p o ein phospha ase 2A ca aly ic subuni , alpha iso o m
(PPP2CA) : 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
PPP2CA encodes he phospha ase 2A ca aly ic subuni and is one o he ou majo
Se ine/ h eonine-p o ein phospha ases. I consis s o a common he e ome ic co e en-
zyme, composed o a ca aly ic subuni and a cons an egula o y subuni , ha asso-
cia es wi h a a ie y o egula o y subuni s and i is implica ed in he nega i e con ol
o cell g ow h and di ision. Guj al and MacBea h [1] p o ides a quan i a i e, and dy-
namic 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 us-
ing sel -o ganizing maps, hey iden i ied clus e s o genes ha exhibi simila exp es-
sion 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 PPP2CA 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 PPP2CA-X-X combina ions, which poin o exis ence o bio-
logical 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 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 PPP2CA 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1Aspec s o unpublished wo k we e p esen ed in a pos e session a Cell Symposia: Technology.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 12, 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 PPP2CA 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
2.2. 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,
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. p o ein phospha ase 2A ca aly ic subuni , alpha iso o m (PPP2CA)
P o ein phospho yla ion is a e e sible p o ein pos ansla ional modi ica ion (PTM).
Phospho yla ion in ol es he ans e o phospha e g oups om ATP o he enzyme,
he ene gy o which comes om hyd olysing ATP in o ADP o AMP. P o ein kinases
(PKs) a e he e ec o s o phospho yla ion and ca alyse he ans e o a γ-phospha e
om ATP o speci ic amino acids on p o eins. P o eins a e phospho yla ed p edom-
inan ly on Se , Th and Ty esidues. In con as , p o ein phospha ases (PPs) a e he
p ima y e ec o s o dephospho yla ion and can be g ouped in o h ee main classes
based on sequence, s uc u e and ca aly ic unc ion. Dephospho yla ion eleases phos-
pha es in o solu ion as ee ions, because a aching hem back o ATP would equi e
ene gy inpu .
PPP2CA is one o he ou majo se ine/ h eonine-p o ein phospha ases. Shi [4]
s udied he mechanism h ough s uc u e o he se ine/ h eonine phospha ases. The en-
zyme p o ein se ine/ h eonine phospha ase ac s upon phospho yla ed se ine/ h eonine
esidues as ollows ( om Wikipedia con ibu o s [5]) :
[p o ein]−se ine/ h eonine−phospha e+H2O= [p o ein]−se ine/ h eonine+phospha e
(1)
Jones e al. [6] localized he he gene o he αiso o m o he ca aly ic subuni o human
PPP2CA o ch omosome 5 using soma ic cell hyb ids, and hen mo e inely mapped
o ch omosome egion 5q23−>q31 by in si u hyb idiza ion using a i ia ed cDNA
p obe. In hei e iew, Seshacha yulu e al. [7] ocus on he s uc u al complexi y
o se ine/ h eonine phospha ase PP2A and summa ize i s exp ession pa e n in cance
while discussing abou he PP2A in e ac ing and egula o y p o eins and subs a es. Fi-
nally, hey also e iew he mouse models de eloped o unde s and he biological ole
o PP2A subuni s in an in i o model sys em. Fu he , Reynhou and Janssens [8] sum-
ma ize cu en knowledge on physiologic unc ions o PP2A in ge m cell ma u a ion,
umo supp ession, me abolic egula ion, emb yonic de elopmen , and homeos asis o
adul b ain, li e , hea , immune sys em, lung, kidney, in es ine, skin, eye and bone,
all o which we e e ie ed om in i o s udies using PP2A ansgenic, knockou o
knockin mice.
3
The phospha ases PP1 and PP2A ca aly ic subuni s exis in cells in o m o holoen-
zymes, which impa subs a e speci ici y and hei con ibu ion o he ecogni ion o
subs a es is unclea . Hoe mann e al. [9] de elop a phosphopep ide lib a y app oach
and a phosphop o eomic assay o demons a e ha he speci ici y o PP1 and PP2A
holoenzymes owa ds pTh and o PP1 o basic mo i s adjacen o he phospho yla ion
si e a e due o in insic p ope ies o he ca aly ic subuni s.
