Deregulation of proteasome function induces Abl-mediated cell death by uncoupling p130CAS and c-CrkII.
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.
Holcomb
Monica
M
The Scripps Research Institute, Department of Immunology, La Jolla, California 92037, USA.
Rufini
Alessandra
A
Barilà
Daniela
D
Klemke
Richard L
RL
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D002522:Chlorocebus aethiops; D050719:Crk-Associated Substrate Protein / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D051379:Mice; D016374:Oncogene Proteins v-abl / Q000502:physiology*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D050737:Proto-Oncogene Proteins c-crk / Q000378:metabolism*; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
D050719:Crk-Associated Substrate Protein; D016374:Oncogene Proteins v-abl; D050737:Proto-Oncogene Proteins c-crk; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease