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J. Biol. Chem., Vol. 281, Issue 5, 2430-2440, February 3, 2006

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Deregulation of Proteasome Function Induces Abl-mediated Cell Death by Uncoupling p130^CAS and c-CrkII^*

Monica Holcomb, Alessandra Rufini¹, Daniela Barilà^¶2, and Richard L. Klemke³

From the The Scripps Research Institute, Department of Immunology, La Jolla, California 92037 and the Laboratory of Immunology and Signal Transduction, Department of Experimental Medicine and Biochemical Sciences, and the ^¶Dulbecco Telethon Institute and Laboratory of Immunology and Signal Transduction, University of Tor Vergata, 00133 Rome, Italy

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 Tyr²²¹ phosphorylation and assembly of the CAS-Crk signaling scaffold.

Received for publication, August 2, 2005 , and in revised form, October 19, 2005.

^* This is manuscript 17547-IMM from the Scripps Research Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by Associazione Italiana per la Ricerca sul Cancro (AIRC).

² D. Barilà is supported by Telethon Foudation TCP00061 and AIRC.

³ Supported by National Institutes of Health Grants CA097022 and GM068487. To whom correspondence should be addressed: The Scripps Research Institute, Dept. of Immunology, SP231, 10550 N. Torrey Pines Road, La Jolla, CA 92037. Tel.: 858-784-7750; Fax: 858-784-7785; E-mail: klemke{at}scripps.edu.

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