PP2A holoenzyme complex comp ises a sca olding (A), egula o y (B), and ca -
aly ic (C) subuni , wi h PPP2CA being he p incipal ca aly ic subuni . To de ine he
ull scope o PP2A subs a es in cells, B ewe e al. [10] employed dTAG p o eolysis-
a ge ing chime as o e icien ly and selec i ely deg ade dTAG-PPP2CA in homozy-
gous knock-in HEK293 cells. Via unbiased global phospho-p o eomics, hey iden i-
ied 2,204 p o eins wi h signi ican ly inc eased phospho yla ion upon dTAG-PPP2CA
deg ada ion, implica ing hem as po en ial PPP2CA subs a es and h ough bioin o -
ma ic analyses, hey e ealed in ol emen o he po en ial PPP2CA subs a es in spliceo-
some unc ion, cell cycle, RNA anspo , and ubiqui in-media ed p o eolysis. Using
quan i a i e phospho-p o eomic analysis, hey iden i ied a o al o 39,103 phospho-
pep ides belonging o 5,829 p o eins, in DMSO- and dTAG-13- ea ed dTAG/dTAGPPP2CA
HEK293 cell ex ac s. O hese, 2,651 phospho-pep ides co esponding o 1,149 p o-
eins showed a signi ican inc ease in abundance o >2- old in dTAG-13- ea ed cells
compa ed o DMSO- ea ed con ols, while 6,280 phospho-pep ides co esponding o
2,204 p o eins showed a signi ican inc ease in abundance o >1.5- old.
I p esen 3 d o de combina ions o PPP2CA 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. 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 [11]. 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 [11].
4
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
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
5
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
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 PPP2CA-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
6
a e Hilbe Schmid Independence C i e ion indices (HSIC) indices (wi h b and linea
ke nel in Da Veiga [12]) and Sobol indicies (wi h 2002 implemen a ion in Sal elli [13]
and ma inez implemen a ion in Ma inez [14] and Baudin e al. [15]).
6.3. Conse ed machine lea ning ankings o es ed PPP2CA-X-X
combina ions
A o al o 2415, 3 d o de combina ions in ol ing PPP2CA 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 combi-
na 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.
6.3.1. Examining he beha iou o AXIN-PPP2CA-X combina ions
Wille e al. [16] show ha AXIN is dephospho yla ed in esponse o WNT signaling
and he dephospho yla ed AXIN binds β-ca enin less e icien ly han he phospho-
yla ed o m. Thus, WNT signaling lowe ed AXIN’s a ini y o β-ca enin, he eby
disengaging β-ca enin om he deg ada ion machine y. Ikeda e al. [17] show ha
he he e odime ic o m o PP2A di ec ly binds o AXIN, and PP2A complexed wi h
AXIN dephospho yla ed APC phospho yla ed by GSK3β. Taken oge he , hei e-
sul s sugges ha GSK3β-dependen phospho yla ion o APC can be modula ed by
β-ca enin and PP2A complexed wi h AXIN. Looking a he ables abo e, one inds he
ollowing combina ions o AXIN1 along wi h PPP2CA, o be p ominen a 3 d o de
le el - AXIN1-FZD2-PPP2CA, AES-AXIN1-PPP2CA and AXIN1-FOXN1-PPP2CA.
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.
