BioPAX pathway converted from "Disassembly of the destruction complex and recruitment of AXIN to the membrane" in the Reactome database.Disassembly of the destruction complex and recruitment of AXIN to the membraneDisassembly of the destruction complex and recruitment of AXIN to the membraneThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>FRAT proteins bind GSK3betaFRAT proteins bind GSK3betaThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 1986191cytosolGO0005829UniProt:P18266 Gsk3bGsk3bGsk3bFUNCTION Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1. Requires primed phosphorylation of the majority of its substrates. In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. May also mediate the development of insulin resistance by regulating activation of transcription factors. Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase. In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes. Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin. Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules. Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair. Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation. Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin. Is necessary for the establishment of neuronal polarity and axon outgrowth. Phosphorylates MARK2, leading to inhibit its activity. Phosphorylates SIK1 at 'Thr-182', leading to sustain its activity. Phosphorylates ZC3HAV1 which enhances its antiviral activity. Phosphorylates SFPQ upon T-cell activation. Phosphorylates SNAI1, leading to its BTRC-triggered ubiquitination and proteasomal degradation. Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and stabilizes it by protecting it from proteasomal degradation. Regulates the circadian clock via phosphorylation of the major clock components including ARNTL/BMAL1, CLOCK and PER2 (By similarity). Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal degradation (By similarity). Phosphorylates ARNTL/BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination and proteasomal degradation (By similarity). Phosphorylates OGT at 'Ser-3' or 'Ser-4' which positively regulates its activity (By similarity). Regulates the circadian rhythmicity of hippocampal long-term potentiation and ARNTL/BMLA1 and PER2 expression (By similarity). Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions, leading to activate KAT5/TIP60 acetyltransferase activity and promote acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (By similarity). Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation (By similarity).ACTIVITY REGULATION Activated by phosphorylation at Tyr-216. In response to insulin, inhibited by phosphorylation at Ser-9 by PKB/AKT1; phosphorylation at this site causes a conformational change, preventing access of substrates to the active site. Inhibited by lithium.SUBUNIT Monomer (By similarity). Interacts with DAB2IP (via C2 domain); the interaction stimulates GSK3B kinase activation (By similarity). Interacts (via C2 domain) with PPP2CA (By similarity). Interacts with ARRB2, AXIN1, CABYR, DISC1, MMP2, MUC1, NIN, PRUNE1 and ZBED3 (By similarity). Interacts with AXIN1; the interaction mediates hyperphosphorylation of CTNNB1 leading to its ubiquitination and destruction (PubMed:9482734). Interacts with and phosphorylates SNAI1 (By similarity). Interacts with DNM1L (via a C-terminal domain) (By similarity). Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B (PubMed:16815997). Interacts with SGK3 (By similarity). Interacts with the CLOCK-ARNTL/BMAL1 heterodimer (By similarity). Interacts with the ARNTL/BMAL1 (By similarity). Interacts with CTNND2 (By similarity). The complex composed, at least, of APC, CTNNB1 and GSK3B interacts with JPT1; the interaction requires the inactive form of GSK3B (phosphorylated at 'Ser-9') (By similarity). Forms a complex composed of PRKAR2A or PRKAR2B, GSK3B and GSKIP through GSKIP interaction; facilitates PKA-induced phosphorylation and regulates GSK3B activity (By similarity). Interacts with GSKIP (By similarity). Interacts with GID8 (By similarity). Interacts with PIWIL2 (By similarity). Interacts with LMBR1L (By similarity). Interacts with DDX3X (By similarity). Interacts with BIRC2 (By similarity). Interacts with