Bcl‐2, Raf‐1 and mitochondrial regulation of apoptosis

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Abstract
Raf‐1 kinase was shown to bind via its catalytic domain (Cat) to Bcl‐2 in a BH4 domain‐dependent manner. Using a green fluorescent protein (GFP)‐Raf‐1 (Cat) fusion protein, Bcl‐2 but not Bcl‐2(Δ BH4) was found to target Raf‐1 to mitochondria in cells. Targeting Raf‐1 (Cat) to mitochondrial membranes by fusing with the transmembrane domain of an outer mitochondrial membrane protein protected cells from apoptosis and resulted in phosphorylation of BAD protein, whereas plasma‐membrane targeted Raf‐1 failed to phosphorylate BAD and did not protect against cell death. Moreover, a Bcl‐2 binding protein, BAG‐1, was shown to not only bind Raf‐1 but also increase the activity of this kinase through a protein—protein interaction. The findings suggest that Bcl‐2 targets Raf‐1 to mitochondria, allowing this kinase to contribute to cellular survival by phosphorylating BAD or possibly other protein substrates in the vicinity of Bcl‐2.