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Phosphorylation of Dishevelled by protein kinase RIPK4 regulates Wnt signaling

XiaoDong Huang1, James C McGann, Bob Y Liu

  • 1Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.

Science (New York, N.Y.)
|February 2, 2013
PubMed

Insights

Receptor-interacting protein kinase 4 (RIPK4) activates Wnt signaling by stabilizing beta-catenin, impacting epidermal development and potentially driving tumor growth. This discovery sheds light on RIPK4

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Developmental biology

Background:

  • Receptor-interacting protein kinase 4 (RIPK4) is crucial for epidermal differentiation and implicated in Bartsocas-Papas syndrome.
  • RIPK4's interaction with protein kinase C is known, but its precise signaling mechanisms remain largely unelucidated.
  • Understanding RIPK4's role in signaling is vital for comprehending epidermal development and related genetic disorders.

Purpose of the Study:

  • To investigate the signaling mechanisms of Receptor-interacting protein kinase 4 (RIPK4).
  • To determine RIPK4's role in Wnt signaling pathways.
  • To explore the implications of RIPK4 function and mutations in both development and disease.

Main Methods:

  • Ectopic expression of wild-type and mutant RIPK4 in cell culture.
  • Analysis of cytosolic beta-catenin accumulation and downstream transcriptional changes.
  • Experiments in Xenopus embryos using Ripk4 morpholinos and coexpression with Xwnt8.
  • Co-immunoprecipitation assays to identify RIPK4 interacting partners.
  • Assessment of RIPK4's effect on Wnt-dependent tumor cell growth in xenograft models.

Main Results:

  • Ectopic RIPK4, but not inactive or mutant forms, induced beta-catenin accumulation and a Wnt-like transcriptional program.
  • In Xenopus, Ripk4 enhanced Wnt signaling, while Ripk4 inhibition or inactive mutants antagonized it.
  • RIPK4 constitutively interacted with DVL2 and, upon Wnt3a stimulation, with LRP6.
  • RIPK4-mediated phosphorylation of DVL2 promoted canonical Wnt signaling.
  • RIPK4 knockdown suppressed Wnt-dependent growth of human tumor xenografts.

Conclusions:

  • RIPK4 acts as a positive regulator of canonical Wnt signaling, influencing beta-catenin stability and downstream gene expression.
  • RIPK4's interaction with DVL2 and LRP6 is critical for its role in Wnt pathway activation.
  • Aberrant RIPK4 activity or overexpression may contribute to the pathogenesis of certain cancers by promoting Wnt-dependent growth.

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