Department of Biochemistry and the Interdisciplinary Program in Molecular and Cellular Biology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Department of Biochemistry and the Interdisciplinary Program in Molecular and Cellular Biology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
J Cell Sci. 2018 Dec 14;131(24):jcs216648. doi: 10.1242/jcs.216648.
The response of cells to mechanical inputs is a key determinant of cell behavior. In response to external forces, E-cadherin initiates signal transduction cascades that allow the cell to modulate its contractility to withstand the force. Much attention has focused on identifying the E-cadherin signaling pathways that promote contractility, but the negative regulators remain undefined. In this study, we identify SHP-2 as a force-activated phosphatase that negatively regulates E-cadherin force transmission by dephosphorylating vinculin Y822. To specifically probe a role for SHP-2 in E-cadherin mechanotransduction, we mutated vinculin so that it retains its phosphorylation but cannot be dephosphorylated. Cells expressing the mutant vinculin have increased contractility. This work provides a mechanism for inactivating E-cadherin mechanotransduction and provides a new method for specifically targeting the action of phosphatases in cells.
细胞对机械输入的反应是细胞行为的关键决定因素。细胞在响应外部力时，E-钙黏蛋白会启动信号转导级联反应，使细胞能够调节其收缩力以抵抗外力。人们已经关注了确定促进收缩力的 E-钙黏蛋白信号通路，但负调节剂仍未确定。在这项研究中，我们发现 SHP-2 是一种力激活的磷酸酶，通过去磷酸化粘着斑蛋白 Vinculin Y822 来负调控 E-钙黏蛋白力传递。为了专门探究 SHP-2 在 E-钙黏蛋白机械转导中的作用，我们突变了粘着斑蛋白，使其保留磷酸化但不能去磷酸化。表达突变粘着斑蛋白的细胞收缩力增加。这项工作为失活 E-钙黏蛋白机械转导提供了一种机制，并为在细胞中专门针对磷酸酶的作用提供了一种新方法。
