Regulatory phosphorylation of Bim: sorting out the ERK from the JNK

Activation of Bax, Bak and the mitochondrial cell death pathway is regulated by the balance between prosurvival Bcl-2 proteins and the expression level or activation state of the proapoptotic ‘BH3-only proteins’.^{1, 2} This life–death balance is exemplified by the genetic interactions between Bcl-2 and the BH3-only protein Bim.³ Loss of Bcl-2 in the mouse undermines the lymphoid system and mice become runted, turn grey and succumb to a form of polycystic kidney disease. Strikingly, most of these phenotypes are ameliorated by the loss of only a single Bim allele, underlining the importance of Bim expression level in determining cell death. Bim expression is regulated by both transcriptional and post-translational mechanisms. Here we consider recent evidence that Bim proteins are regulated by phosphorylation and discuss the kinases responsible, the phosphorylation sites and effect of phosphorylation on Bim protein function, seeking to resolve some of the contradictions.

Bim (Bcl-2 interacting mediator of cell death) was identified by its binding to Bcl-2 in a cDNA expression cloning screen⁴ and, independently, as BOD (Bcl-2-related ovarian death gene) in a yeast two-hybrid screen;⁵ the name Bim is established in the literature. The Bim locus encodes three major isoforms: Bim short (Bim_S), Bim long (Bim_L) and Bim extra long (Bim_EL), generated by alternative splicing.^{4, 5} More recently, additional isoforms have been reported^{6, 7, 8} so that recent estimates suggest that there may be up to 18 different Bim splice variants.⁸ However, the physiological relevance of these unique splice variants has not yet been addressed and while the protein products of endogenous Bim_S, Bim_L and Bim_EL are readily detected, few, if any, studies have identified the naturally occurring protein products of these novel splice variants. For this reason, we have focused largely on the three, canonical forms of Bim, since even this diversity gives rise to proteins that exhibit different apoptotic potencies.

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