A Wnt-CKIvarepsilon-Rap1 pathway regulates gastrulation by modulating SIPA1L1, a Rap GTPase activating protein

Dev Cell. 2007 Mar;12(3):335-47. doi: 10.1016/j.devcel.2007.02.009.

Abstract

Noncanonical Wnt signals control morphogenetic movements during vertebrate gastrulation. Casein kinase I epsilon (CKIvarepsilon) is a Wnt-regulated kinase that regulates Wnt/beta-catenin signaling and has a beta-catenin-independent role(s) in morphogenesis that is poorly understood. Here we report the identification of a CKIvarepsilon binding partner, SIPA1L1/E6TP1, a GAP (GTPase activating protein) of the Rap small GTPase family. We show that CKIvarepsilon phosphorylates SIPA1L1 to reduce its stability and thereby increase Rap1 activation. Wnt-8, which activates CKIvarepsilon, enhances the CKIvarepsilon-dependent phosphorylation and degradation of SIPA1L1. In early Xenopus or zebrafish development, inactivation of the Rap1 pathway results in abnormal gastrulation and a shortened anterior-posterior axis. Although CKIvarepsilon also transduces Wnt/beta-catenin signaling, inhibition of Rap1 does not alter beta-catenin-regulated gene expression. Our data demonstrate a role for CKIvarepsilon in noncanonical Wnt signaling and indicate that Wnt regulates morphogenesis in part through CKIvarepsilon-mediated control of Rap1 signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Patterning / physiology
  • Casein Kinase 1 epsilon / genetics
  • Casein Kinase 1 epsilon / metabolism*
  • Cell Line
  • Embryonic Development / physiology*
  • Enzyme Activation / physiology
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Gastrula / cytology
  • Gastrula / metabolism*
  • Gene Expression Regulation, Developmental / genetics
  • Humans
  • Phosphorylation
  • Signal Transduction / genetics
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • Xenopus
  • Xenopus Proteins / genetics
  • Xenopus Proteins / metabolism
  • Zebrafish
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*
  • beta Catenin / genetics
  • beta Catenin / metabolism
  • rap1 GTP-Binding Proteins / genetics
  • rap1 GTP-Binding Proteins / metabolism*

Substances

  • GTPase-Activating Proteins
  • SIPA1L1 protein, zebrafish
  • Wnt Proteins
  • Xenopus Proteins
  • Zebrafish Proteins
  • beta Catenin
  • wnt8a protein, Xenopus
  • Casein Kinase 1 epsilon
  • rap1 GTP-Binding Proteins