Phosphorylation of the Tumor Suppressor Fat Is Regulated by Its Ligand Dachsous and the Kinase Discs Overgrown

Richelle Sopko, Elizabeth Silva, Lesley Clayton, Laura Gardano, Miriam Barrios-Rodiles, Jeff Wrana, Xaralabos Varelas, Natalia I. Arbouzova, Sanjeev Shaw, Sakura Saburi, Hitoshi Matakatsu, Seth Blair, Helen McNeill

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    82 Citations (Scopus)

    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 [1-4], which controls expression of genes promoting cell proliferation and inhibiting apoptosis (reviewed in [5-11]). The Hippo pathway is highly conserved and is implicated in the regulation of mammalian growth and cancer development [12-18]. Genetic studies suggest that Fat activity is regulated by binding to another large cadherin, Dachsous (Ds) [19-25]. The tumor suppressor discs overgrown (dco)/Casein Kinase I delta/epsilon also regulates Hippo activity and PCP [1, 26,27]. The biochemical natureof 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.

    Original languageEnglish
    Pages (from-to)1112-1117
    Number of pages6
    JournalCurrent Biology
    Volume19
    Issue number13
    DOIs
    Publication statusPublished - 14 Jul 2009

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