title: Src tyrosine kinase inhibits apoptosis through the Erk1/2- dependent degradation of the death accelerator Bik.
abstract: Src, the canonical member of the non-receptor family of tyrosine kinases, is deregulated in numerous cancers, including colon and breast cancers. In addition to its effects on cell proliferation and motility, Src is often considered as an inhibitor of apoptosis, although this remains controversial. Thus, whether the ability of Src to generate malignancies relies on an intrinsic aptitude to inhibit apoptosis or requires preexistent resistance to apoptosis remains somewhat elusive. Here, using mouse fibroblasts transformed with v-Src as a model, we show that the observed Src-dependent resistance to cell death relies on Src ability to inhibit the mitochondrial pathway of apoptosis by specifically increasing the degradation rate of the BH3-only protein Bik. This effect relies on the activation of the Ras-Raf-Mek1/2-Erk1/2 pathway, and on the phosphorylation of Bik on Thr124, driving Bik ubiquitylation on Lys33 and subsequent degradation by the proteasome. Importantly, in a set of human cancer cells with Src-, Kras- or BRAF-dependent activation of Erk1/2, resistances to staurosporine or thapsigargin were also shown to depend on Bik degradation rate via a similar mechanism. These results suggest that Bik could be a rate-limiting factor for apoptosis induction of tumor cells exhibiting deregulated Erk1/2 signaling, which may provide new opportunities for cancer therapies.
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Université Lyon 1 - Inserm U1052 - CNRS UMR5286, Centre Léon Bérard, Bâtiment Cheney D, 28 rue Laënnec, Lyon 69373 Cedex 08, France.
authors.forename: J
authors.initials: J
authors.lastname: Lopez
authors.forename: C
authors.initials: C
authors.lastname: Hesling
authors.forename: J
authors.initials: J
authors.lastname: Prudent
authors.forename: N
authors.initials: N
authors.lastname: Popgeorgiev
authors.forename: R
authors.initials: R
authors.lastname: Gadet
authors.forename: I
authors.initials: I
authors.lastname: Mikaelian
authors.forename: R
authors.initials: R
authors.lastname: Rimokh
authors.forename: G
authors.initials: G
authors.lastname: Gillet
authors.forename: P
authors.initials: P
authors.lastname: Gonzalo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D019311:Staurosporine / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; C111741:Bik protein, mouse; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D019284:Thapsigargin; C482128:MAP2K2 protein, human; D019061:src-Family Kinases; D048490:raf Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse; D015689:Oncogene Protein p21(ras); D019311:Staurosporine