Degradation of beta-catenin by the destruction complex (Homo sapiens)

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461318, 32, 42, 4454638, 39, 41, 5233, 482, 10, 31, 36, 38...26, 30281710, 15, 31, 36, 38...614, 34, 35, 39, 45...37, 47, 4819289, 11, 431, 7, 9, 12, 27...4, 16, 20-22, 254, 9, 20, 24, 25282, 10, 15, 31, 36...cytosolnucleoplasmp-S33,S37,T41,S45 CTNNB1 PPP2CB PPP2R1B PSMB10 TCF7 TCF7L1 PPP2R5A K63polyUb-APC K63polyUbPPP2R5A PPP2R1A RPS27A(1-76) p-S45CTNNB1:p-Axin:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexPPP2R1B PPP2R5C FRAT1,2:GSK3betaCTBPsPPP2R5D TLE1 PPP2R5C PPP2R1B CUL1 TCF7L2 TLE2 PPP2R1A PSMC4 PPP2R1A p-S37,T41,S45CTNNB1:p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexATPunknown ubiquitinligasePSMD4 PPP2CB BTRC p-S33,S37,T41,S45 CTNNB1 UBC(381-456) TCF7L2/TCF7L1PSMB1 GSK3B UBB(1-76) PPP2CB FRAT1 PPP2R1A PPP2R1B TCF7 TLE3 PPP2R5E PPP2CB CUL1 PPP2R5C PPP2CB TLE1 UBC(609-684) K63polyUb-APC HDAC1 PPP2R5B PPP2R5C TLE2 26S proteasomePSMC6 AMER1 UBC(1-76) p-S33,S37,T41,S45 CTNNB1 ATPUbPPP2R1B PPP2R5D PPP2CA CSNK1A1 PSMB9 PPP2R5D PPP2CA UBC(381-456) LEF1 RBX1:SKP1:CUL1:beta-TrCP1:phosphorylated beta-catenin complexp-S37,T41,S45, CTNNB1 PPP2R5D CSNK1A1ATPPPP2R5C PSMD6 PPP2R5D PSMA8 K63polyUb-APC PPP2R5B AMER1CTBP1 p-S33,S37,T41,S45CTNNB1:p-AXIN:CK1alpha:GSK3B:phospho-ub-APC (20 aa repeat region):PP2A:AMER1 complexPPP2R5E PSMB4 MYC mRNA PPP2R1B PSMA3 p-S45 CTNNB1 TLE1 PPP2R1A TCF7 TCF7L2 'canonical' WNTtarget genetranscriptsp-S33,S37,T41,S45CTNNB1:p-AXIN:CK1alpha:GSK3B:phospho-ub-APC (20 aa repeat region):PP2A:AMER1 complexPPP2R5B CSNK1A1 PPP2R5B K63polyUb-APCPPP2CB TLE3 p-ub-APC ADPUBC(533-608) AMER1 PPP2R5D PSMC3 PPP2R5E MYC gene TCF7L2/TCF7L1:CTBPsPPP2CB FRAT2 PPP2R5B TLE4 PPP2R5B PSMD13 PPP2R5B PPP2R5B PSMD9 p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexAXIN1 geneSHFM1 PSMD12 CSNK1A1 PPP2R1A PPP2R5A p-T519,S524,S531-AXIN1 CTNNB1 PPP2R1A GSK3B p-T41,S45CTNNB1:p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexCTNNB1:p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexPSMA7 GSK3B PPP2R5A UBC(153-228) PPP2CB PSMD7 TCF7L1 PPP2R5E LEF1 PPP2R1B PPP2R1B PSMD3 PPP2CB p-ub-APC PSME3 PSMB2 AES PPP2R5C PPP2R5C ATPCTBP2 TLE4 p-T519,S524,S531-AXIN1 PPP2R5E AMER1 GSK3B AXIN2 gene PPP2R1B CTBP2 ATPPPP2R1B TLE2 AXIN2 gene PPP2R5E PSMC1 UBC(457-532) p-T519,S524,S531-AXIN1 PPP2R5B TCF7L2 PSME1 UBC(77-152) p-T519,S524,S531-AXIN1 CSNK1A1 PPP2R5D TCF7L1 GSK3B CUL1 PSMF1 PSMC2 'canonical' WNTtargetgene:TCF/LEF:TLEtetramerPPP2R5A p-T519,S524,S531-AXIN1 PPP2R5B UBC(457-532) PSMD1 RPS27A(1-76) AMER1 PSMB11 PSME2 TLE3 CSNK1A1 PSMA1 PPP2R5A BTRC:CUL1:RBX1:SKP1CSNK1A1 TLE4 PSMD14 RBX1 ADPPPP2CA PPP2CB PPP2R5E UBA52(1-76) AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexPPP2R1A PPP2CA PPP2R5D GSK3B AXIN2 gene PPP2R1A PSMD10 PPP2R5C TLE3 TLE3 LEF1 PPP2R5E PPP2R5A PPP2CB PSMB6 PPP2R5A K63polyUb-APC CSNK1A1 SKP1 p-AXIN:CK1alpha:GSK3B:phospho-APC (20 aa repeat region):PP2A:AMER1 complexRBX1 AXIN1BTRC p-S33,S37,T41,S45-beta-catenin:p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexCSNK1A1 PPP2R5E TCF7L1 UBC(305-380) PSMA5 PPP2CA UBB(77-152) PPP2R1A TCF7L2 MYC gene PSMD5 PPP2CA TLE4 AMER1 p-T519,S524,S531-AXIN1 p-T519,S524,S531-AXIN1 APCGSK3BLEF1 PSMB8 TLE:AESUBB(153-228) GSK3B PPP2R5C K63polyUb-APC UBA52(1-76) CTNNB1PPP2CA UBC(77-152) UBC(609-684) AMER1 p-T519,S524,S531-AXIN1 p-S33,S37,T41,S45 CTNNB1 CSNK1A1 p-ub-APC PPP2CA AESTCF7L1 PPP2R5D AXIN2 gene 'canonical' WNTtargetgenes:TCF/LEF:TLEtetramer:HDAC1p-ub-APC BTRC AXIN1 PPP2R5E TCF7L1 PPP2R1B PPP2R5C TLE1 TCF/LEFTCF7L2 'canonical' WNTtarget genesPSMA6 PPP2CA PPP2CA p-T519,S524,S531-AXIN1 CSNK1A1 ADPTLE4 PP2APSMC5 TLE1 PPP2R5D UBC(229-304) TLE tetramerPPP2CB p-T519,S524,S531-AXIN1 TLE2 SKP1 p-ub-APC PPP2R5D UBC(533-608) PPP2R5B TLE2 AMER1 PSMB5 AMER1 PPP2CA 'canonical' WNTtargetgenes:TCF/LEFPPP2R5C PPP2R1B PPP2R5A p-T519,S524,S531-AXIN1 ATPAMER1 genePPP2R5E PPP2R5B PPP2R5C PPP2R5A UBC(153-228) PPP2CA ADPGSK3B AMER1 ADPGSK3B PPP2R1A PPP2R5B UBB(1-76) PPP2R5A PSME4 TCF7L2 MYC gene AMER1 UBB(77-152) PPP2R5E ubiquitinatedphospho-beta-catenin:RBX1:SCF(beta-TrCP1) complexPSMD2 PSMB3 PSMA4 K63polyUb-APC UBC(229-304) GSK3B PPP2R5C ADPAMER1 p-T41,S45 CTNNB1 PPP2R1B TCF7 PPP2CB SKP1 PPP2R5A TLEPSMA2 PPP2R5D PSMB7 AXIN2 mRNA PPP2R5A CSNK1A1 HDAC1GSK3B PSMD8 p-S33,S37,T41,S45 CTNNB1 RBX1 UBC(305-380) PPP2R1A PSMD11 UBB(153-228) PPP2R1A PPP2R5E PPP2R5D CTBP1 PPP2CA K63polyUb-APC MYC gene UBC(1-76) GSK3B AMER1 GSK3B CSNK1A1 53, 85, 23


