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

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2151063, 41, 11, 145512777PP2A SCF-beta-TrCP1 complex associated with phosphorylated beta-catenin PP2A pS45- beta-catenin cytosolAxinGSK3CK1alphaAPCPP2AFAM123B complex SCF-beta-TrCP1 complex associated with phosphorylated beta-catenin AxinGSK3CK1alphaAPCPP2AFAM123B complex PP2A PP2A p-T41,S45-beta catenin PP2A PP2A p-S33,S37,T41,S45-beta-catenin AxinGSK3CK1alphaAPCPP2AFAM123B complex AxinGSK3CK1alphaAPCPP2AFAM123B complex 26S proteasome PP2A SCF-beta-TrCP1 complex beta-cateninAxinGSK3CK1alphaAPCPP2AFAM123B complex SCF-beta-TrCP1 complex FRAT1 or FRAT2 PP2A p-S33,S37,T41,S45-beta-cateninAxinGSK3CK1alphaAPCPP2AFAM123B complex p-S33,S37,T41,S45-beta-catenin p-S33,S37,T41,S45-beta-catenin ubiquitinated phospho-beta-cateninSCFbeta-TrCP1 complex p-S33,S37,T41,S45-beta-cateninAxinCK1alphaGSK3Bphospho-APC AxinGSK3CK1alphaAPCPP2AFAM123B complex p-S33,S37,T41,S45-beta-cateninAxinCK1alphaGSK3Bphospho-APC p-T41,S45-beta-cateninAxinGSK3CK1alphaAPCPP2AFAM123B complex FRAT1/FRAT2GSK3beta Complex PP2A PP2A PP2A AxinGSK3CK1alphaAPCPP2AFAM123B complex p-S33,S37,T41,S45-beta-catenin SCF-beta-TrCP1 complex p-S33,S37,T41,S45-beta-catenin Ub p-S37,T41,S45-beta-cateninAxin,GSK3CK1alphaAPCPP2AFAM123B complex PP2A pS45-beta-cateninAxinGSK3CK1alphaAPCPP2AFAM123B complex p-S33,S37,T41,S45-beta-cateninAxinCK1alphaGSK3Bphospho-APC p-S37,T41,S45-beta-catenin p-S33,S37,T41,S45-beta-cateninAxinCK1alphaGSK3Bphospho-APC AxinCK1alphaGSK3Bphospho-APC CSNK1A1p-T41,S45-beta-cateninAxinGSK3CK1alphaAPCPP2AFAM123B complexPSMD12 PSMB8 ATPAMER1 GSK3B CSNK1A1PSMC1GSK3B PSMB4 UBCADPCSNK1A1AXIN1 PSMD5 CSNK1A1p-S33,S37,S45,T41-CTNNB1-1 APC p-APC p-S37,T41,S45-beta-cateninAxin,GSK3CK1alphaAPCPP2AFAM123B complex26S proteasomeADPUBCCSNK1A1p-S45,T41-CTNNB1-1 GSK3B p-APC PSMA7PSMB7 AMER1CSNK1A1AMER1 UBCUBCGSK3B APC PSMA4 PSMD7PSMB3 UBBPSMA2 CSNK1A1UBBFRAT1 GSK3B PSMB2 BTRC PSMA3 AXIN1PSME4 RPS27APSMD10 PP2Ap-S33,S37,S45,T41-CTNNB1-1 ADPAPC GSK3B PSMC6p-S33,S37,T41,S45-beta-cateninAxinCK1alphaGSK3Bphospho-APC ADPGSK3B CSNK1A1AXIN1 AMER1 APC PSMB10 UBCPSMC2 PSMD4UBCp-S33,S37,S45,T41-CTNNB1-1 p-S33,S37,S45,T41-CTNNB1-1 ATPPSMB6 FRAT1/FRAT2GSK3beta ComplexPSMD3 GSK3B beta-cateninp-APC PSMB1 ATPATPAPCPSMD9 UBCAMER1 CSNK1A1GSK3B AMER1 APC UBA52PSMD14 UBCPSMC4 ATPAXIN1 p-S45-CTNNB1-1 UBCAXIN1 AXIN1 CSNK1A1GSK3B BTRC p-APC AMER1 AxinCK1alphaGSK3Bphospho-APC PSMD2 GSK3B PSMD11 AMER1 APC PSME3 AXIN1 beta-cateninAxinGSK3CK1alphaAPCPP2AFAM123B complexCUL1 p-APC CUL1 ubiquitinated phospho-beta-cateninSCFbeta-TrCP1 complexCSNK1A1AXIN1 PSMC3 PSMA6 GSK3BPSMD6pS45-beta-cateninAxinGSK3CK1alphaAPCPP2AFAM123B complexCUL1 p-S33,S37,S45,T41-CTNNB1-1 UBBGSK3B SKP1 CTNNB1-1 AXIN1 PSME1 PSMF1ADPAXIN1 PSMA1 PSMD13 p-S33,S37,T41,S45-beta-cateninAxinCK1alphaGSK3Bphospho-APC AMER1 SCF-beta-TrCP1 complexPSMB11 AxinGSK3CK1alphaAPCPP2AFAM123B complexBTRC PSMA8 p-S33,S37,T41,S45-beta-cateninAxinGSK3CK1alphaAPCPP2AFAM123B complexAMER1 AXIN1 PSMD1 PSMB5 AMER1 PSMD8 p-S37,S45,T41-CTNNB1-1 SCF-beta-TrCP1 complex associated with phosphorylated beta-cateninAXIN1 SKP1 PSME2 UbPSMA5 PSMB9 AMER1 FRAT2 SKP1 CSNK1A1PSMC5 8, 9313


