The Kinase RIPK4 Stimulates WNT Transcriptional Activity

Mutations in the receptor-interacting serine–threonine protein kinase 4 (RIPK4) impair normal epidermal differentiation, leading to severe developmental defects in patients with the autosomal recessive Bartsocas-Papas syndrome. Although RIPK4 has been shown to bind protein kinase C (PKC), the mechanisms of RIPK4 signaling are not well studied. Huang and colleagues found that RIPK4 but not related kinases induced expression of WNT target genes, similar to the transcriptional program activated by WNT3A, and promoted accumulation of cytosolic β-catenin. This effect was dependent on the kinase activity of RIPK4, as a catalytically inactive mutant protein was not sufficient to stimulate β-catenin stabilization or WNT transcriptional activity. In addition, RIPK4-mediated regulation of WNT signaling required its interaction with the WNT coreceptor low-density lipoprotein receptor-related protein 6 (LRP6) following ligand stimulation and with the adaptor protein dishevelled 2 (DVL2). RIPK4 directly phosphorylated DVL2 at serines 298 and 480, and modification of these residues in response to WNT3A stimulation was necessary for downstream stabilization of β-catenin and assembly of the DVL2 signalosome. RIPK4 mutations associated with Bartsocas-Papas syndrome also prevented β-catenin accumulation, supporting a role for RIPK4 in the control of WNT pathway activity during development. Indeed, expression of wild-type Ripk4 synergized with Xenopus laevis Wnt8 to regulate axis development in Xenopus embryos, whereas Ripk4 depletion or expression of a kinase-dead mutant reduced WNT target gene expression in vivo, resulting in altered neural tube differentiation. Intriguingly, RIPK4 overexpression and cytosolic β-catenin were detected in several types of human cancers, including ovarian adenocarcinomas; RIPK4 depletion inhibited the growth of WNT-dependent teratoma-derived xenograft tumors and diminished WNT-dependent gene expression. These findings identify RIPK4 as a critical regulator of WNT activity in development and suggest that RIPK4-driven WNT signaling may enhance tumorigenesis.

Huang X, McGann JC, Liu BY, Hannoush RN, Lill JR, Pham V, et al. Phosphorylation of dishevelled by protein kinase RIPK4 regulates Wnt signaling. Science 2013 Jan 31 [Epub ahead of print].