The beta-catenin destruction complex plays a key role in the canonical Wnt signaling pathway. In the absence of Wnt signaling, this complex controls the levels of cytoplamic beta-catenin. Beta-catenin associates with and is phosphorylated by the destruction complex. Phosphorylated beta-catenin is recognized and ubiquitinated by the SCF-beta TrCP ubiquitin ligase complex and is subsequently degraded by the proteasome (reviewed in Kimelman and Xu, 2006). View original pathway at:Reactome.


Pathway is converted from Reactome ID: 195253
Reactome version: 66
Reactome Author 
Reactome Author: Kimelman, D

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101538view11:40, 1 November 2018ReactomeTeamreactome version 66
101073view21:22, 31 October 2018ReactomeTeamreactome version 65
100603view19:57, 31 October 2018ReactomeTeamreactome version 64
100154view16:42, 31 October 2018ReactomeTeamreactome version 63
99704view15:10, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93998view13:50, 16 August 2017ReactomeTeamreactome version 61
93607view11:28, 9 August 2017ReactomeTeamreactome version 61
87171view19:24, 18 July 2016MkutmonOntology Term : 'Wnt signaling pathway' added !
86716view09:24, 11 July 2016ReactomeTeamreactome version 56
83396view11:07, 18 November 2015ReactomeTeamVersion54
81590view13:07, 21 August 2015ReactomeTeamVersion53
77050view08:35, 17 July 2014ReactomeTeamFixed remaining interactions
76755view12:11, 16 July 2014ReactomeTeamFixed remaining interactions
76080view10:14, 11 June 2014ReactomeTeamRe-fixing comment source
75790view11:32, 10 June 2014ReactomeTeamReactome 48 Update
75140view14:08, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74831view10:05, 30 April 2014ReactomeTeamReactome46
74787view08:52, 30 April 2014ReactomeTeamNew pathway

