Huang X, McGann JC, Liu BY et al.Phosphorylation of dishevelled by protein kinase RIPK4 regulates Wnt signaling. Science 339:1441-1445

Department of Physiological Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Science (Impact Factor: 33.61). 01/2013; 339(6126). DOI: 10.1126/science.1232253
Source: PubMed


Receptor-interacting protein kinase 4 (RIPK4) is required for epidermal differentiation and is mutated in Bartsocas-Papas syndrome. RIPK4 binds to protein kinase C, but its signaling mechanisms are largely unknown. Ectopic RIPK4, but not catalytically inactive or Bartsocas-Papas RIPK4 mutants, induced accumulation of cytosolic β-catenin and a transcriptional program similar to that caused by Wnt3a. In Xenopus embryos, Ripk4 synergized with coexpressed Xwnt8, whereas Ripk4 morpholinos or catalytic inactive Ripk4 antagonized Wnt signaling. RIPK4 interacted constitutively with the adaptor protein DVL2 and, after Wnt3a stimulation, with the coreceptor LRP6. Phosphorylation of DVL2 by RIPK4 favored canonical Wnt signaling. Wnt-dependent growth of xenografted human tumor cells was suppressed by RIPK4 knockdown, suggesting that RIPK4 overexpression may contribute to the growth of certain tumor types.

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Available from: Vishva Dixit, Oct 09, 2015
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    • "This is probably because Dvl can be phosphorylated at multiple sites, and Dvl phosphorylation plays both positive and negative roles in Wnt/b-catenin signaling in a manner dependent on the phosphorylation site. For example, Dvl1 phosphorylation at S139 and S142 by CK1 (Klimowski et al., 2006) and Dvl2 phosphorylation at S298 and S480 by RIPK4 (Huang et al., 2013) promote b-catenin signaling, while CK1-mediated Dvl2 phosphorylation at the C-terminal conserved sites negatively regulates b-catenin signaling (Gonzá lez-Sancho et al., 2013). In the present study, we show that Hipk2-PP1c dephosphorylates Dvl1 at the C-terminal CK1 sites but fails to dephosphorylate the Dvl1DCT mutant lacking the C-terminal region (560–695), indicating that Hipk2-PP1c dephosphorylates Dvl1 specifically at the sites that have a negative effect on b-catenin signaling. "
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    ABSTRACT: The phosphoprotein Dishevelled (Dvl) is a common essential component of Wnt/β-catenin and Wnt/planar cell polarity (PCP) signaling pathways. However, the regulation and significance of Dvl phosphorylation are not fully understood. Here, we show that homeodomain-interacting protein kinase 2 (Hipk2) facilitates protein phosphatase 1 catalytic subunit (PP1c)-mediated dephosphorylation of Dvl via its C-terminal domain and that this dephosphorylation blocks ubiquitination and consequent degradation mediated by the E3 ubiquitin ligase Itch, which targets the phosphorylated form of Dvl proteins. Inhibition of Hipk2 or PP1c function reduces Dvl protein levels and suppresses Wnt/β-catenin and Wnt/PCP pathway-dependent events in mammalian cells and zebrafish embryos, suggesting that Hipk2 and PP1c are essential for maintaining Dvl protein levels that are sufficient to activate Wnt signaling. We also show that Wnt-3a, a Wnt/β-catenin ligand, induces dissociation of the Dvl-Hipk2-PP1c complex and Dvl degradation under high-cell-density conditions. This regulation may be a negative feedback mechanism that fine-tunes Wnt/β-catenin signaling.
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    ABSTRACT: A Boston-based team and a group led by Roche's Genentech unit have each identified new kinase regulators of WNT signaling—YES1 and RIPK4, respectively—that provide two new, druggable targets. Each team will now look for the cancer subtypes most likely to respond to inhibitors of these kinases.
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