Caspases cleave focal adhesion kinase during apoptosis to generate a FRNK-like polypeptide
Caspases cleave focal adhesion kinase during apoptosis to generate a FRNK-like polypeptide
复制标题
DOI：
10.1074/jbc.273.27.17102
复制
发表时间：
1998-07-03
影响因子：
4.8
通讯作者：
Roy, S
中科院分区：
文献类型：
--
作者：
Gervais, FG;Thornberry, NA;Roy, S
粘着斑激酶（Fak）是一种非受体蛋白酪氨酸激酶，其通过促进细胞与细胞外基质之间的接触位点（粘着斑）的形成来刺激细胞铺展和运动。它通过细胞外基质成分聚集的跨膜整合素转导从局灶性粘连发出的存活信号来抑制细胞凋亡。我们证明，Fak是裂解的半胱天冬酶在两个不同的网站在凋亡过程中。这些位点定位于DQTD（772）和VSWD 704，DQTD（772）优先被半胱天冬酶-3切割，VSWD 704优先被半胱天冬酶-6和细胞毒性T淋巴细胞衍生的颗粒酶B切割。法克的乳沟。在细胞凋亡期间，酪氨酸激酶结构域与粘着斑靶向（FAT）结构域分开。产生的羧基末端片段抑制内源性Fak的磷酸化。因此类似于Fak的天然变体FRNK，其通过阻止Fak定位于粘着斑来抑制Fak活性。因此，半胱天冬酶对Fak的切割可以通过使Fak的抗凋亡功能失效而在自杀程序的执行中发挥重要作用。有趣的是，啮齿动物Fak缺乏最佳的半胱天冬酶-3共有切割位点，尽管它在经历凋亡的鼠细胞中在上游位点被切割。这似乎是半胱天冬酶底物的第一个例子，其中切割位点在物种之间不保守。
Focal adhesion kinase (Fak) is a non-receptor protein-tyrosine kinase that stimulates cell spreading and motility by promoting the formation of contact sites between the cell and the extracellular matrix (focal adhesions). It suppresses apoptosis by transducing survival signals that emanate from focal adhesions via the clustering of transmembrane integrins by components of the extracellular matrix. We demonstrate that Fak is cleaved by caspases at two distinct sites during apoptosis. The sites were mapped to DQTD(772), which was preferentially cleaved by caspase-3, and VSWD704, which was preferentially cleaved by caspase-6 and cytotoxic T lymphocyte-derived granzyme B. The cleavage of Fak. during apoptosis separates the tyrosine kinase domain from the focal adhesion targeting (FAT) domain. The carboxyl-terminal fragments that are generated suppress phosphorylation of endogenous Fak. and thus resemble a natural variant of Fak, FRNK, that inhibits Fak activity by preventing the localization of Fak to focal adhesions. The cleavage of Fak by caspases may thus play an important role in the execution of the suicide program by disabling the anti-apoptotic function of Fak, Interestingly, rodent Fak lacks an optimal caspase-3 consensus cleavage site although it is cleaved in murine cells undergoing apoptosis at an upstream site. This appears to be the first example of a caspase substrate where the cleavage sites are not conserved between species.