External references


View all...
NameTypeDatabase referenceComment
'canonical' WNT

target gene:TCF/LEF:TLE

ComplexR-HSA-8944351 (Reactome)
'canonical' WNT

target genes:TCF/LEF:TLE

ComplexR-HSA-8944365 (Reactome)
'canonical' WNT


ComplexR-HSA-8944354 (Reactome)
'canonical' WNT

target gene

ComplexR-HSA-4411358 (Reactome)
'canonical' WNT target genesComplexR-HSA-4411390 (Reactome)
26S proteasomeComplexR-HSA-68819 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
AES ProteinQ08117 (Uniprot-TrEMBL)
AESProteinQ08117 (Uniprot-TrEMBL)
AMER1 ProteinQ5JTC6 (Uniprot-TrEMBL)
AMER1 geneGeneProductENSG00000184675 (Ensembl)
AMER1ProteinQ5JTC6 (Uniprot-TrEMBL)
APCProteinP25054 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
AXIN1 ProteinO15169 (Uniprot-TrEMBL)
AXIN1 geneGeneProductENSG00000103126 (Ensembl)
AXIN1ProteinO15169 (Uniprot-TrEMBL)
AXIN2 gene ProteinENSG00000168646 (Ensembl)
AXIN2 mRNA ProteinENST00000307078 (Ensembl)
AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexComplexR-HSA-195250 (Reactome)
BTRC ProteinQ9Y297 (Uniprot-TrEMBL)
BTRC:CUL1:RBX1:SKP1ComplexR-HSA-206748 (Reactome)
CSNK1A1 ProteinP48729 (Uniprot-TrEMBL)
CSNK1A1ProteinP48729 (Uniprot-TrEMBL)
CTBP1 ProteinQ13363 (Uniprot-TrEMBL)
CTBP2 ProteinP56545 (Uniprot-TrEMBL)
CTBPsComplexR-HSA-5333992 (Reactome)
CTNNB1 ProteinP35222 (Uniprot-TrEMBL)
CTNNB1:p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexComplexR-HSA-3601581 (Reactome)
CTNNB1ProteinP35222 (Uniprot-TrEMBL)
CUL1 ProteinQ13616 (Uniprot-TrEMBL)
FRAT1 ProteinQ92837 (Uniprot-TrEMBL)
FRAT1,2:GSK3betaComplexR-HSA-1226052 (Reactome)
FRAT2 ProteinO75474 (Uniprot-TrEMBL)
GSK3B ProteinP49841 (Uniprot-TrEMBL)
GSK3BProteinP49841 (Uniprot-TrEMBL)
HDAC1 ProteinQ13547 (Uniprot-TrEMBL)
HDAC1ProteinQ13547 (Uniprot-TrEMBL)
K63polyUb-APC ProteinP25054 (Uniprot-TrEMBL)
K63polyUb-APCProteinP25054 (Uniprot-TrEMBL)
K63polyUbR-HSA-450152 (Reactome)
LEF1 ProteinQ9UJU2 (Uniprot-TrEMBL)
MYC gene ProteinENSG00000136997 (Ensembl)
MYC mRNA ProteinENST00000377970 (Ensembl)
PP2AComplexR-HSA-196206 (Reactome)
PPP2CA ProteinP67775 (Uniprot-TrEMBL)
PPP2CB ProteinP62714 (Uniprot-TrEMBL)
PPP2R1A ProteinP30153 (Uniprot-TrEMBL)
PPP2R1B ProteinP30154 (Uniprot-TrEMBL)
PPP2R5A ProteinQ15172 (Uniprot-TrEMBL)
PPP2R5B ProteinQ15173 (Uniprot-TrEMBL)
PPP2R5C ProteinQ13362 (Uniprot-TrEMBL)
PPP2R5D ProteinQ14738 (Uniprot-TrEMBL)
PPP2R5E ProteinQ16537 (Uniprot-TrEMBL)
PSMA1 ProteinP25786 (Uniprot-TrEMBL)
PSMA2 ProteinP25787 (Uniprot-TrEMBL)
PSMA3 ProteinP25788 (Uniprot-TrEMBL)
PSMA4 ProteinP25789 (Uniprot-TrEMBL)
PSMA5 ProteinP28066 (Uniprot-TrEMBL)
PSMA6 ProteinP60900 (Uniprot-TrEMBL)
PSMA7 ProteinO14818 (Uniprot-TrEMBL)
PSMA8 ProteinQ8TAA3 (Uniprot-TrEMBL)
PSMB1 ProteinP20618 (Uniprot-TrEMBL)
PSMB10 ProteinP40306 (Uniprot-TrEMBL)
PSMB11 ProteinA5LHX3 (Uniprot-TrEMBL)
PSMB2 ProteinP49721 (Uniprot-TrEMBL)
PSMB3 ProteinP49720 (Uniprot-TrEMBL)
PSMB4 ProteinP28070 (Uniprot-TrEMBL)
PSMB5 ProteinP28074 (Uniprot-TrEMBL)
PSMB6 ProteinP28072 (Uniprot-TrEMBL)
PSMB7 ProteinQ99436 (Uniprot-TrEMBL)
PSMB8 ProteinP28062 (Uniprot-TrEMBL)
PSMB9 ProteinP28065 (Uniprot-TrEMBL)
PSMC1 ProteinP62191 (Uniprot-TrEMBL)
PSMC2 ProteinP35998 (Uniprot-TrEMBL)
PSMC3 ProteinP17980 (Uniprot-TrEMBL)
PSMC4 ProteinP43686 (Uniprot-TrEMBL)
PSMC5 ProteinP62195 (Uniprot-TrEMBL)
PSMC6 ProteinP62333 (Uniprot-TrEMBL)
PSMD1 ProteinQ99460 (Uniprot-TrEMBL)
PSMD10 ProteinO75832 (Uniprot-TrEMBL)