6.3.2. Examining he beha iou o APC-PPP2CA-X combina ions
Seeling e al. [18] show ha PP2A egula o y subuni , B56, in e ac ed wi h APC in he
yeas wo-hyb id sys em and exp ession o B56 educed he abundance o β-ca enin
and inhibi ed ansc ip ion o β-ca enin a ge genes in mammalian cells and Xeno-
pusemb yo explan s. Fu he , he B56-dependen dec ease in β-ca enin was blocked
by oncogenic mu a ions in β-ca enin o APC, and by p o easome inhibi o s. B56 may
di ec PP2A o dephospho yla e speci ic componen s o he APC-dependen signal-
ing complex and he eby inhibi WNT signaling. Thei s udy sugges ed ha PP2A
he e o ime s con aining he B56 egula o y subuni unc ioned in he WNT signaling
complex o down- egula e β-ca enin, pe haps h ough an in e ac ion o B56 and he
NH2- e minus o APC, o dephospho yla e speci ic componen s o he APC-dependen
signaling complex and he eby inhibi WNT signaling. Looking a he ables abo e,
7
RANKING @ iUSING HSIC - LINEAR
3 d o de comb. 1 3 6 12 24 3 d o de comb. 1 3 6 12 24
CXXC4-FZD7-PPP2CA 90 9819 23105 12397 36836 FZD7-PPP2CA-SFRP4 121 6838 2610 6467 34834
FZD1-FZD7-PPP2CA 188 20213 26368 10322 10221 AES-AXIN1-PPP2CA 213 21529 16225 49328 28118
CSNK2A1-MYC-PPP2CA 271 37740 40109 23353 26864 APC-PITX2-PPP2CA 334 14753 2900 19245 30663
NLK-PORCN-PPP2CA 339 30605 43435 41734 4166 PPP2CA-SFRP4-WNT2B 341 52722 25356 52978 1988
KREMEN1-PPP2CA-SFRP4 362 833 2893 48271 49787 FZD7-NKD1-PPP2CA 369 8802 35791 35537 25608
DKK1-JUN-PPP2CA 408 27394 50340 28816 37806 BCL9-PORCN-PPP2CA 415 15959 34237 38189 34019
DIXDC1-NKD1-PPP2CA 440 13162 40123 35144 6197 CXXC4-PORCN-PPP2CA 481 22027 38709 38555 36190
DVL2-JUN-PPP2CA 504 43997 37157 2445 3613 FZD7-PPP2CA-SENP2 540 11483 354 3539 34512
CCND3-PPP2CA-SFRP4 631 37304 7579 35575 51606 PPP2CA-WNT1-WNT3A 732 6546 10800 53535 9982
DKK1-PPP2CA-SFRP4 815 3000 44035 44920 42238 FBXW11-LRP6-PPP2CA 822 25174 30818 7903 41062
FSHB-FZD2-PPP2CA 922 15170 15248 37534 18116 CSNK1G1-NKD1-PPP2CA 926 17356 35232 35369 12912
DVL1-FOXN1-PPP2CA 977 25908 15392 4810 48741 DAAM1-FOXN1-PPP2CA 1014 50289 35190 8828 44977
CTBP1-GSK3A-PPP2CA 1015 17069 883 43553 18661 FOSL1-FOXN1-PPP2CA 1072 22257 16994 9632 25457
CSNK1G1-FZD2-PPP2CA 1082 23722 6311 56537 35909 FOSL1-FZD7-PPP2CA 1103 37962 25642 24479 50931
FZD8-GSK3A-PPP2CA 1156 55038 1341 50154 22462 CTNNBIP1-JUN-PPP2CA 1160 17287 25595 27276 6859
CSNK1D-FOXN1-PPP2CA 1252 17427 16752 21509 34632 FBXW11-FOXN1-PPP2CA 1357 8568 16917 13742 17017
FRZB-JUN-PPP2CA 1383 13534 31714 933 1610 CSNK2A1-FOXN1-PPP2CA 1415 18676 25465 10950 9597
PPP2CA-T-WNT3A 1435 46308 13460 20855 21652 FRZB-FZD2-PPP2CA 1437 17024 10096 32430 33434
CSNK1G1-FSHB-PPP2CA 1518 8523 49087 1235 27660 CCND1-JUN-PPP2CA 1525 10554 35624 43398 54711
CSNK2A1-FSHB-PPP2CA 1544 21794 56458 12205 17377 KREMEN1-PPP2CA-WNT2B 1585 14425 197 53141 37098
DKK1-FOXN1-PPP2CA 1604 39842 25588 9674 22711 FRZB-GSK3A-PPP2CA 1624 17689 1801 14917 16232
BTRC-PPP2CA-WNT4 1638 35087 32587 22025 51750 FZD5-CCND3-PPP2CA 1659 15307 15361 43028 36850
PPP2CA-WNT1-WNT4 1668 20515 14866 23920 21265 AES-FOXN1-PPP2CA 1682 1873 24710 15282 25404
FZD8-PORCN-PPP2CA 1713 51044 29439 20913 20485 FZD5-PPP2CA-SFRP4 1743 159 4915 40308 39122
CSNK1A1-LRP6-PPP2CA 1764 14481 17648 2115 28490 FOSL1-NKD1-PPP2CA 1845 14335 40783 24581 23211
FZD7-PPP2CA-WNT2B 1854 16103 178 39687 33132 APC-BTRC-PPP2CA 1858 9257 27876 20401 45249
FOSL1-PORCN-PPP2CA 1917 33808 39279 26918 22451 FRZB-NKD1-PPP2CA 1923 12714 42040 19751 23511
AXIN1-FZD2-PPP2CA 2006 16397 13459 38219 30167 DKK1-PPP2CA-SENP2 2068 7041 27771 41618 51588
CSNK1D-FGF4-PPP2CA 2103 20756 11349 39534 15407 FZD8-JUN-PPP2CA 2138 54751 19454 329 37826
DKK1-NKD1-PPP2CA 2158 21388 52610 49493 9273 CSNK1G1-JUN-PPP2CA 2194 17201 31808 2244 24092
FBXW11-JUN-PPP2CA 2233 16460 49863 18037 53295 FZD6-GSK3A-PPP2CA 2263 8382 9486 47912 53738
FOSL1-GSK3A-PPP2CA 2355 22861 911 45587 39936 DAAM1-LRP6-PPP2CA 2361 55059 33326 5010 40824
CSNK1A1-GSK3B-PPP2CA 2386 9444 19245 4822 2538 BCL9-JUN-PPP2CA 2418 12028 23042 32377 49157
FRZB-PPP2CA-SFRP4 2426 1736 4164 8420 12593 CTBP2-FOXN1-PPP2CA 2521 39676 20597 7309 30523
DKK1-GSK3A-PPP2CA 2529 18354 4501 38825 41214 BCL9-FGF4-PPP2CA 2534 11917 24166 51167 48006
FRAT1-JUN-PPP2CA 2547 32152 28002 1650 1276 APC-PORCN-PPP2CA 2593 14870 33789 20601 17503
CXXC4-FZD2-PPP2CA 2607 29974 9988 18663 50107 FRAT1-GSK3A-PPP2CA 2638 38412 1286 35232 13767
BTRC-PPP2CA-SFRP4 2649 45450 55216 41081 48220 FRZB-PORCN-PPP2CA 2663 20449 38661 30250 22743
EP300-FZD2-PPP2CA 2702 12448 13262 50046 20911 DAAM1-GSK3A-PPP2CA 2745 56040 14776 51085 48063
CCND3-PPP2CA-WNT2 2799 33277 2300 17044 49518 FBXW2-NKD1-PPP2CA 2839 23721 34814 16169 56279
PITX2-PORCN-PPP2CA 2847 24874 33030 43172 21878 CTBP1-FOXN1-PPP2CA 2940 12144 24777 14758 54034
FZD7-PPP2CA-WNT2 2964 18295 2936 723 46075 CCND3-PPP2CA-SENP2 3064 34905 2328 40674 48547
PPP2CA-WNT1-WNT5A 3127 17958 20275 50785 22700 AXIN1-FOXN1-PPP2CA 3158 9114 17327 16618 10071
