Phosphorylation of the Tumor Suppressor Fat Is Regulated by Its Ligand Dachsous and the Kinase Discs Overgrown
Phosphorylation of the Tumor Suppressor Fat Is Regulated by Its Ligand Dachsous and the Kinase Discs Overgrown
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DOI：
10.1016/j.cub.2009.05.049
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发表时间：
2009-07-14
期刊：
影响因子：
9.2
通讯作者：
McNeill, Helen
中科院分区：
文献类型：
--
作者：
Sopko, Richelle;Silva, Elizabeth;McNeill, Helen
果蝇肿瘤抑制基因fat编码一个大的钙粘蛋白，调节生长和一种称为平面细胞极性（PCP）的组织组织形式。脂肪通过Hippo激酶途径调节生长[1-4]，该途径控制促进细胞增殖和抑制细胞凋亡的基因的表达（综述见[5-11]）。Hippo途径是高度保守的，并且涉及哺乳动物生长和癌症发展的调节[12-18]。遗传研究表明，脂肪活性通过与另一种大的钙粘蛋白Dachsous（Ds）结合来调节[19-25]。肿瘤抑制盘过度生长（dco）/酪蛋白激酶I δ/β也调节Hippo活性和PCP [1，26，27]。Fat、Ds和Dco如何相互作用来调节这些通路的生物化学性质知之甚少。在这里，我们证明了脂肪被切割产生450 kDa和110 kDa的片段（脂肪（450）和脂肪（110））。脂肪（110）含有细胞质和跨膜结构域。Fat的胞质结构域结合Dco并在多个位点被Dco磷酸化。重要的是，我们显示脂肪形式的顺式二聚体和脂肪磷酸化调节Dachsous和Dco在体内。我们建议，Ds调节Dco依赖的脂肪和脂肪相关蛋白的磷酸化，以控制生长和PCP中的脂肪信号。
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.