PSMD11 ProteinO00231 (Uniprot-TrEMBL)
PSMD12 ProteinO00232 (Uniprot-TrEMBL)
PSMD13 ProteinQ9UNM6 (Uniprot-TrEMBL)
PSMD14 ProteinO00487 (Uniprot-TrEMBL)
PSMD2 ProteinQ13200 (Uniprot-TrEMBL)
PSMD3 ProteinO43242 (Uniprot-TrEMBL)
PSMD4 ProteinP55036 (Uniprot-TrEMBL)
PSMD5 ProteinQ16401 (Uniprot-TrEMBL)
PSMD6 ProteinQ15008 (Uniprot-TrEMBL)
PSMD7 ProteinP51665 (Uniprot-TrEMBL)
PSMD8 ProteinP48556 (Uniprot-TrEMBL)
PSMD9 ProteinO00233 (Uniprot-TrEMBL)
PSME1 ProteinQ06323 (Uniprot-TrEMBL)
PSME2 ProteinQ9UL46 (Uniprot-TrEMBL)
PSME3 ProteinP61289 (Uniprot-TrEMBL)
PSME4 ProteinQ14997 (Uniprot-TrEMBL)
PSMF1 ProteinQ92530 (Uniprot-TrEMBL)
RBX1 ProteinP62877 (Uniprot-TrEMBL)
RBX1:SKP1:CUL1:beta-TrCP1:phosphorylated beta-catenin complexComplexR-HSA-2130280 (Reactome) B-TrCP associates with phosphorylated beta-catenin through the B-TrCP WD40 repeat region. Currently, it is unclear whether the ubiquitin ligase binds beta-catenin after it leaves the complex. It is equally possible that it binds beta-catenin while beta-catenin is still bound to Axin.
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
SHFM1 ProteinP60896 (Uniprot-TrEMBL)
SKP1 ProteinP63208 (Uniprot-TrEMBL)
TCF/LEFComplexR-HSA-3299546 (Reactome)
TCF7 ProteinP36402 (Uniprot-TrEMBL)
TCF7L1 ProteinQ9HCS4 (Uniprot-TrEMBL)
TCF7L2 ProteinQ9NQB0 (Uniprot-TrEMBL)
TCF7L2/TCF7L1:CTBPsComplexR-HSA-5334048 (Reactome)
TCF7L2/TCF7L1ComplexR-HSA-5334046 (Reactome)
TLE tetramerComplexR-HSA-3299565 (Reactome)
TLE1 ProteinQ04724 (Uniprot-TrEMBL)
TLE2 ProteinQ04725 (Uniprot-TrEMBL)
TLE3 ProteinQ04726 (Uniprot-TrEMBL)
TLE4 ProteinQ04727 (Uniprot-TrEMBL)
TLE:AESComplexR-HSA-4649013 (Reactome)
TLEComplexR-HSA-4649011 (Reactome)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UbComplexR-HSA-113595 (Reactome)
p-AXIN:CK1alpha:GSK3B:phospho-APC (20 aa repeat region):PP2A:AMER1 complexComplexR-HSA-196222 (Reactome) In this complex Axin is bound to beta-catenin.
p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexComplexR-HSA-3601577 (Reactome)
p-S33,S37,T41,S45 CTNNB1:p-AXIN:CK1alpha:GSK3B:phospho-ub-APC (20 aa repeat region):PP2A:AMER1 complexComplexR-HSA-195297 (Reactome) In this complex Axin is bound to beta-catenin.
p-S33,S37,T41,S45 CTNNB1:p-AXIN:CK1alpha:GSK3B:phospho-ub-APC (20 aa repeat region):PP2A:AMER1 complexComplexR-HSA-195322 (Reactome) In this form of the destruction complex, beta-catenin is no longer associated with Axin, but instead with phospho-(20aa) APC.
p-S33,S37,T41,S45 CTNNB1 ProteinP35222 (Uniprot-TrEMBL)
p-S33,S37,T41,S45-beta-catenin:p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexComplexR-HSA-195282 (Reactome)
p-S37,T41,S45 CTNNB1:p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexComplexR-HSA-195305 (Reactome)
p-S37,T41,S45, CTNNB1 ProteinP35222 (Uniprot-TrEMBL)
p-S45 CTNNB1:p-Axin:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexComplexR-HSA-195277 (Reactome)
p-S45 CTNNB1 ProteinP35222 (Uniprot-TrEMBL)
p-T41,S45 CTNNB1:p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexComplexR-HSA-195313 (Reactome)
p-T41,S45 CTNNB1 ProteinP35222 (Uniprot-TrEMBL)
p-T519,S524,S531-AXIN1 ProteinO15169 (Uniprot-TrEMBL)
p-ub-APC ProteinP25054 (Uniprot-TrEMBL)
ubiquitinated phospho-beta-catenin:RBX1:SCF(beta-TrCP1) complexComplexR-HSA-2130284 (Reactome)
unknown ubiquitin ligaseR-HSA-5250898 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
'canonical' WNT