NKD1-PPP2CA-SFRP4 3169 46409 13326 29656 43339 FGF4-FOSL1-PPP2CA 3175 29507 37541 48577 51007
AES-EP300-PPP2CA 3218 22740 43678 26060 41565 CTBP1-FGF4-PPP2CA 3224 17798 20777 35300 21473
DIXDC1-FOXN1-PPP2CA 3235 4976 13715 8671 2172 APC-FOXN1-PPP2CA 3259 6614 11418 7307 27730
CXXC4-FOXN1-PPP2CA 3277 19301 19575 24116 33763 CCND3-NKD1-PPP2CA 3285 34449 42225 49257 26308
GSK3B-LRP6-PPP2CA 3297 38834 21470 36021 39453 FOSL1-JUN-PPP2CA 3303 25232 24882 2685 4764
FBXW11-FZD2-PPP2CA 3313 19812 19095 30619 15139 FOSL1-PPP2CA-SFRP4 3331 18404 4076 19432 6798
CXXC4-FGF4-PPP2CA 3340 9402 29074 35299 53290 CCND1-NKD1-PPP2CA 3363 11274 37598 54652 44854
PPP2CA-TCF7-WNT3A 3403 35126 15557 53522 39901 FBXW2-PORCN-PPP2CA 3520 27173 22022 46128 27903
AES-DVL1-PPP2CA 3635 6018 44845 39717 52837 CXXC4-JUN-PPP2CA 3661 32213 26859 462 30021
DIXDC1-FZD2-PPP2CA 3662 17928 10686 40372 29250 DAAM1-FGF4-PPP2CA 3665 54152 33362 55780 29602
FZD8-NKD1-PPP2CA 3681 49836 33279 27543 15965 APC-FZD6-PPP2CA 3769 15339 20803 56646 49253
FZD6-PORCN-PPP2CA 3788 4773 43421 3483 7109 BTRC-PPP2CA-T 3795 43011 19216 31904 44253
FBXW11-GSK3A-PPP2CA 3852 26830 8953 53718 5344 FZD5-PORCN-PPP2CA 3939 10638 39482 21947 53216
CSNK2A1-NKD1-PPP2CA 4025 15782 45180 27270 33423 CSNK1D-GSK3A-PPP2CA 4064 22624 794 37163 9946
DIXDC1-PITX2-PPP2CA 4123 13781 1911 14325 45522 DKK1-DVL2-PPP2CA 4138 22771 24516 8573 52303
FZD8-LEF1-PPP2CA 4177 56827 23717 17918 45636 FRAT1-PORCN-PPP2CA 4204 33092 39327 31761 14446
CCND3-PPP2CA-RHOU 4207 37434 5715 53381 50362 CSNK2A1-GSK3A-PPP2CA 4214 31336 13790 24722 34871
PPP2CA-WNT1-WNT2B 4221 27679 5501 15908 49412 FZD1-PORCN-PPP2CA 4258 20050 38961 32098 15000
FZD7-PPP2CA-TLE2 4271 5239 7231 4827 26456 CTNNB1-GSK3A-PPP2CA 4281 19241 845 32420 18538
CCND1-CTNNBIP1-PPP2CA 4294 35830 34555 37986 51377 KREMEN1-PPP2CA-SENP2 4308 6165 521 42127 55415
Table 1: Rankings o PPP2CA-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
one inds he ollowing combina ions o AXIN1 along wi h PPP2CA, o be p omi-
nen a 3 d o de le el - APC-PITX2-PPP2CA, APC-BTRC-PPP2CA, APC-PORCN-
PPP2CA, APC-FOXN1-PPP2CA and APC-FZD6-PPP2CA . All hese combina ions
indica e he exis ence o a possible syne gy when hey ake a highe ank in he lis o
8
RANKING @ iUSING HSIC - RBF
3 d o de comb. 1 3 6 12 24 3 d o de comb. 1 3 6 12 24
CXXC4-FZD7-PPP2CA 7569 8146 8359 8809 29695 FZD7-PPP2CA-SFRP4 55917 24461 55999 42034 109
FZD1-FZD7-PPP2CA 25993 15034 5386 38356 42649 AES-AXIN1-PPP2CA 35492 17204 7775 30194 15980
