Phosphorylation of the Tumor Suppressor Fat Is Regulated by Its Ligand Dachsous and the Kinase Discs Overgrown. / Sopko, Richelle; Silva, Elizabeth; Clayton, Lesley; Gardano, Laura; Barrios-Rodiles, Miriam; Wrana, Jeff; Varelas, Xaralabos; Arbouzova, Natalia I.; Shaw, Sanjeev; Saburi, Sakura; Matakatsu, Hitoshi; Blair, Seth; McNeill, Helen.
In: Current Biology, Vol. 19, No. 13, 14.07.2009, p. 1112-1117.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Phosphorylation of the Tumor Suppressor Fat Is Regulated by Its Ligand Dachsous and the Kinase Discs Overgrown
A1 - Sopko,Richelle
A1 - Silva,Elizabeth
A1 - Clayton,Lesley
A1 - Gardano,Laura
A1 - Barrios-Rodiles,Miriam
A1 - Wrana,Jeff
A1 - Varelas,Xaralabos
A1 - Arbouzova,Natalia I.
A1 - Shaw,Sanjeev
A1 - Saburi,Sakura
A1 - Matakatsu,Hitoshi
A1 - Blair,Seth
A1 - McNeill,Helen
AU - Sopko,Richelle
AU - Silva,Elizabeth
AU - Clayton,Lesley
AU - Gardano,Laura
AU - Barrios-Rodiles,Miriam
AU - Wrana,Jeff
AU - Varelas,Xaralabos
AU - Arbouzova,Natalia I.
AU - Shaw,Sanjeev
AU - Saburi,Sakura
AU - Matakatsu,Hitoshi
AU - Blair,Seth
AU - McNeill,Helen
PY - 2009/7/14
Y1 - 2009/7/14
N2 - <p>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.</p>
AB - <p>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.</p>
U2 - 10.1016/j.cub.2009.05.049
DO - 10.1016/j.cub.2009.05.049
M1 - Article
JO - Current Biology
JF - Current Biology
SN - 0960-9822
IS - 13
VL - 19
SP - 1112
EP - 1117
ER -