TNFRSF10B; TNFRSF10B stimulation inhibits GSK3B kinase activity (By similarity).PTM Phosphorylated by AKT1 and ILK1. Upon insulin-mediated signaling, the activated PKB/AKT1 and RPS6KA3 protein kinases phosphorylate and desactivate GSK3B, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-216 (By similarity). Inactivated by phosphorylation at Ser-9 (By similarity). Phosphorylated in a circadian manner in the hippocampus (By similarity).PTM Mono-ADP-ribosylation by PARP10 negatively regulates kinase activity.MISCELLANEOUS Simultaneous silencing of GSK3A and GSK3B by RNAi stimulates replication and promotes survival of INS-1E pancreatic beta cells.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. GSK-3 subfamily.Reactomehttp://www.reactome.orgRattus norvegicusNCBI Taxonomy10116UniProtP18266Chain Coordinates1EQUAL420EQUALConverted from EntitySet in ReactomeReactome DB_ID: 98394781FRAT1,2 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityFrat2 [cytosol]Peg12 [cytosol]UniProtM0R5Z2UniProtD3Z8R0Reactome DB_ID: 98394801FRAT1,2:GSK3beta [cytosol]FRAT1,2:GSK3betaReactome DB_ID: 19861911EQUAL420EQUALConverted from EntitySet in ReactomeReactome DB_ID: 98394781Reactome Database ID Release 759839480Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9839480ReactomeR-RNO-12260521Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-1226052.1Reactome Database ID Release 759893247Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9893247ReactomeR-RNO-53235261Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5323526.1The FRAT genes, which were initially identified as a target of Frequent Rearrangement in Advanced T-cell lymphoma, encode potent activators of canonical WNT signaling and are highly conserved in vertebrates. Xenopus and zebrafish each have one FRAT gene, while the human and mouse genomes contains two and three, respectively (Jonkers et al, 1997; reviewed in van Amerongen and Berns, 2005). Frat proteins activate WNT signaling by binding to GSK3beta and inhibiting its phosphorylation of beta-catenin (Yost et al, 1998; van Amerongen et al, 2004). The interaction with GSK3beta is mediated by a highly conserved IKEA box in the C-terminal domain of FRAT (Yost et al, 1998; van Amerongen et al, 2004; Thomas et al, 1999). This region of FRAT is able to compete with AXIN for binding to GSK3beta, suggesting a model where FRAT is able to destabilize the destruction complex by abrogating the GSK3beta-AXIN interaction (Farr et al, 2000; Thomas et al, 1999; Fraser at el, 2002; Ferkey et al, 2002). This model is supported by structural studies showing that AXIN and FRAT bind to the same region on the surface of GSK3beta (Bax et al, 2001; Dajani et al, 2003). Endogenous FRAT1 has also been shown to interact with DVL3, and this reaction persists in a FRAT1 mutant lacking the GSK3beta-interacting domain (Li et al, 1999). FRAT proteins may thus help bridge between GSK3beta’s role in the destruction complex and its role in activating signaling in response to WNT.<br><br>Despite the apparent importance of FRAT proteins in beta-catenin-dependent signaling, a triple FRAT knockout mouse shows no readily evident defects in canonical signaling and, unlike the GBP knockout in Xenopus, no overt phenotypic defects (van Amerongen et al, 2005; Yost et al, 1989). The in vivo role and significance of the FRAT proteins in WNT signaling remains to be resolved; it is worth noting, however, that FRAT proteins have also recently been shown to be involved in non-canonical WNT signaling in a GSK3beta-independent manner. It is possible that it is through this non-canonical role that FRAT proteins contribute to oncogenesis (van Amerongen et al, 2010; Walf-Vorderwülbecke et al, 2012).11707456Pubmed2002Identification of the Axin and Frat binding region of glycogen synthase kinase-3Fraser, ElizabethYoung, NevilleDajani, RanaFranca-Koh, JonathanRyves, JonathanWilliams, Robin S BYeo, MargaretWebster, Marie-ThereseRichardson, ChrisSmalley, Matthew JPearl, Laurence HHarwood, AdrianDale, Trevor CJ. Biol. Chem. 277:2176-8510428961Pubmed1999Axin and Frat1 interact with dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1Li, LYuan, HuidongWeaver, Carole DMao, JunhaoFarr, Gist HSussman, Daniel