Phosphorylation of Dishevelled by protein kinase RIPK4 regulates Wnt signaling.
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.
Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
XiaoDong
X
Huang
James C
JC
McGann
Bob Y
BY
Liu
Rami N
RN
Hannoush
Jennie R
JR
Lill
Victoria
V
Pham
Kim
K
Newton
Michael
M
Kakunda
Jinfeng
J
Liu
Christine
C
Yu
Sarah G
SG
Hymowitz
Jo-Anne
JA
Hongo
Anthony
A
Wynshaw-Boris
Paul
P
Polakis
Richard M
RM
Harland
Vishva M
VM
Dixit
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D000072261:Dishevelled Proteins; D005260:Female; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000378:metabolism; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D010750:Phosphoproteins; D060509:Wnt3A Protein; D029867:Xenopus Proteins; D051176:beta Catenin; C417187:RIPK4 protein, human; D017346:Protein Serine-Threonine Kinases