Phosphorylation of the tumor suppressor fat is regulated by its ligand Dachsous and the kinase discs overgrown

Curr Biol. 2009 Jul 14;19(13):1112-7. doi: 10.1016/j.cub.2009.05.049. Epub 2009 Jun 18.

Abstract

The Drosophila tumor suppressor gene fat encodes a large cadherin that regulates growth and a form of tissue organization known as planar cell polarity (PCP). Fat regulates growth via the Hippo kinase pathway, which controls expression of genes promoting cell proliferation and inhibiting apoptosis (reviewed in). The Hippo pathway is highly conserved and is implicated in the regulation of mammalian growth and cancer development. Genetic studies suggest that Fat activity is regulated by binding to another large cadherin, Dachsous (Ds). The tumor suppressor discs overgrown (dco)/Casein Kinase I delta/epsilon also regulates Hippo activity and PCP. The biochemical nature of how Fat, Ds, and Dco interact to regulate these pathways is poorly understood. Here we demonstrate that Fat is cleaved to generate 450 kDa and 110 kDa fragments (Fat(450) and Fat(110)). Fat(110) contains the cytoplasmic and transmembrane domain. The cytoplasmic domain of Fat binds Dco and is phosphorylated by Dco at multiple sites. Importantly, we show Fat forms cis-dimers and that Fat phosphorylation is regulated by Dachsous and Dco in vivo. We propose that Ds regulates Dco-dependent phosphorylation of Fat and Fat-associated proteins to control Fat signaling in growth and PCP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Casein Kinase Idelta / genetics
  • Casein Kinase Idelta / metabolism
  • Casein Kinase Iepsilon / genetics
  • Casein Kinase Iepsilon / metabolism*
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Cell Line
  • Cell Polarity
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / physiology*
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / physiology
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Ligands
  • Mice
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Processing, Post-Translational
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Transgenes

Substances

  • Cadherins
  • Cell Adhesion Molecules
  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Protein Isoforms
  • Recombinant Fusion Proteins
  • dco protein, Drosophila
  • ds protein, Drosophila
  • ft protein, Drosophila
  • Casein Kinase Idelta
  • Casein Kinase Iepsilon
  • Protein-Serine-Threonine Kinases
  • hpo protein, Drosophila