c-Cbl is not required for ERK1/2-dependent degradation of BimEL

BimEL the most abundant Bim splice variant, is subject to ERK1/2-catalysed phosphorylation, which targets it for ubiquitination and proteasome-dependent destruction. In contrast, inactivation of ERK1/2, following withdrawal of survival factors, promotes stabilization of BimEL. It has been proposed that the RING finger protein Cbl binds to BimEL and serves as its E3 ubiquitin ligase. However, this is controversial since most Cbl substrates are tyrosine phosphoproteins and yet BimEL is targeted for destruction by ERK1/2-catalysed serine phosphorylation. Consequently, a role for Cbl could suggest a second pathway for BimEL turnover, regulated by direct tyrosine phosphorylation, or could suggest that BimEL is a coincidence detector, requiring phosphorylation by ERK1/2 and a tyrosine kinase. Here we show that degradation of BimEL does not involve its tyrosine phosphorylation; indeed, BimEL is not a tyrosine phosphoprotein. Furthermore, BimEL fails to interact with Cbl and growth factor-stimulated, ERK1/2-dependent BimEL turnover proceeds normally in Cbl-containing or Cbl−/− fibroblasts. These results indicate that Cbl is not required for ERK1/2-dependent BimEL turnover in fibroblasts and epithelial cells and any role it has in other cell types is likely to be indirect.