Caspase-mediated cleavage of focal adhesion kinase pp125FAK and disassembly of focal adhesions in human endothelial cell apoptosis.
Caspase-mediated cleavage of focal adhesion kinase pp125FAK and disassembly of focal adhesions in human endothelial cell apoptosis.
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DOI：
10.1084/jem.187.4.579
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发表时间：
1998-02-16
期刊：
影响因子：
--
通讯作者：
Raines EW
中科院分区：
文献类型：
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作者：
Levkau B;Herren B;Koyama H;Ross R;Raines EW
当细胞粘附和扩散被阻止时，正常的内皮和上皮细胞发生凋亡，这意味着细胞存活需要来自细胞外基质的抗凋亡信号。我们研究了在生长因子剥夺诱导的人脐静脉内皮细胞融合单层细胞凋亡过程中发生在局灶性粘连中的分子变化。在凋亡过程开始后的第一个形态学变化是膜起泡，粘着斑的损失，并从基质中回缩，然后脱离。我们观察到一个特定的粘着斑激酶（pp 125 FAK），粘着斑复合物的重要组成部分，蛋白水解裂解，并确定pp 125 FAK作为一种新的底物caspase-3和caspase-3样凋亡caspase。最初的分裂前脱离，并符合损失pp 125 FAK和桩蛋白从粘着斑和他们的重新分配到特征性的膜泡aprototically垂死的细胞。PP 125 FAK的裂解差异影响其与粘着斑复合物的信号传导和细胞骨架组分的关联;桩蛋白（但不是PP 130 Cas（Cas，Crk相关底物）和黏着斑蛋白）与COOH末端截短的PP 125 FAK的结合被废除。因此，半胱天冬酶介导的pp 125 FAK裂解可能参与了粘着斑复合物的分解，并主动中断了来自细胞外基质的存活信号，从而传播了细胞死亡程序。
Normal endothelial and epithelial cells undergo apoptosis when cell adhesion and spreading are prevented, implying a requirement for antiapoptotic signals from the extracellular matrix for cell survival. We investigated some of the molecular changes occurring in focal adhesions during growth factor deprivation–induced apoptosis in confluent monolayers of human umbilical vein endothelial cells. Among the first morphologic changes after initiation of the apoptotic process are membrane blebbing, loss of focal adhesion sites, and retraction from the matrix followed by detachment. We observe a specific proteolytic cleavage of focal adhesion kinase (pp125FAK), an important component of the focal adhesion complex, and identify pp125FAK as a novel substrate for caspase-3 and caspase-3–like apoptotic caspases. The initial cleavage precedes detachment, and coincides with loss of pp125FAK and paxillin from focal adhesion sites and their redistribution into the characteristic membrane blebs of apoptotically dying cells. Cleavage of pp125FAK differentially affects its association with signaling and cytoskeletal components of the focal adhesion complex; binding of paxillin, but not pp130Cas (Cas, Crk-associated substrate) and vinculin, to the COOH terminally truncated pp125FAK is abolished. Therefore, caspase-mediated cleavage of pp125FAK may be participating in the disassembly of the focal adhesion complex and actively interrupting survival signals from the extracellular matrix, thus propagating the cell death program.