JJonkers, JosKimelman, DavidWu, DianqingEMBO J. 18:4233-4016082208Pubmed2005Re-evaluating the role of Frat in Wnt-signal transductionvan Amerongen, RBerns, AntonCell Cycle 4:1065-7211861647Pubmed2002Glycogen synthase kinase-3 beta mutagenesis identifies a common binding domain for GBP and AxinFerkey, Denise MKimelman, DavidJ. Biol. Chem. 277:16147-5211738041Pubmed2001The structure of phosphorylated GSK-3beta complexed with a peptide, FRATtide, that inhibits beta-catenin phosphorylationBax, BenjaminCarter, Paul SLewis, CeriGuy, Angela RBridges, AngelaTanner, RobertPettman, GaryMannix, ChrisCulbert, Ainsley ABrown, Murray JSmith, David GReith, Alastair DStructure 9:1143-5210481074Pubmed1999A GSK3-binding peptide from FRAT1 selectively inhibits the GSK3-catalysed phosphorylation of axin and beta-cateninThomas, Gareth MFrame, SheelaghGoedert, MichelNathke, InkePolakis, PaulCohen, PFEBS Lett. 458:247-5123074275Pubmed2012Frat2 mediates the oncogenic activation of Rac by MLL fusionsWalf-Vorderwülbecke, Vanessade Boer, JasperHorton, Sarah Jvan Amerongen, RProost, NatalieBerns, AntonWilliams, OwenBlood 120:4819-2819802005Pubmed2010Frat oncoproteins act at the crossroad of canonical and noncanonical Wnt-signaling pathwaysvan Amerongen, RNawijn, M CLambooij, J-PProost, NJonkers, JosBerns, AntonOncogene 29:93-10415073180Pubmed2004Characterization and functional analysis of the murine Frat2 genevan Amerongen, Rvan der Gulden, HannekeBleeker, FonnetJonkers, JosBerns, AntonJ. Biol. Chem. 279:26967-749034327Pubmed1997Activation of a novel proto-oncogene, Frat1, contributes to progression of mouse T-cell lymphomasJonkers, JosKorswagen, Hendrik CActon, DennisBreuer, MarcoBerns, AntonEMBO J. 16:441-5010684251Pubmed2000Interaction among GSK-3, GBP, axin, and APC in Xenopus axis specificationFarr, Gist HFerkey, Denise MYost, CynthiaPierce, Sarah BWeaver, CaroleKimelman, DavidJ. Cell Biol. 148:691-70215681612Pubmed2005Frat is dispensable for canonical Wnt signaling in mammalsvan Amerongen, RNawijn, MartijnFranca-Koh, JonathanZevenhoven, Johnvan der Gulden, HannekeJonkers, JosBerns, AntonGenes Dev. 19:425-3012554650Pubmed2003Structural basis for recruitment of glycogen synthase kinase 3beta to the axin-APC scaffold complexDajani, RFraser, ERoe, S MarkYeo, MGood, VMThompson, VDale, TCPearl, Laurence HEMBO J 22:494-5019635432Pubmed1998GBP, an inhibitor of GSK-3, is implicated in Xenopus development and oncogenesisYost, CynthiaFarr, Gist HPierce, Sarah BFerkey, Denise MChen, Michelle MingziKimelman, DavidCell 93:1031-41inferred by electronic annotationIEAGOIEADVL recruits GSK3beta:AXIN1 to the receptor complexDVL recruits GSK3beta:AXIN1 to the receptor complexThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 98415631GSK3B:AXIN1 [cytosol]GSK3B:AXIN1Reactome DB_ID: 98415611Ghost homologue of AXIN1 [cytosol]Ghost homologue of AXIN1Reactome DB_ID: 19861911EQUAL420EQUALReactome Database ID Release 759841563Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9841563ReactomeR-RNO-15042041Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-1504204.1Reactome DB_ID: 98416241plasma membraneGO0005886WNT:FZD:LRP5/6:DVL [plasma membrane]WNT:FZD:LRP5/6:DVLConverted from EntitySet in ReactomeReactome DB_ID: 98416221pp-DVL [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityphospho-Dvl3 [cytosol]phospho-Dvl1 [cytosol]phospho-Dvl2 [cytosol]UniProtD4ADV8UniProtQ9WVB9UniProtD3ZB71Reactome DB_ID: 98416091WNT:FZD:LRP5/6 [plasma membrane]WNT:FZD:LRP5/6Converted from EntitySet in ReactomeReactome DB_ID: 98416071extracellular regionGO0005576canonical WNTs [extracellular region]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityWnt3a [extracellular region]Wnt8b [extracellular region]Wnt8a [extracellular region]Wnt1 [extracellular region]UniProtF1M077UniProtD3ZND6UniProtD4A9D7UniProtD4A9J2Converted from EntitySet in ReactomeReactome DB_ID: 98415811canonical FZD receptors [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityFzd1 [plasma membrane]Fzd2 [plasma membrane]UniProtQ08463UniProtQ08464Converted from EntitySet in ReactomeReactome DB_ID: 98415731LRP5/6 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityLrp6 [plasma membrane]UniProtA0A0G2K0H3Reactome Database ID Release 