title: The v-Crk oncogene enhances cell survival and induces activation of protein kinase B/Akt.
abstract: The v-Crk oncogene encodes an adaptor protein containing an SH2 domain and an SH3 domain. v-Crk-transformed fibroblast cells display enhanced tyrosine phosphorylation levels, and the v-Crk protein localizes in focal adhesions, suggesting that transformation may be due to enhanced focal complex signaling. Here we investigated the mechanism of transformation and found that v-Crk-transformed NIH 3T3 cells display growth rates and serum requirements similar to control cells. However, v-Crk enhanced survival in conditions of serum starvation. Both an intact SH2 and SH3 domain are required; moreover, SH2 mutants displayed dominant interfering properties, enhancing cell death. Using other cell death-inducing stimuli, it appeared that v-Crk in general inhibits apoptosis and enhances cell survival. In search of the signaling pathways involved, we found that v-Crk-transformed cells show constitutively higher levels of phospho-protein kinase B (PKB)/Akt and PKB/Akt activity, especially in conditions of serum starvation. These data strongly suggest involvement of the phosphatidylinositol 3-kinase/PKB survival pathway in the v-Crk-induced protection against apoptosis. In accordance, inhibition of this pathway by wortmannin or LY924002 reduced protection against starvation-induced apoptosis. In addition to the phosphatidylinositol 3-kinase/PKB pathway, a MEK-dependent pathway and an unknown additional pathway are also implicated in resistance against apoptosis. Activation of survival pathways may be the most important function of v-Crk in its oncogenic properties.
authors.affiliation: Utrecht University, Utrecht Institute of Biomembranes, Molecular Cell Biology, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: J C
authors.initials: JC
authors.lastname: Stam
authors.forename: W J
authors.initials: WJ
authors.lastname: Geerts
authors.forename: H H
authors.initials: HH
authors.lastname: Versteeg
authors.forename: A J
authors.initials: AJ
authors.lastname: Verkleij
authors.forename: P M
authors.initials: PM
authors.lastname: van Bergen en Henegouwen
mesh_terms: D016475:3T3 Cells; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019556:COS Cells; D002470:Cell Survival / Q000187:drug effects*; D006224:Cricetinae; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D051379:Mice; D050736:Oncogene Protein v-crk; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015682:Retroviridae Proteins, Oncogenic / Q000494:pharmacology*; D015398:Signal Transduction; D014162:Transfection; D000077191:Wortmannin; D018909:src Homology Domains
chemical_list: D000730:Androstadienes; D050736:Oncogene Protein v-crk; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D015682:Retroviridae Proteins, Oncogenic; D000077191:Wortmannin