CSNK2A1-MYC-PPP2CA 1074 26347 29622 32938 20490 APC-PITX2-PPP2CA 4042 33446 8698 18579 52910
NLK-PORCN-PPP2CA 6640 37879 19229 30844 45007 PPP2CA-SFRP4-WNT2B 55580 46429 27467 46270 1672
KREMEN1-PPP2CA-SFRP4 19893 13395 43502 13961 6353 FZD7-NKD1-PPP2CA 15127 35957 31673 37533 1778
DKK1-JUN-PPP2CA 872 31181 33266 21737 30431 BCL9-PORCN-PPP2CA 19443 12204 3989 2860 44188
DIXDC1-NKD1-PPP2CA 9807 43231 37477 30170 1078 CXXC4-PORCN-PPP2CA 9663 20715 7491 12348 51537
DVL2-JUN-PPP2CA 12969 55374 21200 14940 32734 FZD7-PPP2CA-SENP2 32571 2154 49346 21000 26293
CCND3-PPP2CA-SFRP4 46916 36878 55760 47246 5936 PPP2CA-WNT1-WNT3A 4487 6874 35552 24125 19493
DKK1-PPP2CA-SFRP4 55812 1395 43571 11747 8786 FBXW11-LRP6-PPP2CA 1498 23055 36283 10416 6272
FSHB-FZD2-PPP2CA 3195 15838 9446 3827 55246 CSNK1G1-NKD1-PPP2CA 8799 37693 42013 33688 15900
DVL1-FOXN1-PPP2CA 3346 22402 46063 15109 11834 DAAM1-FOXN1-PPP2CA 609 47634 41711 1552 16742
CTBP1-GSK3A-PPP2CA 841 30822 34980 31747 27039 FOSL1-FOXN1-PPP2CA 2050 20570 56654 7068 31115
CSNK1G1-FZD2-PPP2CA 21192 37740 25191 13344 44898 FOSL1-FZD7-PPP2CA 54451 46826 3194 28518 28447
FZD8-GSK3A-PPP2CA 2976 56637 43724 15698 9354 CTNNBIP1-JUN-PPP2CA 38196 36635 20141 33944 38991
CSNK1D-FOXN1-PPP2CA 677 25144 54449 22625 44186 FBXW11-FOXN1-PPP2CA 551 13483 50027 13549 5121
FRZB-JUN-PPP2CA 5873 49297 3845 20493 26715 CSNK2A1-FOXN1-PPP2CA 278 35287 48412 13705 23060
PPP2CA-T-WNT3A 5197 44818 17755 38317 4985 FRZB-FZD2-PPP2CA 5746 32562 6231 841 53357
CSNK1G1-FSHB-PPP2CA 50070 6934 23453 5427 21042 CCND1-JUN-PPP2CA 40595 14062 3971 9088 1571
CSNK2A1-FSHB-PPP2CA 14473 24470 49869 6189 28547 KREMEN1-PPP2CA-WNT2B 25164 28694 34566 35971 17687
DKK1-FOXN1-PPP2CA 318 42768 43072 5776 28884 FRZB-GSK3A-PPP2CA 1260 45624 46852 17140 25632
BTRC-PPP2CA-WNT4 13782 33555 41012 5416 5243 FZD5-CCND3-PPP2CA 12325 45904 23439 31013 47189
PPP2CA-WNT1-WNT4 1316 18383 42717 1659 16550 AES-FOXN1-PPP2CA 2186 37914 47459 13594 25139
FZD8-PORCN-PPP2CA 4402 55143 2005 12002 37055 FZD5-PPP2CA-SFRP4 47311 664 55943 2216 11593
CSNK1A1-LRP6-PPP2CA 16978 31404 24202 26610 21103 FOSL1-NKD1-PPP2CA 21934 29546 42661 35675 17456
FZD7-PPP2CA-WNT2B 54842 24004 41817 52487 4145 APC-BTRC-PPP2CA 4261 9237 29395 1410 54704
FOSL1-PORCN-PPP2CA 857 51996 6161 7188 48966 FRZB-NKD1-PPP2CA 1942 36043 22753 20309 35265
AXIN1-FZD2-PPP2CA 7416 35245 5191 10583 50255 DKK1-PPP2CA-SENP2 54622 26587 44748 26854 52986
CSNK1D-FGF4-PPP2CA 3187 47005 13018 23779 39413 FZD8-JUN-PPP2CA 6710 57073 4320 19608 19584