759841609Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9841609ReactomeR-RNO-14588761Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-1458876.1Reactome Database ID Release 759841624Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9841624ReactomeR-RNO-15041921Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-1504192.1Reactome DB_ID: 98416261WNT:FZD:LRP5/6:DVL:AXIN:GSK3B [plasma membrane]WNT:FZD:LRP5/6:DVL:AXIN:GSK3BReactome DB_ID: 98415631Reactome DB_ID: 98416241Reactome Database ID Release 759841626Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9841626ReactomeR-RNO-15041841Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-1504184.1Reactome Database ID Release 759872708Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9872708ReactomeR-RNO-15041861Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-1504186.1The DIX domains of DVL and AXIN interact and this interaction brings GSK3beta:AXIN1 to the receptor complex (Schwarz-Romond et al, 2007). Subsequently, sequential phosphorylation of LRP5/6 by GSK3beta and CSNK1 generates high affinity AXIN binding sites and functions to amplify recruitment to the membrane (Mao et al, 2001; Zeng et al, 2008). In some models, this recruitment of AXIN to the membrane is facilitated by clustering of DVL and/or LRP5/6 into a 'signalosome' (Bilic et al, 2007).11336703Pubmed2001Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathwayMao, JWang, JLiu, BPan, WFarr GH, 3rdFlynn, CYuan, HTakada, SKimelman, DLi, LWu, DMol Cell 7:801-917529994Pubmed2007The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerizationSchwarz-Romond, ThomasFiedler, MarcShibata, NaokiButler, P Jonathan GKikuchi, AkiraHiguchi, YoshikiBienz, MNat. Struct. Mol. Biol. 14:484-9218077588Pubmed2008Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functionsZeng, XHuang, HTamai, KZhang, XHarada, YYokota, CAlmeida, KWang, JDoble, BWoodgett, JWynshaw-Boris, AHsieh, JCHe, XiDevelopment 135:367-7517569865Pubmed2007Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylationBilic, JHuang, YLDavidson, GaryZimmermann, TCruciat, CMBienz, MNiehrs, CScience 316:1619-22inferred by electronic annotationIEAGOIEA2.7.11Phosphorylation of LRP5/6 cytoplasmic domain by membrane-associated GSK3betaPhosphorylation of LRP5/6 cytoplasmic domain by membrane-associated GSK3betaThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 98416261Reactome DB_ID: 1135925ATP(4-) [ChEBI:30616]ATP(4-)Adenosine 5'-triphosphateatpATPChEBI30616Reactome DB_ID: 293705ADP(3-) [ChEBI:456216]ADP(3-)ADP trianion5&apos;-O-[(phosphonatooxy)phosphinato]adenosineADPChEBI456216Reactome DB_ID: 98416391WNT:FZD:p5S/T-LRP5/6:DVL:AXIN:GSK3B [plasma membrane]WNT:FZD:p5S/T-LRP5/6:DVL:AXIN:GSK3BConverted from EntitySet in ReactomeReactome DB_ID: 98416071Reactome DB_ID: 98415631Converted from EntitySet in ReactomeReactome DB_ID: 98416371p5S/T-LRP5/6 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityphospho-Lrp6 [plasma membrane]phospho-Lrp5 [plasma membrane]UniProtF1MAD0Converted from EntitySet in ReactomeReactome DB_ID: 98415811Converted from EntitySet in ReactomeReactome DB_ID: 98416221Reactome Database ID Release 759841639Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9841639ReactomeR-RNO-14588971Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-1458897.1PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 9841626GO0004674GO molecular functionReactome Database ID Release 759841640Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9841640Reactome Database ID Release 759841642Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9841642ReactomeR-RNO-2016771Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-201677.1LRP5/6 contains 5 PPP(S/T)PxS motifs in its intracellular domain which have been shown to be phosphorylated by a membrane-associated pool of GSK3beta. Individual phosphorylation of each of these motifs promotes interaction with AXIN and stimulates WNT signaling as assessed by activation of a TCF/beta-catenin responsive reporter (Tamai et al, 2004; Zeng et al, 2005; MacDonald et al, 2008). In the context of full length LRP6, phosphorylation of the five motifs shows cooperative stimulation of AXIN binding and WNT signaling. GSK3beta-mediated phosphorylation of LRP6 is thought to prime the receptor