Description

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). Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=195253

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114976view16:50, 25 January 2021ReactomeTeamReactome version 75
113420view11:49, 2 November 2020ReactomeTeamReactome version 74
112622view16:00, 9 October 2020ReactomeTeamReactome version 73
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

DataNodes

View all...
NameTypeDatabase referenceComment
26S proteasomeComplexREACT_2353 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
AMER1 ProteinQ5JTC6 (Uniprot-TrEMBL)
AMER1ProteinQ5JTC6 (Uniprot-TrEMBL)
APC ProteinP25054 (Uniprot-TrEMBL)
APCProteinP25054 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
AXIN1 ProteinO15169 (Uniprot-TrEMBL)
AXIN1ProteinO15169 (Uniprot-TrEMBL)
Axin

CK1alpha GSK3B

phospho-APC 		ComplexREACT_10381 (Reactome) In this complex Axin is bound to beta-catenin.
Axin

GSK3 CK1alpha APC PP2A

FAM123B complex		ComplexREACT_10218 (Reactome)
BTRC ProteinQ9Y297 (Uniprot-TrEMBL)
CSNK1A1ProteinP48729 (Uniprot-TrEMBL)
CTNNB1-1 ProteinP35222-1 (Uniprot-TrEMBL)
CUL1 ProteinQ13616 (Uniprot-TrEMBL)
FRAT1 ProteinQ92837 (Uniprot-TrEMBL)
FRAT1/FRAT2 GSK3beta ComplexComplexREACT_76688 (Reactome)
FRAT2 ProteinO75474 (Uniprot-TrEMBL)
GSK3B ProteinP49841 (Uniprot-TrEMBL)
GSK3BProteinP49841 (Uniprot-TrEMBL)
PP2AComplexREACT_10628 (Reactome)
PSMA1 ProteinP25786 (Uniprot-TrEMBL)
PSMA2 ProteinP25787 (Uniprot-TrEMBL)
PSMA3 ProteinP25788 (Uniprot-TrEMBL)
PSMA4 ProteinP25789 (Uniprot-TrEMBL)
PSMA5 ProteinP28066 (Uniprot-TrEMBL)
PSMA6 ProteinP60900 (Uniprot-TrEMBL)
PSMA7ProteinO14818 (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)
PSMC1ProteinP62191 (Uniprot-TrEMBL)
PSMC2 ProteinP35998 (Uniprot-TrEMBL)
PSMC3 ProteinP17980 (Uniprot-TrEMBL)
PSMC4 ProteinP43686 (Uniprot-TrEMBL)
PSMC5 ProteinP62195 (Uniprot-TrEMBL)
PSMC6ProteinP62333 (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)
PSMD4ProteinP55036 (Uniprot-TrEMBL)
PSMD5 ProteinQ16401 (Uniprot-TrEMBL)
PSMD6ProteinQ15008 (Uniprot-TrEMBL)
PSMD7ProteinP51665 (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)
PSMF1ProteinQ92530 (Uniprot-TrEMBL)
RPS27AProteinP62979 (Uniprot-TrEMBL)
SCF-beta-TrCP1 complex associated with phosphorylated beta-cateninComplexREACT_10593 (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.
SCF-beta-TrCP1 complexComplexREACT_6992 (Reactome)
SKP1 ProteinP63208 (Uniprot-TrEMBL)
UBA52ProteinP62987 (Uniprot-TrEMBL)
UBBProteinP0CG47 (Uniprot-TrEMBL)
UBCProteinP0CG48 (Uniprot-TrEMBL)
UbProteinREACT_3316 (Reactome)
beta-catenin