target gene:TCF/LEF:TLE

ArrowR-HSA-8944349 (Reactome)
'canonical' WNT

target gene:TCF/LEF:TLE

R-HSA-4641231 (Reactome)
'canonical' WNT

target genes:TCF/LEF:TLE

ArrowR-HSA-4641231 (Reactome)
'canonical' WNT

target genes:TCF/LEF:TLE

TBarR-HSA-5229348 (Reactome)
'canonical' WNT


ArrowR-HSA-8944352 (Reactome)
'canonical' WNT


R-HSA-8944349 (Reactome)
'canonical' WNT

target gene

ArrowR-HSA-5229348 (Reactome)
'canonical' WNT target genesR-HSA-5229348 (Reactome)
'canonical' WNT target genesR-HSA-8944352 (Reactome)
26S proteasomemim-catalysisR-HSA-2130282 (Reactome)
ADPArrowR-HSA-195275 (Reactome)
ADPArrowR-HSA-195283 (Reactome)
ADPArrowR-HSA-195287 (Reactome)
ADPArrowR-HSA-195300 (Reactome)
ADPArrowR-HSA-195318 (Reactome)
ADPArrowR-HSA-5229343 (Reactome)
AESR-HSA-4649028 (Reactome)
AMER1 geneR-HSA-5251557 (Reactome)
AMER1ArrowR-HSA-5251557 (Reactome)
AMER1R-HSA-195251 (Reactome)
APCR-HSA-5246693 (Reactome)
ATPR-HSA-195275 (Reactome)
ATPR-HSA-195283 (Reactome)
ATPR-HSA-195287 (Reactome)
ATPR-HSA-195300 (Reactome)
ATPR-HSA-195318 (Reactome)
ATPR-HSA-5229343 (Reactome)
AXIN1 geneR-HSA-5251555 (Reactome)
AXIN1ArrowR-HSA-5251555 (Reactome)
AXIN1R-HSA-195251 (Reactome)
AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexArrowR-HSA-195251 (Reactome)
AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexR-HSA-5229343 (Reactome)
AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexmim-catalysisR-HSA-5229343 (Reactome)
BTRC:CUL1:RBX1:SKP1ArrowR-HSA-2130282 (Reactome)
BTRC:CUL1:RBX1:SKP1R-HSA-2130279 (Reactome)
CSNK1A1R-HSA-195251 (Reactome)
CTBPsR-HSA-5334050 (Reactome)
CTNNB1:p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexArrowR-HSA-195304 (Reactome)
CTNNB1:p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexR-HSA-195318 (Reactome)
CTNNB1:p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexmim-catalysisR-HSA-195318 (Reactome)
CTNNB1R-HSA-195304 (Reactome)
FRAT1,2:GSK3betaTBarR-HSA-195283 (Reactome)
FRAT1,2:GSK3betaTBarR-HSA-195287 (Reactome)
FRAT1,2:GSK3betaTBarR-HSA-195300 (Reactome)
GSK3BR-HSA-195251 (Reactome)
HDAC1R-HSA-4641231 (Reactome)
K63polyUb-APCArrowR-HSA-5246693 (Reactome)
K63polyUb-APCR-HSA-195251 (Reactome)
K63polyUbR-HSA-5246693 (Reactome)
PP2AR-HSA-195251 (Reactome)
R-HSA-195251 (Reactome) The exact composition of the destruction complex is not known. A number of components appear to form a core complex, while others may associate with the complex transiently when a Wnt signal is present (reviewed in Kimelman and Xu, 2006). The core components include Axin, glycogen synthase kinase 3 (GSK-3), Casein kinase 1 (CKI) alpha, beta-catenin, Protein phosphatase 2A (PP2A) and Adenomatous Polyposis Coli (APC). CK1 epsilon, Diversin and PP1 may also be components of the complex.
R-HSA-195275 (Reactome) APC is phosphorylated on the 20 aa repeats by CK1 and potentially GSK-3. This significantly increases the binding affinity of the APC 20 aa repeats for beta-catenin, causing one of them to bind b-catenin in the same region as beta-catenin binds Axin, thus displacing beta-catenin from Axin ( Step 5 above) (Reviewed in Kimelman, 2006).
R-HSA-195280 (Reactome) The phosphorylation of the 20 aa repeats in APC results in an increase in affinity for beta-catenin (Ha et al., 2004, Xing et al., 2004; Liu et al., 2006). The binding site of phospho -(20 aa) APC on beta-catenin overlaps the binding site of Axin on beta catenin. In addition, phosphorylated APC prevents the association of Axin with beta-catenin (Ha et al., 2004, Xing et al., 2004). In this model, phosphorylated APC may compete with Axin for beta-catenin binding, resulting in dissociation of the Axin:beta-catenin interaction in the destruction complex (see Kimelman and Xu 2006).
R-HSA-195283 (Reactome) Phospho-(Ser45, Thr41) beta-catenin is phosphorylated by GSK3 at Ser37.
R-HSA-195287 (Reactome) Following CKI-mediated phosphorylation at Ser45, beta-catenin is phosphorylated by GSK3 at Thr41.
R-HSA-195300 (Reactome) Beta-catenin is then phosphorylated at Ser33. Phosphorylated S37 and S33 together with neighboring residues constitute the recognition motif for beta-TrCP.
