Disassembly of the destruction complex and recruitment of AXIN to the membrane

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R-HSA-4641262
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Pathway
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Homo sapiens
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Upon 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).

Literature References
PubMed ID Title Journal Year
14551908 The roles of APC and Axin derived from experimental and theoretical analysis of the Wnt pathway

Lee, E, Salic, A, Kruger, R, Heinrich, R, Kirschner, MW

PLoS Biol 2003
11336703 Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway

Mao, J, Wang, J, Liu, B, Pan, W, Farr GH, 3rd, Flynn, C, Yuan, H, Takada, S, Kimelman, D, Li, L, Wu, D

Mol Cell 2001
16341017 A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation

Zeng, X, Tamai, K, Doble, B, Li, S, Huang, H, Habas, R, Okamura, H, Woodgett, J, He, X

Nature 2005
22363759 Wnt signalling pathway parameters for mammalian cells

Tan, CW, Gardiner, BS, Hirokawa, Y, Layton, MJ, Smith, DW, Burgess, AW

PLoS ONE 2012
10421629 Wnt-induced dephosphorylation of axin releases beta-catenin from the axin complex

Willert, K, Shibamoto, S, Nusse, R

Genes Dev 1999
17318175 Protein phosphatase 1 regulates assembly and function of the beta-catenin degradation complex

Luo, W, Peterson, A, Garcia, BA, Coombs, G, Kofahl, B, Heinrich, R, Shabanowitz, J, Hunt, DF, Yost, HJ, Virshup, DM

EMBO J. 2007
10581160 A GSK3beta phosphorylation site in axin modulates interaction with beta-catenin and Tcf-mediated gene expression

Jho, E, Lomvardas, S, Costantini, F

Biochem Biophys Res Commun 1999
14731402 A mechanism for Wnt coreceptor activation

Tamai, K, Zeng, X, Liu, C, Zhang, X, Harada, Y, Chang, Z, He, X

Mol Cell 2004
19759537 Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling

Huang, SM, Mishina, YM, Liu, S, Cheung, A, Stegmeier, F, Michaud, GA, Charlat, O, Wiellette, E, Zhang, Y, Wiessner, S, Hild, M, Shi, X, Wilson, CJ, Mickanin, C, Myer, V, Fazal, A, Tomlinson, R, Serluca, F, Shao, W, Cheng, H, Shultz, M, Rau, C, Schirle, M, Schlegl, J, Ghidelli, S, Fawell, S, Lu, C, Curtis, D, Kirschner, MW, Lengauer, C, Finan, PM, Tallarico, JA, Bouwmeester, T, Porter, JA, Bauer, A, Cong, F

Nature 2009
17569865 Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation

Bilic, J, Huang, YL, Davidson, G, Zimmermann, T, Cruciat, CM, Bienz, M, Niehrs, C

Science 2007
15084453 LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way

He, X, Semenov, M, Tamai, K, Zeng, X

Development 2004
10647780 Modulation of Wnt signaling by Axin and Axil

Kikuchi, A

Cytokine Growth Factor Rev. 1999
15459103 Wnt signals across the plasma membrane to activate the beta-catenin pathway by forming oligomers containing its receptors, Frizzled and LRP

Cong, F, Schweizer, L, Varmus, H

Development 2004
19619488 Wnt/beta-catenin signaling: components, mechanisms, and diseases

MacDonald, BT, Tamai, K, He, X

Dev Cell 2009
18234723 Adenomatous polyposis coli is present near the minimal level required for accurate graded responses to the Wingless morphogen

Benchabane, H, Hughes, EG, Takacs, CM, Baird, JR, Ahmed, Y

Development 2008
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