DKK1-NKD1-PPP2CA 845 43108 38644 15851 21492 CSNK1G1-JUN-PPP2CA 3740 31530 16470 29436 25461
FBXW11-JUN-PPP2CA 9373 17254 50937 17677 11233 FZD6-GSK3A-PPP2CA 5274 18421 36558 40884 12260
FOSL1-GSK3A-PPP2CA 12185 33599 52257 41997 37270 DAAM1-LRP6-PPP2CA 7255 52778 39048 19324 16287
CSNK1A1-GSK3B-PPP2CA 49785 6326 16521 6418 41571 BCL9-JUN-PPP2CA 32542 20885 2900 20877 26335
FRZB-PPP2CA-SFRP4 52697 31347 51732 14973 22371 CTBP2-FOXN1-PPP2CA 11045 38092 52532 1356 32277
DKK1-GSK3A-PPP2CA 55 13432 43272 11984 17851 BCL9-FGF4-PPP2CA 11758 12541 2912 24152 44954
FRAT1-JUN-PPP2CA 5774 39371 22955 20982 28298 APC-PORCN-PPP2CA 1049 35875 5774 24955 45838
CXXC4-FZD2-PPP2CA 11564 33338 12458 3001 54858 FRAT1-GSK3A-PPP2CA 761 45444 39194 15449 37603
BTRC-PPP2CA-SFRP4 23701 47316 54163 28713 3631 FRZB-PORCN-PPP2CA 4450 31541 6488 11176 47491
EP300-FZD2-PPP2CA 8059 21295 864 5359 44323 DAAM1-GSK3A-PPP2CA 5817 54945 44951 39069 16387
CCND3-PPP2CA-WNT2 36713 24526 54134 13742 8094 FBXW2-NKD1-PPP2CA 15124 44885 17926 12733 2217
PITX2-PORCN-PPP2CA 9603 23189 295 19554 39138 CTBP1-FOXN1-PPP2CA 5258 32520 39917 10063 30654
FZD7-PPP2CA-WNT2 40336 26902 57064 15776 2793 CCND3-PPP2CA-SENP2 42453 28981 45394 1751 13534
PPP2CA-WNT1-WNT5A 1188 16609 32224 18050 32772 AXIN1-FOXN1-PPP2CA 5167 25187 29990 1127 16140
NKD1-PPP2CA-SFRP4 40324 48641 51898 9183 19710 FGF4-FOSL1-PPP2CA 42277 28170 8091 25442 19223
AES-EP300-PPP2CA 40675 14926 3496 32198 22117 CTBP1-FGF4-PPP2CA 3823 27672 4141 30441 47610
DIXDC1-FOXN1-PPP2CA 1796 26077 33448 2622 1308 APC-FOXN1-PPP2CA 1206 4752 36187 915 15627
CXXC4-FOXN1-PPP2CA 1922 14941 49768 109 32177 CCND3-NKD1-PPP2CA 19772 35706 47585 36014 3731
GSK3B-LRP6-PPP2CA 3750 50098 25527 8818 33308 FOSL1-JUN-PPP2CA 21063 49029 6511 48244 44672
FBXW11-FZD2-PPP2CA 3595 19254 48774 3116 27274 FOSL1-PPP2CA-SFRP4 31966 44588 53340 39850 33169
CXXC4-FGF4-PPP2CA 896 24972 12137 33837 43059 CCND1-NKD1-PPP2CA 31094 31919 45839 10804 5523
PPP2CA-TCF7-WNT3A 36467 12019 36560 49458 39632 FBXW2-PORCN-PPP2CA 13731 19973 12814 22383 21062
AES-DVL1-PPP2CA 19128 12832 8371 36154 55869 CXXC4-JUN-PPP2CA 2697 40480 12704 20114 45550
DIXDC1-FZD2-PPP2CA 8902 30326 5894 8118 11004 DAAM1-FGF4-PPP2CA 1734 53041 30385 36043 10689
FZD8-NKD1-PPP2CA 31727 55399 17443 4434 10950 APC-FZD6-PPP2CA 9255 28099 28345 32780 55276
FZD6-PORCN-PPP2CA 15 24063 29679 24492 40813 BTRC-PPP2CA-T 42753 54274 45558 42965 26218
FBXW11-GSK3A-PPP2CA 5045 19409 45810 19725 16426 FZD5-PORCN-PPP2CA 23568 21263 11481 8780 45819
