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

Monica Holcomb1, Alessandra Rufini, Daniela Barilà

  • 1The Scripps Research Institute, Department of Immunology, La Jolla, California 92037, USA.

The Journal of Biological Chemistry
|November 4, 2005
PubMed

Insights

Regulated protein degradation controls cell death by influencing Abl-mediated Crk Tyr221 phosphorylation and CAS-Crk complex assembly. This process specifically induces apoptosis rather than affecting cell migration.

Area of Science:

  • Cell biology
  • Molecular biology
  • Biochemistry

Background:

  • Cell migration and survival are regulated by c-Abl tyrosine kinases.
  • c-Abl activation phosphorylates c-CrkII at Tyr221, disrupting p130(CAS)-Crk binding.
  • This disruption inhibits cell migration and focal adhesion assembly, promoting apoptosis.

Purpose of the Study:

  • To investigate the role of proteasome inhibition and ubiquitination in Abl-mediated Crk phosphorylation.
  • To determine the effect of disrupting CAS-Crk complexes on cell migration and apoptosis.
  • To elucidate the role of extracellular matrix attachment in regulating apoptosis via Abl and Crk cleavage.

Main Methods:

  • Inhibition of the 26 S proteasome and ubiquitination pathways.
  • Analysis of CAS-Crk complex disassembly.
  • Assessment of cell migration and apoptosis.
  • Investigation of caspase-mediated cleavage of Abl and Crk-Y221-P.

Main Results:

  • Inhibition of proteasome and ubiquitination facilitates Abl-mediated Crk-Y221-P, disassembling CAS-Crk complexes.
  • Disruption of these interactions specifically induces apoptosis, without affecting cell migration.
  • Extracellular matrix attachment regulates apoptosis through caspase-mediated cleavage of Abl and Crk-Y221-P.

Conclusions:

  • Regulated protein degradation by the proteasome controls cell death.
  • This control is mediated by regulating Abl-mediated Crk Tyr221 phosphorylation and CAS-Crk signaling scaffold assembly.
  • The findings highlight a specific mechanism linking protein degradation, signaling scaffolds, and apoptosis.

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