-WNT2 9044 42513 11318 10102 41349 KREMEN1-PORCN-TCF7L1 55719 32088 53306 30161 3431
FRAT1-JUN-KREMEN1 40594 22021 35719 33231 5409 CXXC4-FGF4-KREMEN1 9212 1819 7168 7601 47095
APC-FOXN1-KREMEN1 29547 40708 55148 45215 3732 DIXDC1-JUN-KREMEN1 460 53163 11120 19183 46244
FZD5-FGF4-KREMEN1 6216 5651 2403 7647 52951 KREMEN1-WNT1-WNT2B 36576 35166 39887 54348 48410
KREMEN1-FBXW4-WNT3A 45167 47280 56590 48968 2663 DAAM1-GSK3A-KREMEN1 13384 15668 12158 498 56140
FZD6-GSK3A-KREMEN1 12895 32903 20439 2759 51190 FBXW2-FGF4-KREMEN1 22248 48690 8637 9586 46423
CTBP1-GSK3A-KREMEN1 26256 33539 19902 1842 38069 AES-DVL1-KREMEN1 22925 17355 8573 17311 25079
KREMEN1-T-WNT2B 7236 31182 12044 18634 52339 KREMEN1-PORCN-SFRP4 1575 45337 8949 23208 52407
CTBP1-FOXN1-KREMEN1 39964 20046 56465 43731 25806 KREMEN1-MYC-TLE2 45670 47473 48642 49391 21316
FBXW2-GSK3A-KREMEN1 25123 9865 17408 393 41917 KREMEN1-LRP6-TCF7 1727 7976 1357 1445 52140
DAAM1-FGF4-KREMEN1 7127 14101 26191 16548 35458 KREMEN1-NKD1-TLE2 15875 10503 2532 217 43597
APC-BTRC-KREMEN1 37985 37331 55282 41112 5158 FZD5-CCND1-KREMEN1 20691 21099 3090 417 50939
KREMEN1-NKD1-WNT3A 3850 55089 612 11917 55918 CCND3-FOXN1-KREMEN1 51128 56410 37630 41173 22159
BTRC-FOXN1-KREMEN1 50834 8273 50274 53098 8493 FBXW2-FOXN1-KREMEN1 31050 48418 48879 52531 24819
KREMEN1-WIF1-WNT3A 36608 31863 33558 56397 51574 KREMEN1-WNT3-WNT3A 46697 24784 33813 55605 41537
FZD1-JUN-KREMEN1 50807 8217 31011 33476 7864 DKK1-FZD2-KREMEN1 8878 48703 16689 25640 46207
CXXC4-FZD7-KREMEN1 38479 27988 31220 33378 4766 CSNK1G1-CTBP2-KREMEN1 54343 4395 40167 51788 18755
KREMEN1-PYGO1-WNT2B 49601 24278 44028 43212 12272 FZD7-JUN-KREMEN1 13407 6514 26939 4591 30820
AXIN1-DVL1-KREMEN1 14308 33186 25541 10671 49471 BTRC-GSK3A-KREMEN1 8824 50530 21375 2882 33323
FOSL1-GSK3A-KREMEN1 52307 56531 47402 55645 3684 KREMEN1-NKD1-FBXW4 15922 39691 1142 12162 54069
KREMEN1-LRP6-SENP2 3201 51293 12356 14720 31932 FOXN1-KREMEN1-SLC9A3R1 8920 18978 27908 10801 36087
FRAT1-GSK3A-KREMEN1 7872 42308 28346 8689 37391 FBXW11-FGF4-KREMEN1 23854 8666 12120 5305 31743
FZD8-JUN-KREMEN1 44256 39609 38215 56844 3545 FBXW11-JUN-KREMEN1 28638 40636 44640 48839 7440
DIXDC1-GSK3A-KREMEN1 56097 50759 42458 41643 27236 CCND2-FOXN1-KREMEN1 7182 3689 8117 4641 42356
DVL1-EP300-KREMEN1 53244 4343 43692 35471 20160 KREMEN1-MYC-WNT3A 53432 44377 45039 45412 2524
CXXC4-FRAT1-KREMEN1 17526 25193 23946 23550 12450 KREMEN1-SLC9A3R1-WNT3A 7391 2325 5102 8894 56781
KREMEN1-PORCN-FBXW4 55579 11951 48161 33924 4762 FBXW2-JUN-KREMEN1 40033 20545 34038 56164 16905
KREMEN1-PORCN-TCF7 1434 24959 3863 27001 53818 CSNK1G1-CTNNBIP1-KREMEN1 28185 25608 21278 2355 52283
KREMEN1-LRP6-FBXW4 54867 1776 44391 39618 1479 AES-EP300-KREMEN1 29288 36103 39298 31122 2254
KREMEN1-MYC-TCF7L1 56751 50531 56726 45121 4763 KREMEN1-NKD1-WNT4 53306 2099 56540 45244 1241
CTNNB1-FGF4-KREMEN1 52691 24612 41182 40890 28618 CTBP2-GSK3A-KREMEN1 22993 39974 5113 13082 37125
KREMEN1-PORCN-TLE2 54746 5958 46990 32840 4508 KREMEN1-T-TCF7L1 18200 10728 3144 4198 52427
KREMEN1-WNT1-WNT5A 41161 34326 39043 56585 47900 KREMEN1-PORCN-TLE1 2413 51146 10205 24334 52670
Table 3: Rankings o KREMEN1-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
highe ank in he lis o combina ions.
6.3.3. Examining he beha iou o WNT-KREMEN1-X combina ions
Since he e is inhibi ion o he WNT singaling pa hway due o p esence o KREMEN
ac i i y (and ice e sa), combina ions o WNTs ha migh be ge ing inhibi ed ia
KREMEN1 could ell which WNT molecules a e ge ing a ec ed. Looking a he a-
9