CSNK2A1-NKD1-PPP2CA 6422 22743 30647 42195 19402 CSNK1D-GSK3A-PPP2CA 1046 40897 47094 14850 34061
DIXDC1-PITX2-PPP2CA 5166 50281 13595 5982 18374 DKK1-DVL2-PPP2CA 2732 42296 39816 1658 9495
FZD8-LEF1-PPP2CA 4960 57112 5320 15616 6681 FRAT1-PORCN-PPP2CA 2795 32747 21472 22562 46364
CCND3-PPP2CA-RHOU 24349 40806 49185 54625 8752 CSNK2A1-GSK3A-PPP2CA 8360 44268 37323 48745 27502
PPP2CA-WNT1-WNT2B 5623 15143 40493 2300 24871 FZD1-PORCN-PPP2CA 4367 38671 4743 23669 51214
FZD7-PPP2CA-TLE2 56558 28223 50599 11481 3392 CTNNB1-GSK3A-PPP2CA 2288 19240 46473 33276 26230
CCND1-CTNNBIP1-PPP2CA 9077 28086 5722 5046 6609 KREMEN1-PPP2CA-SENP2 3092 4451 26948 15879 51552
Table 2: Rankings o PPP2CA-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
combina ions.
9
6.3.11. Examining he beha iou o EP300-PPP2CA-X combina ions
T ansc ip ional coac i a o p300 (o EP300) is equi ed o emb yonic de elopmen
and cell p oli e a ion. Valp oic acid, a his one deace ylase inhibi o , is widely used in
he he apy o epilepsy and bipola diso de . Chen e al. [31] epo ha alp oic acid
s imula es p o easome-dependen p300 deg ada ion h ough augmen a ion o gene ex-
p ession o he B56γ egula o y subuni s o p o ein phospha ase 2A. The B56γ3 eg-
ula o y and ca aly ic subuni s o p o ein phospha ase 2A in e ac wi h p300. O e -
exp ession o he B56γ3 subuni led o p o easome-media ed p300 deg ada ion and
ep essed p300-dependen ansc ip ional ac i a ion, which equi ed he B56γ3 in e -
ac ion domain o p300. Con e sely, silencing o he B56γsubuni exp ession by RNA
in e e ence inc eased he s abili y and ansc ip ional ac i i y o p300. Via quan i a-
i e phospho-p o eomic analysis, B ewe e al. [10] iden i ied EP300 o be subs a e o
PPP2CA.
Looking a he ables abo e, one inds he ollowing combina ions o Ep300 along
wi h PPP2CA, o be p ominen a 3 d o de le el - EP300-FZD2-PPP2CA and AES-
EP300-PPP2CA. 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. Conclusion
This manusc ip s udies he ime beha iou o 3 d o de combina ions o PPP2CA in
WNT3A s imula ed HEK 293 cells. Based on he ex ablished 2nd o de combina-
ions o he PPP2CA, 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.
16
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.
Supplemen a y
The ollowing iles (ending wi h . x and can be opened in R o in simple ex p o-
cessing p og am) wi h hese names a e made a ailable wi h his manusc ip . Fo
PPP2CA, (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.
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