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

Monica Holcomb, Alessandra Rufini, Daniela Barilà, Richard L. Klemke

Research output: Contribution to journalArticle

Abstract

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 p130CAS (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.

Original languageEnglish
Pages (from-to)2430-2440
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number5
DOIs
Publication statusPublished - Feb 3 2006

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Deregulation
Cell death
Proteasome Endopeptidase Complex
Cell Movement
Crk-Associated Substrate Protein
Cell Death
Apoptosis
Phosphorylation
Molecular interactions
Caspases
Scaffolds
Protein-Tyrosine Kinases
Machinery
Tyrosine
Actins
Focal Adhesions
Adhesion
Ubiquitination
Chemical activation
Actin Cytoskeleton

ASJC Scopus subject areas

  • Biochemistry

Cite this

Deregulation of proteasome function induces Abl-mediated cell death by uncoupling p130CAS and c-CrkII. / Holcomb, Monica; Rufini, Alessandra; Barilà, Daniela; Klemke, Richard L.

In: Journal of Biological Chemistry, Vol. 281, No. 5, 03.02.2006, p. 2430-2440.

Research output: Contribution to journalArticle

Holcomb, Monica ; Rufini, Alessandra ; Barilà, Daniela ; Klemke, Richard L. / Deregulation of proteasome function induces Abl-mediated cell death by uncoupling p130CAS and c-CrkII. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 5. pp. 2430-2440.
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