R-HSA-195304 (Reactome) Beta-catenin associates with the destruction complex through an interaction with Axin and or APC. This association may also involve interactions with the 15 aa repeats in APC (Spink et al., 2001) or the third APC 20aa repeat and its N-terminal flanking residues (Ha et al., 2004, Xing et al., 2004; Liu et al., 2006).
R-HSA-195318 (Reactome) CK1a binds to Axin and phosphorylates beta-catenin at Ser45 priming GSK3 mediated phosphorylation at the more N-terminal residues (Amit et al., 2002; Liu et al., 2002; Yanagawa et al., 2002).
R-HSA-2130279 (Reactome) B-TrCP associates with phosphorylated beta-catenin through the B-TrCP WD40 repeat region. Currently, it is unclear whether the ubiquitin ligase binds beta-catenin after it leaves the complex. It is equally possible that it binds beta-catenin while beta-catenin is still bound to Axin.
R-HSA-2130282 (Reactome) Ubiquitinated beta-catenin is degraded by the proteasome.
R-HSA-2130286 (Reactome) Beta-catenin is ubiquitinated by the SCF-B-TrCP1 complex.
R-HSA-4641229 (Reactome) TCF1, LEF1, TCF3 and TCF4 are HMG box-containing DNA-binding proteins that recognize WNT-responsive elements (WREs) in the promoters of WNT target genes (reviewed in Brantjes et al, 2002). In the absence of a WNT signal, promoter-bound TCF/LEF is bound by one of four Groucho homologues, TLE1, 2, 3 or 4 (Levanon et al, 1998; Brantjes et al, 2001; Daniels and Weis, 2005). Groucho/TLE proteins are co-repressors for a variety of DNA-binding transcription factors and mediate repression at least in part through their interaction with histone deacetylases such as RPD3/HDAC1 (Arce et al, 2009; Brantjes et al, 2001; Chen et al, 1999; reviewed in Chen and Courey, 2000). Groucho proteins have been shown to homo-tetramerize through a glutamine rich Q domain at the N-terminus, and this oligomerization is required for repression. The Q domain is also sufficient for interaction with TCF/LEF proteins (Brantjes et al, 2001; Chen et al, 1998; Pinto and Lobe, 1996; Song et al, 2004). Studies with purified proteins have shown that human TLE1 and 2 bind to an amino-terminal truncated form of LEF1(69-397) with an affinity comparable to that for full length LEF1 (Daniels and Weis, 2005).
R-HSA-4641231 (Reactome) Groucho/TLE mediates repression of WNT target genes in part by recruiting a histone deacetlyase to the promoter. The weakly conserved central GP domain of Groucho/TLE has been shown to interact with the histone deacetylase RPD3/HDAC1 (Brantjes et al, 2001; Chen et al, 1999). Knockdown of rpd3 in Drosophila cells, or treatment of human or Drosophila cells with the histone deacetylase inhibitor Trichostatin A significantly decreases repression of a Groucho/TLE dependent reporter gene, and Groucho and RPD3 have been shown to co-localize to chromatin of target genes by ChIP leading to deacetylation of H3K9, H3K14, K4K5, H4K8 and H4K12 (Chen et al, 1999; Choi et al 1999; Winkler et al, 2010).
R-HSA-4649028 (Reactome) AES is a naturally occuring truncated form of TLE that contains only the Q and GP domain. AES has been shown to have a dominant negative effect on TLE-mediated repression (Miyasaka et al, 1993; Roose et al, 1998; Ren et al, 1999; Swingler et al, 2004). AES is believed to form oligomers with full length TLE proteins mediated by the Q domains; because AES is unable to interact with HDAC1, these oligomers are thought to be non-functional (Muhr et al, 2001; Brantjes et al, 2001).
R-HSA-5229343 (Reactome) In the absence of WNT signal, AXIN is a phosphoprotein; candidate kinases include both GSK3beta and CK1 (Ikeda et al, 1998; Willert et al, 1999; Jho et al, 1999; Yamamoto et al, 1999; Luo et al, 2007). Phosphorylation of AXIN is thought to increase its binding affinity for beta-catenin and GSK3beta, stabilizing the destruction complex and promoting efficient degradation of beta-catenin (Willert et al, 1999; Jho et al, 1999; Luo et al, 2007). A more recent model suggests that AXIN phosphorylation may disrupt an intramolecular interaction between its DIX domain and the beta-catenin binding region, which would otherwise keep AXIN in a 'closed' inactive state (Kim et al, 2013). Activation of the WNT pathway upon ligand binding favours dephosphorylation of AXIN by inactivating the kinases and allowing the steady state dephosphorylation by candidate phosphatases PP2A and PP1 to predominate (Willert et al, 1999; Luo et al, 2007; reviewed in Saito-Diaz et al, 2013).
