Src tyrosine kinase inhibits apoptosis through the Erk1/2- dependent degradation of the death accelerator Bik

• Published in: Cell death and differentiation 2012-09, Vol.19 (9), p.1459-1469
• Main Authors: Lopez, J, Hesling, C, Prudent, J, Popgeorgiev, N, Gadet, R, Mikaelian, I, Rimokh, R, Gillet, G, Gonzalo, P
• Format: Article
• Language: English
• Subjects: 631/80/82/23; 631/80/86; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Biochemistry; Biomedical and Life Sciences; Cancer; Cell Biology; Cell Cycle Analysis; Cell death; Cell Line, Tumor; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Enzyme Activation - drug effects; Enzyme Activation - genetics; Enzyme Inhibitors - pharmacology; Humans; Kinases; Life Sciences; MAP Kinase Kinase 1 - genetics; MAP Kinase Kinase 1 - metabolism; MAP Kinase Kinase 2 - genetics; MAP Kinase Kinase 2 - metabolism; MAP Kinase Signaling System; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mitochondria; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Motility; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; NIH 3T3 Cells; Oncogene Protein p21(ras) - genetics; Oncogene Protein p21(ras) - metabolism; Original Paper; Phosphorylation; Proteins; Proteolysis; raf Kinases - genetics; raf Kinases - metabolism; src-Family Kinases - genetics; src-Family Kinases - metabolism; Staurosporine - pharmacology; Stem Cells; Thapsigargin - pharmacology
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2012.21

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.