Deregulation of proteasome function induces Abl-mediated cell death by uncoupling p130CAS and c-CrkII

被引:21
作者
Holcomb, M
Rufini, A
Barilà, D
Klemke, RL
机构
[1] Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
[2] Univ Roma Tor Vergata, Dulbecco Telethon Inst, I-00133 Rome, Italy
[3] Univ Roma Tor Vergata, Lab Immunol & Signal Transduct, I-00133 Rome, Italy
[4] Univ Roma Tor Vergata, Lab Immunol & Signal Transduct, Dept Expt Med & Biochem Sci, I-00133 Rome, Italy
关键词
D O I
10.1074/jbc.M508454200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:2430 / 2440
页数:11
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