Axin GSK3 CK1alpha APC PP2A

FAM123B complex		ComplexREACT_10837 (Reactome)
beta-cateninProteinREACT_10304 (Reactome)
p-APC ProteinP25054 (Uniprot-TrEMBL)
p-S33,S37,S45,T41-CTNNB1-1 ProteinP35222-1 (Uniprot-TrEMBL)
p-S33,S37,T41,S45-beta-catenin

Axin CK1alpha GSK3B

phospho-APC 		ComplexREACT_10660 (Reactome) In this complex Axin is bound to beta-catenin.
p-S33,S37,T41,S45-beta-catenin

Axin CK1alpha GSK3B

phospho-APC 		ComplexREACT_10886 (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-beta-catenin

Axin GSK3 CK1alpha APC PP2A

FAM123B complex		ComplexREACT_10610 (Reactome)
p-S37,S45,T41-CTNNB1-1 ProteinP35222-1 (Uniprot-TrEMBL)
p-S37,T41,S45-beta-catenin

Axin,GSK3 CK1alpha APC PP2A

FAM123B complex		ComplexREACT_10861 (Reactome)
p-S45,T41-CTNNB1-1 ProteinP35222-1 (Uniprot-TrEMBL)
p-S45-CTNNB1-1 ProteinP35222-1 (Uniprot-TrEMBL)
p-T41,S45-beta-catenin

Axin GSK3 CK1alpha APC PP2A

FAM123B complex		ComplexREACT_10844 (Reactome)
pS45-beta-catenin

Axin GSK3 CK1alpha APC PP2A

FAM123B complex		ComplexREACT_10809 (Reactome)
ubiquitinated phospho-beta-catenin

SCF

beta-TrCP1 complex		ComplexREACT_10202 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
26S proteasomemim-catalysisREACT_10017 (Reactome)
ADPArrowREACT_9955 (Reactome)
ADPArrowREACT_9959 (Reactome)
ADPArrowREACT_9978 (Reactome)
ADPArrowREACT_9983 (Reactome)
ADPArrowREACT_9987 (Reactome)
AMER1REACT_10134 (Reactome)
APCREACT_10134 (Reactome)
ATPREACT_9955 (Reactome)
ATPREACT_9959 (Reactome)
ATPREACT_9978 (Reactome)
ATPREACT_9983 (Reactome)
ATPREACT_9987 (Reactome)
AXIN1REACT_10134 (Reactome)
Axin

