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Science. March 22, 2013; 339 (6126): 1441-5.

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: R01 GM042341 NIGMS NIH HHS , R01 NS073159 NINDS NIH HHS

Genes referenced: apcdd1 axin1 axin2 ccnd1 chrd.1 ctnnb1 dvl1 dvl2 dvl3 en2 gad1.1 gsk3a gsk3b jun lef1 lrp6 myc nkx1-2 nodal3.1 prkcd pstpip1 ripk1 ripk2 ripk3 ripk4 tcf7 wnt3a wnt8a xk81a1

Morpholinos referenced: ripk4 MO1 ripk4 MO2

External Resources:

Adams, 2007, Pubmed[+]

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