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Proteolysis of the Docking Protein HEF1 and Implications for Focal Adhesion Dynamics

机译：对接蛋白HEF1的蛋白水解及其对粘着动力学的影响

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The dynamic regulation of focal adhesions is implicated in cellular processes of proliferation, differentiation, migration, and apoptosis. The focal adhesion-associated docking protein HEF1 is cleaved by caspases during both mitosis and apoptosis. Common to both of these cellular processes is the loss of focal adhesions, transiently during mitosis and permanently during apoptosis. The proteolytic processing of HEF1 during both mitosis and apoptosis therefore posits a general role for HEF1 as a sensor of altered adhesion states. In this study, we find that HEF1 undergoes proteolytic processing specifically in response to cellular detachment, while HEF1 proteolysis is prevented by specific integrin receptor ligation and focal adhesion formation. We show that overexpression of a C-terminal caspase-derived 28-kDa HEF1 peptide causes cellular rounding that is demonstrably separable from apoptosis. Mutation of the divergent helix-loop-helix motif found in 28-kDa HEF1 significantly reduces the induction of apoptosis by this peptide, while deletion of the amino-terminal 28 amino acids of 28-kDa HEF1 completely abrogates the induction of apoptosis. Conversely, these mutations have no effect on the rounding induced by 28-kDa HEF1. Finally, we detect a novel focal adhesion targeting domain located in the C terminus of HEF1 and show that this activity is necessary for HEF1-induced cell spreading. Together, these data suggest that proteolytic and other posttranslational modifications of HEF1 in response to loss of adhesion serve to modulate the disassembly of focal adhesions.
机译：粘着斑的动态调节与增殖，分化，迁移和凋亡的细胞过程有关。在有丝分裂和凋亡过程中，半胱天冬酶裂解与粘着斑相关的对接蛋白HEF1。这两种细胞过程的共同点是在有丝分裂过程中短暂地和细胞凋亡过程中永久性的粘着斑损失。因此，在有丝分裂和凋亡过程中，HEF1的蛋白水解过程为HEF1作为改变粘附状态的传感器发挥了普遍作用。在这项研究中，我们发现HEF1专门针对细胞脱离而经历了蛋白水解过程，而HEF1的蛋白水解被特定的整联蛋白受体连接和粘着斑形成所阻止。我们表明，C末端半胱天冬酶衍生的28 kDa HEF1肽的过表达会导致细胞舍入，可证明与凋亡无关。在28 kDa HEF1中发现的不同螺旋-环-螺旋基序突变显着降低了该肽诱导的细胞凋亡，而28kDa HEF1的氨基末端28个氨基酸的缺失则完全消除了细胞凋亡的诱导。相反，这些突变对28 kDa HEF1诱导的舍入没有影响。最后，我们检测到位于HEF1 C末端的新型黏着斑靶向结构域，并表明该活性对于HEF1诱导的细胞扩散是必需的。总之，这些数据表明，HEF1的蛋白水解和其他翻译后修饰响应于粘连的丧失，可用于调节粘着斑的分解。

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