for subsequent phosphorylation by CSNK1 (Zeng et al, 2005; reviewed in He et al, 2004).16341017Pubmed2005A dual-kinase mechanism for Wnt co-receptor phosphorylation and activationZeng, XTamai, KDoble, BLi, SHuang, HHabas, RaymondOkamura, HWoodgett, JHe, XiNature 438:873-715084453Pubmed2004LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the wayHe, XiSemenov, MTamai, KZeng, XDevelopment 131:1663-7714731402Pubmed2004A mechanism for Wnt coreceptor activationTamai, KZeng, XLiu, CZhang, XHarada, YChang, ZHe, XiMol Cell 13:149-5618362152Pubmed2008Wnt signal amplification via activity, cooperativity, and regulation of multiple intracellular PPPSP motifs in the Wnt co-receptor LRP6MacDonald, BTYokota, CTamai, KZeng, XHe, XiJ Biol Chem 283:16115-23inferred by electronic annotationIEAGOIEAWNT3A stimulates the caveolin-dependent internalization of FZD5:p-LRP6WNT3A stimulates the caveolin-dependent internalization of FZD5:p-LRP6This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 98940091WNT3A:FZD5:p-LRP6:GSK3B:AXIN:CAV1 [plasma membrane]WNT3A:FZD5:p-LRP6:GSK3B:AXIN:CAV1Reactome DB_ID: 98415931UniProt:F1M077Wnt3aN4-glycosyl-L-asparagine at unknown positionN4-glycosyl-L-asparagineO-palmitoleyl-L-serine at 209 (in Homo sapiens)209EQUALO-palmitoleyl-L-serine19EQUAL352EQUALReactome DB_ID: 98417901UniProt:P41350 Cav1Cav1Cav1CavFUNCTION May act as a scaffolding protein within caveolar membranes. Forms a stable heterooligomeric complex with CAV2 that targets to lipid rafts and drives caveolae formation. Mediates the recruitment of CAVIN proteins (CAVIN1/2/3/4) to the caveolae (By similarity). Interacts directly with G-protein alpha subunits and can functionally regulate their activity (By similarity). Involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. Its binding to DPP4 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner (By similarity). Recruits CTNNB1 to caveolar membranes and may regulate CTNNB1-mediated signaling through the Wnt pathway (By similarity). Negatively regulates TGFB1-mediated activation of SMAD2/3 by mediating the internalization of TGFBR1 from membrane rafts leading to its subsequent degradation (By similarity).SUBUNIT Homooligomer. Interacts (via the N-terminus) with DPP4; the interaction is direct. Forms a stable heterooligomeric complex with CAV2 that targets to lipid rafts and drives caveolae formation. Interacts with PACSIN2; this interaction induces membrane tubulation (By similarity). Interacts with BMX, BTK, CTNNB1, CDH1, GLIPR2, JUP and NOSTRIN (By similarity). Interacts with SNAP25 and STX1A (PubMed:11883949). Interacts with SLC7A9 (PubMed:16358225). Interacts with TGFBR1. Interacts with CAVIN3 (via leucine-zipper domain) in a cholesterol-sensitive manner. Interacts with CAVIN1. Interacts with EHD2 in a cholesterol-dependent manner (By similarity). Forms a ternary complex with UBXN6 and VCP; mediates CAV1 targeting to lysosomes for degradation (By similarity). Interacts with ABCG1; this interaction regulates ABCG1-mediated cholesterol efflux (By similarity). Interacts with NEU3; this interaction enhances NEU3 sialidase activity within caveola.TISSUE SPECIFICITY Cortex and inner medulla of kidney (at protein level). Expressed in the hippocampus.PTM Phosphorylated at Tyr-14 by ABL1 in response to oxidative stress.PTM Ubiquitinated. Undergo monoubiquitination and multi- and/or polyubiquitination. Monoubiquitination of N-terminal lysines promotes integration in a ternary complex with UBXN6 and VCP which promotes oligomeric CAV1 targeting to lysosomes for degradation.SIMILARITY Belongs to the caveolin family.UniProtP413502EQUAL178EQUALReactome DB_ID: 98415631Reactome DB_ID: 98897001UniProt:Q8CHL0Fzd5UniProtQ8CHL027EQUAL585EQUALReactome DB_ID: 98416521UniProt:A0A0G2K0H3Lrp6O-phospho-L-serine at 1490 (in Homo sapiens)1490EQUALO-phospho-L-serine [MOD:00046]O-phospho-L-threonine at 1479 (in Homo sapiens)1479EQUALO-phospho-L-threonine [MOD:00047]O-phospho-L-threonine at 1493 (in Homo sapiens)1493EQUALO-phospho-L-threonine at unknown positionO-phospho-L-threonine at unknown positionO-phospho-L-threonine at unknown positionO-phospho-L-serine at unknown positionO-phospho-L-serine at unknown positionO-phospho-L-serine at unknown positionO-phospho-L-serine