Proto-Oncoprotein

The proto-oncoprotein c-Cbl controls several down-regulation signals leading to degradation of tyrosine-kinase receptors (TKR) or endocytic trafficking. It interacts with numerous signalling proteins through their Src homology-2 or -3 (SH2 or SH3) domains. Several groups, including ours, have reported an association between down-regulation of apoptosis and c-Cbl. First, oncogenic forms of c-Cbl are anti-apoptotic. The pro-apoptotic Bim EL BH3- only protein has been shown to be down-regulated by c-Cbl in primary culture of osteoclastes. We found a similar, though probably indirect, regulation of BimEL through c-Cbl in mouse testicular germ cells and extended these findings to the pro-apoptotic factor Smac/ DIALO, indicating that c-Cbl likely exerts an anti-apoptotic effect. Langdon et al. reported that a c-Cbl RING finger mutant leads to thymocyte apoptosis and to an unexpected Akt activation, as well as an increase expression of Bim EL. Sproul et al., using PC12 cells and primary cultures of neurons, reinforced the anti-apoptotic effect of c-Cbl, reporting that c-Cbl inhibits the ability of mixed lineage kinase (MLK), from the mitogen-activated protein (MAP) kinase family, to activate c-Jun N-terminal kinase (JNK). Finally, it has been reported that c-Cbl regulates the degradation of the pro-apoptotic TRAIL receptors and that the TRAIL/MEKK4/HSP27/Akt survival network is modulated by the Src/CIN85-c-Cbl complex

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Last date updated on April, 2024