Ishikawa Hiroyuki O, Takeuchi Hideyuki, Haltiwanger Robert S, Irvine Kenneth D
Howard Hughes Medical Institute, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08854, USA.
Science. 2008 Jul 18;321(5887):401-4. doi: 10.1126/science.1158159.
The atypical cadherin Fat acts as a receptor for a signaling pathway that regulates growth, gene expression, and planar cell polarity. Genetic studies in Drosophila identified the four-jointed gene as a regulator of Fat signaling. We show that four-jointed encodes a protein kinase that phosphorylates serine or threonine residues within extracellular cadherin domains of Fat and its transmembrane ligand, Dachsous. Four-jointed functions in the Golgi and is the first molecularly defined kinase that phosphorylates protein domains destined to be extracellular. An acidic sequence motif (Asp-Asn-Glu) within Four-jointed was essential for its kinase activity in vitro and for its biological activity in vivo. Our results indicate that Four-jointed regulates Fat signaling by phosphorylating cadherin domains of Fat and Dachsous as they transit through the Golgi.
非典型钙黏蛋白Fat作为一种信号通路的受体，该信号通路可调节生长、基因表达和平面细胞极性。果蝇中的遗传学研究将四关节基因鉴定为Fat信号传导的调节因子。我们发现四关节基因编码一种蛋白激酶，该激酶可磷酸化Fat及其跨膜配体Dachsous的细胞外钙黏蛋白结构域内的丝氨酸或苏氨酸残基。四关节基因在高尔基体中发挥作用，是首个在分子水平上明确的可磷酸化注定位于细胞外的蛋白质结构域的激酶。四关节基因内的一个酸性序列基序（天冬氨酸-天冬酰胺-谷氨酸）对于其体外激酶活性和体内生物学活性至关重要。我们的结果表明，四关节基因通过在Fat和Dachsous的钙黏蛋白结构域穿过高尔基体时对其进行磷酸化来调节Fat信号传导。
