Mechanisms of p130Cas-mediated mechano-sensing in cells

p130Cas介导的细胞机械传感机制

• 批准号: 232394966
• 负责人: Professor Dr. Ben Fabry
• 金额: --
• 依托单位: Department of Cell Biology
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/232394966?language=en
• 关键词: Mechanisms; p130Cas; mediated; mechano; sensing

Adherent cells, when mechanically stressed, show a wide range of responses including large-scale changes in their mechanical behavior and gene expression pattern. This is in part facilitated by activating the focal adhesion protein p130Cas through force-induced conformational changes that subsequently lead to activation of downstream pathways such as extracellular-signal-regulated kinase (ERK1/2) phosphorylation. We have recently demonstrated that the phosphorylation site Y12 on p130Cas modulates the binding with vinculin, which is a prominent mechano-coupling protein in the focal adhesion complex. Preliminary data show that phosphorylation of Y12 or mutation with phospho-mimicking glutamate Y12E suppresses the binding of p130Cas to vinculin, leads to a decline of p130Cas localization in focal adhesions, and to a reduction of stretch-induced p130Cas activation and downstream ERK1/2 signaling. These observations demonstrate that vinculin is an important modulator of the p130Cas-mediated mechano-transduction pathway in cells. The central aim of this project is to test the hypothesis that vinculin is critical for p130Cas incorporation into the focal adhesion complex and for transmitting forces to the p130Cas molecule.

贴壁细胞在受到机械应力时表现出广泛的反应，包括其机械行为和基因表达模式的大规模变化。这在一定程度上是通过激活粘着斑蛋白p130 Cas通过力诱导的构象变化，随后导致激活下游途径，如细胞外信号调节激酶（ERK 1/2）磷酸化。我们最近已经证明，磷酸化位点Y12 p130 Cas调制与黏着斑蛋白，这是一个突出的机械耦合蛋白在粘着斑复合物的结合。初步数据表明，磷酸化的Y1/2或突变与磷酸模拟谷氨酸Y1/2 E抑制p130 Cas的结合到黏着斑蛋白，导致p130 Cas定位在粘着斑的下降，并减少牵张诱导的p130 Cas激活和下游ERK 1/2信号转导。这些观察结果表明黏着斑蛋白是细胞中p130 Cas介导的机械转导途径的重要调节剂。本项目的主要目的是检验黏着斑蛋白对p130 Cas掺入粘着斑复合物和向p130 Cas分子传递力至关重要的假设。