R-HSA-5229348 (Reactome) Transcription of WNT genes is repressed in the absence of WNT signal by TLE:HDAC complexes (reviewed in Cinnamon and Paroush, 2008; Saito-Diaz et al, 2013). Represssion may also be mediated by CTBP proteins binding to TCF7L1 and TCF7L3 (Duval et al, 2000; Cuilliere-Dartigues et al, 2006; Tang et al, 2008).
R-HSA-5246693 (Reactome) In unstimulated cells, APC is K63 polyubiquitinated in a manner that depends on its association with AXIN. Although the precise timing of APC polyubiquitination is unclear, it is disrupted by abrogation of GSK3 kinase activity and in the presence of phosphodegron mutants of beta-catenin, suggesting that the formation of a functional destruction complex is required. Destruction complex formation is also dependent upon AXIN levels, which may be regulated at least in part by the balance of its ubiquitination and sumoylation (Kim et al, 2008).
Upon WNT3A stimulation, APC K63 polyubiquitination is lost coincident with disruption of the APC-AXIN interaction (Tran and Polakis, 2012). Interestingly, another study has shown that DVL is K63 polyubiquitinated upon WNT signaling (Tauriello et al, 2010), suggesting a possible model in which WNT signaling promotes a change in AXIN-K63 polyubiquitin binding partner to destabilize the destruction complex and promote pathway activation. Alternately, APC K63 polyubiquitination may protect beta-catenin from PP2A-mediated dephosphorylation and thus favour its degradation (Su et al, 2008).
R-HSA-5251555 (Reactome) AXIN1 was first identified as the product of the mouse gene fused and has since been shown to have a key role in the degradation of beta-catenin by the destruction complex (Zeng et al, 1997; reviewed in Saito-Diaz et al, 2013). Deletion, missense and nonsense mutations that lead to activated WNT signaling have been identified in the AXIN1 gene in human cancers, making AXIN1 a tumor suppressor gene (reviewed in Salahshor and Woodgett, 2005).
R-HSA-5251557 (Reactome) AMER1 was identified as a gene mutated in a subset of Wilms tumors (Rivera et al, 2007) and the protein has been shown to be a component of the beta-catenin destruction complex (Major et al, 2007).
R-HSA-5334050 (Reactome) In addition to repressing WNT-dependent targets through Groucho/TLE proteins, some TCF/LEF transcription factors may also work by recruiting the CTBP1 and CTBP2 repressors (Duval et al, 2000). CTBP-binding regions are present in the 'E-form' splice variants of TCF7L2 and in TCF7L1 and in vitro interactions have been demonstrated in Xenopus and mammals, although the in vivo relevance of these interactions is unclear (Brannon et al, 1999; Valenta et al, 2003; Cuilliere-Dartigues et al, 2006; Tang et al, 2008; Hamada and Bienz, 2004). Abrogation of the interaction interface results in a loss of TCF-CTBP colocalization and increased expression of a TCF-dependent reporter gene (Cuilliere-Dartigues et al, 2006; Tang et al, 2008).
R-HSA-8944349 (Reactome) In the absence of a WNT signal, promoter-bound TCF/LEF is bound by one of four Groucho homologues, TLE1, 2, 3 or 4 (Levanon et al, 1998; Brantjes et al, 2001; Daniels and Weis, 2005). Groucho/TLE proteins are co-repressors for a variety of DNA-binding transcription factors and mediate repression at least in part through their interaction with histone deacetylases such as RPD3/HDAC1 (Arce et al, 2009; Brantjes et al, 2001; Chen et al, 1999; reviewed in Chen and Courey, 2000). Groucho proteins have been shown to homo-tetramerize through a glutamine rich Q domain at the N-terminus, and this oligomerization is required for repression. The Q domain is also sufficient for interaction with TCF/LEF proteins (Brantjes et al, 2001; Chen et al, 1998; Pinto and Lobe, 1996; Song et al, 2004). Studies with purified proteins have shown that human TLE1 and 2 bind to an amino-terminal truncated form of LEF1(69-397) with an affinity comparable to that for full length LEF1 (Daniels and Weis, 2005)

