Deregulation of proteasome function induces Abl-mediated cell death by uncoupling p130CAS and c-CrkII
Deregulation of proteasome function induces Abl-mediated cell death by uncoupling p130CAS and c-CrkII
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DOI：
10.1074/jbc.m508454200
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发表时间：
2006-02-03
影响因子：
4.8
通讯作者：
Klemke, RL
中科院分区：
文献类型：
--
作者：
Holcomb, M;Rufini, A;Klemke, RL
细胞迁移和存活通过c-Abl（Abl）家族酪氨酸激酶的激活而协调调节。活化的Abl使c-Crk II的酪氨酸221（Crk; Crk-Y221-P）磷酸化，这阻止Crk与对接蛋白p130（CAS）（CAS）结合。CAS-Crk结合的破坏阻断了肌动蛋白细胞骨架和粘着斑组装的下游效应物，抑制了细胞迁移，并破坏了导致细胞凋亡的存活信号。在这里，我们表明，26 S蛋白酶体和泛素化的抑制，促进case-Y 221-P介导的Crk，导致在细胞中的CAS-Crk复合物的拆卸。令人惊讶的是，这些分子相互作用的抑制并不干扰细胞迁移，而是特异性诱导细胞凋亡。此外，我们证明，连接到细胞外基质中起着关键作用，通过半胱天冬酶介导的切割Abl和Crk-Y221-P的调节凋亡机制。我们的研究结果表明，受调节的蛋白质降解的蛋白酶体通过调节β介导的Crk Tyr（221）磷酸化和装配的CAS-Crk信号支架特异性控制细胞死亡。
Cell migration and survival are coordinately regulated through activation of c-Abl (Abl) family tyrosine kinases. Activated Abl phosphorylates tyrosine 221 of c-CrkII (Crk; Crk-Y221-P), which prevents Crk from binding to the docking protein p130(CAS) (CAS). Disruption of CAS-Crk binding blocks downstream effectors of the actin cytoskeleton and focal adhesion assembly, inhibits cell migration, and disrupts survival signals leading to apoptosis. Here we show that inhibition of the 26 S proteasome and ubiquitination facilitates Abl-mediated Crk-Y221-P, leading to disassembly of CAS-Crk complexes in cells. Surprisingly, inhibition of these molecular interactions does not perturb cell migration but rather specifically induces apoptosis. Furthermore, we demonstrate that attachment to an extracellular matrix plays a key role in regulating the apoptotic machinery through caspase-mediated cleavage of Abl and Crk-Y221-P. Our findings indicate that regulated protein degradation by the proteasome specifically controls cell death through regulation of Abl-mediated Crk Tyr(221) phosphorylation and assembly of the CAS-Crk signaling scaffold.