Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 339 (6126): 1441-1445

Copyright © 2013 by the American Association for the Advancement of Science

Phosphorylation of Dishevelled by Protein Kinase RIPK4 Regulates Wnt Signaling

XiaoDong Huang,1,2 James C. McGann,3,* Bob Y. Liu,4,* Rami N. Hannoush,5,* Jennie R. Lill,6 Victoria Pham,6 Kim Newton,1 Michael Kakunda,2 Jinfeng Liu,7 Christine Yu,8 Sarah G. Hymowitz,8 Jo-Anne Hongo,9 Anthony Wynshaw-Boris,10 Paul Polakis,4 Richard M. Harland,3 Vishva M. Dixit1,{dagger}

Abstract: 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.

1 Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
2 Department of Molecular Diagnostics and Cancer Cell Biology, Genentech, South San Francisco, CA 94080, USA.
3 Department of Molecular and Cell Biology and Center for Integrative Genomics, University of California, Berkeley, CA 94720, USA.
4 Department of Cancer Targets, Genentech, South San Francisco, CA 94080, USA.
5 Department of Early Discovery Biochemistry, Genentech, South San Francisco, CA 94080, USA.
6 Department of Protein Chemistry, Genentech, South San Francisco, CA 94080, USA.
7 Department of Bioinformatics, Genentech, South San Francisco, CA 94080, USA.
8 Department of Structural Biology, Genentech, South San Francisco, CA 94080, USA.
9 Department of Antibody Engineering, Genentech, South San Francisco, CA 94080, USA.
10 Department of Pediatrics and Institute for Human Genetics, School of Medicine, University of California, San Francisco, CA 94143, USA.

* These authors contributed equally to this work.

{dagger} Corresponding author. E-mail: dixit{at}gene.com


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Peptide Level Immunoaffinity Enrichment Enhances Ubiquitination Site Identification on Individual Proteins.
V. G. Anania, V. C. Pham, X. Huang, A. Masselot, J. R. Lill, and D. S. Kirkpatrick (2014)
Mol. Cell. Proteomics 13, 145-156
   Abstract »    Full Text »    PDF »
Protein Kinase PKN1 Represses Wnt/{beta}-Catenin Signaling in Human Melanoma Cells.
R. G. James, K. A. Bosch, R. M. Kulikauskas, P. T. Yang, N. C. Robin, R. A. Toroni, T. L. Biechele, J. D. Berndt, P. D. von Haller, J. K. Eng, et al. (2013)
J. Biol. Chem. 288, 34658-34670
   Abstract »    Full Text »    PDF »
Making a Point with Wnt Signals.
J. D. Berndt and R. T. Moon (2013)
Science 339, 1388-1389
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882