R-HSA-8944352 (Reactome) TCF7 (TCF1), LEF1, TCF7L1 (TCF3) and TCF7L2 (TCF4) are HMG box-containing DNA-binding proteins that recognize WNT-responsive elements (WREs) in the promoters of WNT target genes. The WRE consensus sequence is CCTTTGWW, where W represents either T or A (reviewed in Brantjes et al, 2002). In the absence of a WNT signal, promoter-bound TCF/LEF is bound by one of four Groucho homologues, TLE1, 2, 3 or 4 (Levanon et al, 1998; Brantjes et al, 2001; Daniels and Weis, 2005). Groucho/TLE proteins are co-repressors for a variety of DNA-binding transcription factors and mediate repression at least in part through their interaction with histone deacetylases such as RPD3/HDAC1 (Arce et al, 2009; Brantjes et al, 2001; Chen et al, 1999; reviewed in Chen and Courey, 2000).
RBX1:SKP1:CUL1:beta-TrCP1:phosphorylated beta-catenin complexArrowR-HSA-2130279 (Reactome)
RBX1:SKP1:CUL1:beta-TrCP1:phosphorylated beta-catenin complexR-HSA-2130286 (Reactome)
TCF/LEFR-HSA-8944352 (Reactome)
TCF7L2/TCF7L1:CTBPsArrowR-HSA-5334050 (Reactome)
TCF7L2/TCF7L1:CTBPsTBarR-HSA-5229348 (Reactome)
TCF7L2/TCF7L1R-HSA-5334050 (Reactome)
TLE tetramerArrowR-HSA-4641229 (Reactome)
TLE tetramerR-HSA-8944349 (Reactome)
TLE:AESArrowR-HSA-4649028 (Reactome)
TLER-HSA-4641229 (Reactome)
TLER-HSA-4649028 (Reactome)
UbArrowR-HSA-2130282 (Reactome)
UbR-HSA-2130286 (Reactome)
p-AXIN:CK1alpha:GSK3B:phospho-APC (20 aa repeat region):PP2A:AMER1 complexArrowR-HSA-2130282 (Reactome)
p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexArrowR-HSA-5229343 (Reactome)
p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexR-HSA-195304 (Reactome)
p-S33,S37,T41,S45 CTNNB1:p-AXIN:CK1alpha:GSK3B:phospho-ub-APC (20 aa repeat region):PP2A:AMER1 complexArrowR-HSA-195275 (Reactome)
p-S33,S37,T41,S45 CTNNB1:p-AXIN:CK1alpha:GSK3B:phospho-ub-APC (20 aa repeat region):PP2A:AMER1 complexArrowR-HSA-195280 (Reactome)
p-S33,S37,T41,S45 CTNNB1:p-AXIN:CK1alpha:GSK3B:phospho-ub-APC (20 aa repeat region):PP2A:AMER1 complexR-HSA-195280 (Reactome)
p-S33,S37,T41,S45 CTNNB1:p-AXIN:CK1alpha:GSK3B:phospho-ub-APC (20 aa repeat region):PP2A:AMER1 complexR-HSA-2130279 (Reactome)
p-S33,S37,T41,S45-beta-catenin:p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexArrowR-HSA-195300 (Reactome)
p-S33,S37,T41,S45-beta-catenin:p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexR-HSA-195275 (Reactome)
p-S33,S37,T41,S45-beta-catenin:p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexmim-catalysisR-HSA-195275 (Reactome)
p-S37,T41,S45 CTNNB1:p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexArrowR-HSA-195283 (Reactome)
p-S37,T41,S45 CTNNB1:p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexR-HSA-195300 (Reactome)
p-S37,T41,S45 CTNNB1:p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexmim-catalysisR-HSA-195300 (Reactome)
p-S45 CTNNB1:p-Axin:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexArrowR-HSA-195318 (Reactome)
p-S45 CTNNB1:p-Axin:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexR-HSA-195287 (Reactome)
p-S45 CTNNB1:p-Axin:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexmim-catalysisR-HSA-195287 (Reactome)
p-T41,S45 CTNNB1:p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexArrowR-HSA-195287 (Reactome)
p-T41,S45 CTNNB1:p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexR-HSA-195283 (Reactome)
p-T41,S45 CTNNB1:p-AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexmim-catalysisR-HSA-195283 (Reactome)
ubiquitinated phospho-beta-catenin:RBX1:SCF(beta-TrCP1) complexArrowR-HSA-2130286 (Reactome)
ubiquitinated phospho-beta-catenin:RBX1:SCF(beta-TrCP1) complexR-HSA-2130282 (Reactome)
unknown ubiquitin ligasemim-catalysisR-HSA-5246693 (Reactome)
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