at unknown position20EQUAL1613EQUALReactome Database ID Release 759894009Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894009ReactomeR-RNO-53685211Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5368521.1Reactome DB_ID: 98940191early endosome membraneGO0031901WNT3A:FZD5:p-LRP6:GSK3B:AXIN:CAV1 [early endosome membrane]WNT3A:FZD5:p-LRP6:GSK3B:AXIN:CAV1Reactome DB_ID: 98940171O-phospho-L-serine at 1490 (in Homo sapiens)1490EQUALO-phospho-L-threonine at 1479 (in Homo sapiens)1479EQUALO-phospho-L-threonine at 1493 (in Homo sapiens)1493EQUALO-phospho-L-threonine at unknown positionO-phospho-L-threonine at unknown positionO-phospho-L-threonine at unknown positionO-phospho-L-serine at unknown positionO-phospho-L-serine at unknown positionO-phospho-L-serine at unknown positionO-phospho-L-serine at unknown position20EQUAL1613EQUALReactome DB_ID: 98415631Reactome DB_ID: 989401112EQUAL178EQUALReactome DB_ID: 98940151N4-glycosyl-L-asparagine at unknown positionO-palmitoleyl-L-serine at 209 (in Homo sapiens)209EQUAL19EQUAL352EQUALReactome DB_ID: 9894013127EQUAL585EQUALReactome Database ID Release 759894019Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894019ReactomeR-RNO-53685191Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5368519.1Reactome Database ID Release 759894021Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9894021ReactomeR-RNO-53685961Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-5368596.1After stimulation by WNT3A, FZD5 and phosphorylated LRP6 are internalized from lipid rafts in a caveolin- and RAB5-dependent manner (Yamamoto et al, 2006; Yamamoto et al, 2008). Recruitment of CAV1 to the activated receptor complex inhibits the binding of beta-catenin to AXIN in the destruction complex, resulting in the accumulation of cytosolic beta-catenin and the induction of WNT-dependent signaling (Yamamoto et al, 2006; Yamamoto et al, 2008).18606139Pubmed2008Wnt3a and Dkk1 regulate distinct internalization pathways of LRP6 to tune the activation of beta-catenin signalingYamamoto, HidekiSakane, HiroshiYamamoto, HidekiMichiue, TatsuoKikuchi, AkiraDev. Cell 15:37-4816890161Pubmed2006Caveolin is necessary for Wnt-3a-dependent internalization of LRP6 and accumulation of beta-cateninYamamoto, HidekiKomekado, HideyukiKikuchi, AkiraDev. Cell 11:213-23inferred by electronic annotationIEAGOIEABeta-catenin is released from the destruction complexBeta-catenin is released from the destruction complexThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 98416461CTNNB1:AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complex [cytosol]CTNNB1:AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexReactome DB_ID: 98394951UniProt:Q9WU82Ctnnb1UniProtQ9WU821EQUAL781EQUALReactome DB_ID: 98416441AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complex [cytosol]AXIN:GSK3:CK1alpha:ub-APC:PP2A:AMER1 complexReactome DB_ID: 98415611Reactome DB_ID: 98394271UniProt:D3ZCP6Amer1UniProtD3ZCP61EQUAL1135EQUALReactome DB_ID: 98394231UniProt:P97633 Csnk1a1Csnk1a1Csnk1a1FUNCTION Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. It can phosphorylate a large number of proteins. Participates in Wnt signaling. Phosphorylates CTNNB1 at 'Ser-45'. May phosphorylate PER1 and PER2. May play a role in segregating chromosomes during mitosis. May play a role in keratin cytoskeleton disassembly and thereby, it may regulate epithelial cell migration (By similarity).SUBUNIT Monomer. Interacts with the Axin complex. Interacts with TUT1, leading to TUT1 phosphorylation. Interacts with FAM83H; recruits CSNK1A1 to keratin filaments.SIMILARITY Belongs to the protein kinase superfamily. CK1 Ser/Thr protein kinase family. Casein kinase I subfamily.UniProtP976332EQUAL337EQUALReactome DB_ID: 19861911EQUAL420EQUALReactome DB_ID: 98311241PP2A [cytosol]PP2AConverted from EntitySet in ReactomeReactome DB_ID: 98311161PP2A-subunit A [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityConverted from EntitySet in ReactomeReactome DB_ID: 98311221PP2A-catalytic subunit C [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityConverted from EntitySet in ReactomeReactome DB_ID: 98311101PP2A regulatory subunit B56 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityReactome Database ID