Force sensing by mechanical extension of the Src family kinase substrate p130Cas
Force sensing by mechanical extension of the Src family kinase substrate p130Cas
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DOI：
10.1016/j.cell.2006.09.044
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发表时间：
2006-12-01
期刊：
影响因子：
64.5
通讯作者：
Sheetz, Michael P.
中科院分区：
文献类型：
--
作者：
Sawada, Yasuhiro;Tamada, Masako;Sheetz, Michael P.
物理力是如何被细胞感知并转导到细胞信号通路的，目前还不清楚。之前，我们发现细胞骨架复合体中p130Cas的酪氨酸磷酸化参与了小GTPase Rap1的力依赖性激活。在这里，我们在体外机械延长细菌表达的Cas底物结构域蛋白（CasSD），发现Src家族激酶显著增强了磷酸化，但激酶活性没有明显变化。使用一种能够识别体外延伸casd的抗体，我们观察到Cas在扩散细胞外周区域的完整细胞中延伸，在那里预期会有更高的牵引力，并且在那里检测到磷酸化的Cas，这表明CasSD的体外延伸和磷酸化与生理力转导有关。因此，我们提出Cas作为主要的力传感器，将力转化为机械延伸，从而引发磷酸化和下游信号的激活。
How physical force is sensed by cells and transduced into cellular signaling pathways is poorly understood. Previously, we showed that tyrosine phosphorylation of p130Cas (Cas) in a cytoskeletal complex is involved in force-dependent activation of the small GTPase Rap1. Here, we mechanically extended bacterially expressed Cas substrate domain protein (CasSD) in vitro and found a remarkable enhancement of phosphorylation by Src family kinases with no apparent change in kinase activity. Using an antibody that recognized extended CasSD in vitro, we observed Cas extension in intact cells in the peripheral regions of spreading cells, where higher traction forces are expected and where phosphorylated Cas was detected, suggesting that the in vitro extension and phosphorylation of CasSD are relevant to physiological force transduction. Thus, we propose that Cas acts as a primary force sensor, transducing force into mechanical extension and thereby priming phosphorylation and activation of downstream signaling.