Combinatorial ShcA docking interactions support diversity in tissue morphogenesis
Combinatorial ShcA docking interactions support diversity in tissue morphogenesis
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DOI：
10.1126/science.1140114
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发表时间：
2007-07-13
期刊：
影响因子：
56.9
通讯作者：
Pawson, Tony
中科院分区：
文献类型：
--
作者：
Hardy, W. Rod;Li, Lingying;Pawson, Tony
蛋白质-蛋白质相互作用的变化可能允许多肽执行意想不到的调节功能。哺乳动物ShcA对接蛋白具有氨基末端磷酸酪氨酸（pTyr）结合（PTB）和羧基末端Src同源2（SH 2）结构域，其识别活化受体上的特异性pTyr位点，以及具有两个磷酸化酪氨酸-X-天冬酰胺（pYXN）基序（其中X表示任何氨基酸）的中心区域，每个基序结合生长因子受体结合蛋白2（Grb 2）衔接子。系统发育分析表明ShcA可能通过pYXN依赖性和非依赖性两种途径进行信号转导。我们发现，在小鼠中，心肌细胞表达的ShcA通过PTB依赖性机制指导妊娠中期心脏发育，该机制不需要pYXN基序。相比之下，pYXN基序与PTB和SH 2结构域在同一ShcA分子中是形成肌梭所必需的，肌梭是调节运动行为的骨骼肌感觉器官。因此，ShcA对接相互作用的组合差异可能产生多种信号传导机制，以支持组织形态发生的多样性。
Changes in protein-protein interactions may allow polypeptides to perform unexpected regulatory functions. Mammalian ShcA docking proteins have amino-terminal phosphotyrosine (pTyr) binding (PTB) and carboxyl-terminal Src homology 2 (SH2) domains, which recognize specific pTyr sites on activated receptors, and a central region with two phosphorylated tyrosine-X-asparagine (pYXN) motifs ( where X represents any amino acid) that each bind the growth factor receptor-bound protein 2 (Grb2) adaptor. Phylogenetic analysis indicates that ShcA may signal through both pYXN-dependent and - independent pathways. We show that, in mice, cardiomyocyte-expressed ShcA directs mid-gestational heart development by a PTB-dependent mechanism that does not require the pYXN motifs. In contrast, the pYXN motifs are required with PTB and SH2 domains in the same ShcA molecule for the formation of muscle spindles, skeletal muscle sensory organs that regulate motor behavior. Thus, combinatorial differences in ShcA docking interactions may yield multiple signaling mechanisms to support diversity in tissue morphogenesis.