Release 759831124Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9831124ReactomeR-RNO-1962061Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-196206.1Reactome DB_ID: 98394351UniProt:P70478ApcUniProtP70478ubiquitinylated lysine (K63polyUb [cytosol]) at unknown positionubiquitinylated lysine [MOD:01148]1EQUAL2843EQUALReactome Database ID Release 759841644Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9841644ReactomeR-RNO-1952501Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-195250.1Reactome Database ID Release 759841646Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9841646ReactomeR-RNO-44167371Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-4416737.1Reactome DB_ID: 983942711EQUAL1135EQUALReactome DB_ID: 98415631Reactome DB_ID: 983942312EQUAL337EQUALReactome DB_ID: 983949511EQUAL781EQUALReactome DB_ID: 98311241Reactome DB_ID: 98394351ubiquitinylated lysine (K63polyUb [cytosol]) at unknown position1EQUAL2843EQUALReactome Database ID Release 759841658Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9841658ReactomeR-RNO-2016851Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-201685.1Stimulation of the WNT pathway results in the recruitment of the GSK3beta:AXIN complex to the membrane (Willert et al, 1999; Schwarz Romond et al, 2007; Bilic et al, 2007; reviewed in Saito-Diaz et al, 2013). Activation of WNT signaling is believed to transiently inhibit GSK3beta kinase activity preventing its phosphorylation of beta-catenin (described in detail in the pathway "Degradation of beta-catenin by the destruction complex"; Piao et al, 2008; reviewed in Saito-Diaz et al, 2013). Inhibition of GSK3beta activity also prevents phosphorylation of AXIN allowing the constitutive dephosphorylation of AXIN at GSK3beta-dependent phosphorylation sites by PP2A predominate. This is believed to weaken the interaction between AXIN and beta-catenin (Willert et al, 1999). AXIN has also been shown to be dephosphorylated by PP1 at several serinve residues initially phosphorylated by CSNK1. The dephosphorylation by PP1 weakens the interaction between AXIN-GSK3beta and inhibits beta-catenin phosphorylation/degradation (Luo et al, 2007; reviewed in Huang et al, 2008). A recent study suggests that sustained inactivation of GSK3beta may result from its sequestration in multivesicular bodies (Taelman et al, 2010; reviewed in Niehrs and Acebon, 2010; Schuldt, 2011). Together, these changes destabilize the destruction complex and allow beta-catenin to accumulate.18339531Pubmed2008Wnt/beta-catenin signaling: new (and old) players and new insightsHuang, HeHe, XiCurr. Opin. Cell Biol. 20:119-2523256519Pubmed2013The way Wnt works: Components and mechanismSaito-Diaz, KenyiChen, Tony WWang, XiaoxiThorne, Curtis AWallace, Heather APage-McCaw, AndreaLee, EthanGrowth Factors 31:1-3110421629Pubmed1999Wnt-induced dephosphorylation of axin releases beta-catenin from the axin complexWillert, KShibamoto, SNusse, RoelGenes Dev 13:1768-7319107203Pubmed2008Direct inhibition of GSK3beta by the phosphorylated cytoplasmic domain of LRP6 in Wnt/beta-catenin signalingPiao, ShunfuLee, Sun-HyeKim, HyunjoonYum, SoohwanStamos, Jennifer LXu, YongbinLee, Su-JinLee, JaewonOh, SangtaekHan, JKPark, Bum-JoonWeis, William IHa, Nam-ChulPLoS ONE 3:e404621183076Pubmed2010Wnt signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomesTaelman, Vincent FDobrowolski, RadoslawPlouhinec, Jean-LouisFuentealba, Luis CVorwald, Peggy PGumper, IwonaSabatini, David DDe Robertis, Edward MCell 143:1136-4821252990Pubmed2011Membrane trafficking: a GSK3 lockdownSchuldt, AlisonNat. Rev. Mol. Cell Biol. 12:7217318175Pubmed2007Protein phosphatase 1 regulates assembly and function of the beta-catenin degradation complexLuo, WenPeterson, AnnitaGarcia, Benjamin ACoombs, GaryKofahl, BenteHeinrich, ReinhartShabanowitz, JeffreyHunt, Donald FYost, H JosephVirshup, David MEMBO J. 26:1511-2121183070Pubmed2010Wnt signaling: multivesicular bodies hold GSK3 captiveNiehrs, CAcebron, Sergio PCell 143:1044-6inferred by electronic annotationIEAGOIEAACTIVATIONReactome Database ID Release 759841659Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9841659Reactome DB_ID: 9841656WNT:FZD:p10S/T-LRP5/6:DVL:AXIN:GSK3B [plasma