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Science 2013 Mar 22;3396126:1441-5. doi: 10.1126/science.1232253.
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Phosphorylation of Dishevelled by protein kinase RIPK4 regulates Wnt signaling.

Huang X , McGann JC , Liu BY , Hannoush RN , Lill JR , Pham V , Newton K , Kakunda M , Liu J , Yu C , Hymowitz SG , Hongo JA , Wynshaw-Boris A , Polakis P , Harland RM , Dixit VM .

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 co-receptor 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.

PubMed ID: 23371553
PMC ID: PMC4094295
Article link: Science
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: apcdd1 axin1 axin2l ccnd1 chrd ctnnb1 dvl1 dvl2 dvl3 en2 gad1.1 gsk3a gsk3b jun krt12.4 lef1 lrp6 myc nkx1-2 nodal3.1 prkcd pstpip1 ripk1 ripk2 ripk3l.2 ripk4 tcf7 wnt3a wnt8a
Morpholinos: ripk4 MO1 ripk4 MO2

References [+] :
Adams, Regulation of NF-kappaB activity and keratinocyte differentiation by the RIP4 protein: implications for cutaneous wound repair. 2007, Pubmed