CK1alpha GSK3B

phospho-APC 		ArrowREACT_10017 (Reactome)
Axin

GSK3 CK1alpha APC PP2A

FAM123B complex		REACT_10111 (Reactome)
CSNK1A1REACT_10134 (Reactome)
FRAT1/FRAT2 GSK3beta ComplexTBarREACT_9955 (Reactome)
FRAT1/FRAT2 GSK3beta ComplexTBarREACT_9959 (Reactome)
FRAT1/FRAT2 GSK3beta ComplexTBarREACT_9987 (Reactome)
GSK3BREACT_10134 (Reactome)
PP2AREACT_10134 (Reactome)
REACT_10017 (Reactome) Ubiquitinated beta-catenin is degraded by the proteasome.
REACT_10082 (Reactome) Beta-catenin is ubiquitinated by the SCF-B-TrCP1 complex.
REACT_10111 (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).
REACT_10127 (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).
REACT_10134 (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.
REACT_9955 (Reactome) Following CKI-mediated phosphorylation at Ser45, beta-catenin is phosphorylated by GSK3 at Thr41.
REACT_9959 (Reactome) Phospho-(Ser45, Thr41) beta-catenin is phosphorylated by GSK3 at Ser37.
REACT_9977 (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.
REACT_9978 (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).
REACT_9983 (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).
REACT_9987 (Reactome) Beta-catenin is then phosphorylated at Ser33. Phosphorylated S37 and S33 together with neighboring residues constitute the recognition motif for beta-TrCP.
SCF-beta-TrCP1 complex associated with phosphorylated beta-cateninREACT_10082 (Reactome)
SCF-beta-TrCP1 complexArrowREACT_10017 (Reactome)
SCF-beta-TrCP1 complexREACT_9977 (Reactome)
UbArrowREACT_10017 (Reactome)
UbREACT_10082 (Reactome)
beta-catenin

Axin GSK3 CK1alpha APC PP2A

FAM123B complex		REACT_9978 (Reactome)
beta-catenin

Axin GSK3 CK1alpha APC PP2A

FAM123B complex		mim-catalysisREACT_9978 (Reactome)
beta-cateninREACT_10111 (Reactome)
p-S33,S37,T41,S45-beta-catenin

Axin CK1alpha GSK3B

phospho-APC 		ArrowREACT_9983 (Reactome)
p-S33,S37,T41,S45-beta-catenin

Axin CK1alpha GSK3B

phospho-APC 		REACT_9977 (Reactome)
p-S33,S37,T41,S45-beta-catenin

Axin GSK3 CK1alpha APC PP2A

FAM123B complex		ArrowREACT_9987 (Reactome)
p-S33,S37,T41,S45-beta-catenin

Axin GSK3 CK1alpha APC PP2A

FAM123B complex		REACT_9983 (Reactome)
p-S33,S37,T41,S45-beta-catenin

Axin GSK3 CK1alpha APC PP2A

FAM123B complex		mim-catalysisREACT_9983 (Reactome)
p-S37,T41,S45-beta-catenin

Axin,GSK3 CK1alpha APC PP2A

FAM123B complex		ArrowREACT_9959 (Reactome)
p-S37,T41,S45-beta-catenin

Axin,GSK3 CK1alpha APC PP2A

FAM123B complex		REACT_9987 (Reactome)
p-S37,T41,S45-beta-catenin

Axin,GSK3 CK1alpha APC PP2A

FAM123B complex		mim-catalysisREACT_9987 (Reactome)
p-T41,S45-beta-catenin

Axin GSK3 CK1alpha APC PP2A

FAM123B complex		ArrowREACT_9955 (Reactome)
p-T41,S45-beta-catenin

Axin GSK3 CK1alpha APC PP2A

FAM123B complex		REACT_9959 (Reactome)
p-T41,S45-beta-catenin

Axin GSK3 CK1alpha APC PP2A

FAM123B complex		mim-catalysisREACT_9959 (Reactome)
pS45-beta-catenin

Axin GSK3 CK1alpha APC PP2A

FAM123B complex		ArrowREACT_9978 (Reactome)
pS45-beta-catenin

Axin GSK3 CK1alpha APC PP2A

FAM123B complex		REACT_9955 (Reactome)
pS45-beta-catenin

Axin GSK3 CK1alpha APC PP2A

FAM123B complex		mim-catalysisREACT_9955 (Reactome)
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