membrane]WNT:FZD:p10S/T-LRP5/6:DVL:AXIN:GSK3BConverted from EntitySet in ReactomeReactome DB_ID: 98416071Reactome DB_ID: 98415631Converted from EntitySet in ReactomeReactome DB_ID: 98415811Converted from EntitySet in ReactomeReactome DB_ID: 98416541p10S/T-LRP5/6 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityphospho-Lrp5 [plasma membrane]phospho-Lrp6 [plasma membrane]Converted from EntitySet in ReactomeReactome DB_ID: 98416221Reactome Database ID Release 759841656Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9841656ReactomeR-RNO-14588901Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-1458890.1Reactome Database ID Release 759928832Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9928832ReactomeR-RNO-46412621Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-4641262.1GO1904886GO biological processUpon stimulation with WNT ligand, AXIN and GSK3beta are recruited to the plasma membrane through interaction with DVL (Tamai et al, 2004; Mao et al, 2001; reviewed in He et al, 2004). Polymerization of membrane-associated DVL and GSK3beta- and CSNK1-mediated phosphorylation of LRP5/6 establish a feed-forward mechanism for enhanced membrane recruitment of AXIN upon WNT signaling (Tamai et al, 2004; Cong et al, 2004; Zeng et al, 2005; Bilic et al, 2007). In Xenopus oocytes, but not necessarily all sytems, AXIN is present in limiting concentrations and is considered rate limiting for the assembly of the destruction complex (Lee et al, 2003; Benchabane et al, 2008; Tan et al, 2012; reviewed in MacDonald et al, 2009). The recruitment of AXIN away from the destruction complex upon WNT stimulation effectively destabilizes the destruction complex and contributes to the accumulation of free beta-catenin (Kikuchi, 1999; Lee et al, 2003). AXIN association with the destruction complex is also regulated by phosphorylation. In the active destruction complex, AXIN is phosphorylated by GSK3beta; dephosphorylation by protein phosphatase 1 (PP1) or protein phosphatase 2A (PP2A) destabilizes the interaction of AXIN with the other components of the destruction complex and promotes its disassembly (Luo et al, 2007; Willert et al, 1999; Jho et al, 1999). Free AXIN is also subject to degradation by the 26S proteasome in a manner that depends on the poly-ADP-ribosylating enzymes tankyrase 1 and 2 (Huang et al, 2009). <br>19759537Pubmed2009Tankyrase inhibition stabilizes axin and antagonizes Wnt signallingHuang, Shih-Min AMishina, Yuji MLiu, ShanmingCheung, AtwoodStegmeier, FrankMichaud, Gregory ACharlat, OlgaWiellette, ElizabethZhang, YWiessner, StephanieHild, MarcShi, XiaoyingWilson, Christopher JMickanin, CraigMyer, VicFazal, AleemTomlinson, RonaldSerluca, FabrizioShao, WenlinCheng, HongShultz, MichaelRau, ChristinaSchirle, MarkusSchlegl, JudithGhidelli, SonjaFawell, StephenLu, ChrisCurtis, DanielKirschner, Marc WLengauer, ChristophFinan, Peter MTallarico, John ABouwmeester, TewisPorter, Jeffery ABauer, ACong, FNature 461:614-2022363759Pubmed2012Wnt signalling pathway parameters for mammalian cellsTan, Chin WeeGardiner, Bruce SHirokawa, YumikoLayton, Meredith JSmith, David WBurgess, Antony WPLoS ONE 7:e3188210647780Pubmed1999Modulation of Wnt signaling by Axin and AxilKikuchi, AkiraCytokine Growth Factor Rev. 10:255-6518234723Pubmed2008Adenomatous polyposis coli is present near the minimal level required for accurate graded responses to the Wingless morphogenBenchabane, HassinaHughes, Edward GTakacs, Carter MBaird, Jason RAhmed, YashiDevelopment 135:963-7110581160Pubmed1999A GSK3beta phosphorylation site in axin modulates interaction with beta-catenin and Tcf-mediated gene expressionJho, ELomvardas, SCostantini, FBiochem Biophys Res Commun 266:28-3515459103Pubmed2004Wnt signals across the plasma membrane to activate the beta-catenin pathway by forming oligomers containing its receptors, Frizzled and LRPCong, FSchweizer, LVarmus, HDevelopment 131:5103-1519619488Pubmed2009Wnt/beta-catenin signaling: components, mechanisms, and diseasesMacDonald, BTTamai, KHe, XiDev Cell 17:9-2614551908Pubmed2003The roles of APC and Axin derived from experimental and theoretical analysis of the Wnt pathwayLee, ESalic, AKruger, RHeinrich, RKirschner, Marc WPLoS Biol 1:E10inferred by electronic annotationIEAGOIEA