WNT mediated activation of DVL

Stable Identifier
R-HSA-201688
Type
Pathway
Species
Homo sapiens
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The three human Dishevelled (DVL) proteins play a central and overlapping role in the transduction of the WNT signaling cascade (Lee et al, 2008; reviewed in Gao and Chen 2010). DVL activity is regulated by phosphorylation, although the details are not completely worked out. DVL likely exists as a phosphoprotein even in the absence of WNT stimulation, and is further phosphorylated upon ligand binding. Casein kinase 1epsilon (CSNK1E), casein kinase 2 (CSNK2) and PAR1 have all been reported to phosphorylate DVL (Willert et al, 1997; Sun et al, 2001; Cong et al, 2004; Ossipova et al, 2005). Upon pathway activation, phosphorylated DVL translocates to the plasma membrane through an interaction between the DVL PDZ domain and the FZD KTxxxW motif (Wong et al, 2003; Umbhauer et al, 2000; Kikuchi et al, 2011). At the plasma membrane, DVL is believed to oligomerize through its DIX domain, providing a platform for AXIN recruitment; recruitment of AXIN is also facilitated by interaction with LRP (Schwarz-Romond et al, 2007; Mao et al, 2001). DVL interacts with phosphatidylinositol-4-kinase type II (PI4KII) and phophatidylinositol-4-phosphate 5-kinase type I (PIP5KI) to promote formation of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) in the membrane, which is required for the clustering and phosphorylation of LRP6 and the recruitment of AXIN (Pan et al, 2008; Qin et al, 2009).

Literature References
PubMed ID Title Journal Year
22017973 New insights into the mechanism of Wnt signaling pathway activation

Kikuchi, A, Yamamoto, H, Sato, A, Matsumoto, S

Int Rev Cell Mol Biol 2011
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
10990458 The C-terminal cytoplasmic Lys-thr-X-X-X-Trp motif in frizzled receptors mediates Wnt/beta-catenin signalling

Umbhauer, M, Djiane, A, Goisset, C, Penzo-Mend├Ęz, A, Riou, JF, Boucaut, JC, Shi, DL

EMBO J. 2000
19561074 Regulation of phosphatidylinositol kinases and metabolism by Wnt3a and Dvl

Qin, Y, Li, L, Pan, W, Wu, D

J. Biol. Chem. 2009
11433294 PAR-1 is a Dishevelled-associated kinase and a positive regulator of Wnt signalling

Sun, TQ, Lu, B, Feng, JJ, Reinhard, C, Jan, YN, Fantl, WJ, Williams, LT

Nat. Cell Biol. 2001
18093802 Differential mediation of the Wnt canonical pathway by mammalian Dishevelleds-1, -2, and -3

Lee, YN, Gao, Y, Wang, HY

Cell. Signal. 2008
9214626 Casein kinase 2 associates with and phosphorylates dishevelled

Willert, K, Brink, M, Wodarz, A, Varmus, H, Nusse, R

EMBO J. 1997
15935773 Distinct PAR-1 proteins function in different branches of Wnt signaling during vertebrate development

Ossipova, O, Dhawan, S, Sokol, S, Green, JB

Dev. Cell 2005
20006983 Dishevelled: The hub of Wnt signaling

Gao, C, Chen, YG

Cell. Signal. 2010
17529994 The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerization

Schwarz-Romond, T, Fiedler, M, Shibata, N, Butler, PJ, Kikuchi, A, Higuchi, Y, Bienz, M

Nat. Struct. Mol. Biol. 2007
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
18772438 Wnt3a-mediated formation of phosphatidylinositol 4,5-bisphosphate regulates LRP6 phosphorylation

Pan, W, Choi, SC, Wang, H, Qin, Y, Volpicelli-Daley, L, Swan, L, Lucast, L, Khoo, C, Zhang, X, Li, L, Abrams, CS, Sokol, SY, Wu, D

Science 2008
14636582 Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled

Wong, HC, Bourdelas, A, Krauss, A, Lee, HJ, Shao, Y, Wu, D, Mlodzik, M, Shi, DL, Zheng, J

Mol Cell 2003
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