Phosphorylation of the tumor suppressor fat is regulated by its ligand Dachsous and the kinase discs overgrown.
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.
Sopko
Richelle
R
Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada.
Silva
Elizabeth
E
Clayton
Lesley
L
Gardano
Laura
L
Barrios-Rodiles
Miriam
M
Wrana
Jeff
J
Varelas
Xaralabos
X
Arbouzova
Natalia I
NI
Shaw
Sanjeev
S
Saburi
Sakura
S
Matakatsu
Hitoshi
H
Blair
Seth
S
McNeill
Helen
H
D000595:Amino Acid Sequence; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D048149:Casein Kinase 1 epsilon / Q000235:genetics / Q000378:metabolism*; D048148:Casein Kinase Idelta / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D016764:Cell Polarity; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D019076:Transgenes; D000099317:Hippo Kinases
D015820:Cadherins; D048149:Casein Kinase 1 epsilon; D048148:Casein Kinase Idelta; D015815:Cell Adhesion Molecules; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D011993:Recombinant Fusion Proteins; C113519:dco protein, Drosophila; C094449:ds protein, Drosophila; C472307:ft protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases