Caspase cleavage of HER-2 promotes apoptosis by releasing a BH3 domain-containing product

1595 The human epidermal growth factor receptor-2 (HER-2/ErbB2/ neu ) is amplified or over-expressed in breast and ovarian carcinomas, and confers resistance to apoptosis by activating multiple cell survival pathways. Here we describe a novel pro-apoptotic function of HER-2 that is activated by caspases. Specifically, we demonstrate that the cytoplasmic tail of HER-2 is cleaved by initiator and executioner caspases at Asp 1016 /Asp 1019 to release a ~47 kDa product, which is subsequently proteolyzed by caspases at Asp 1125 into an unstable ~22 kDa polypeptide which is degraded by the proteasome and a ~25 kDa product. Both the 47 and 25 kDa products translocate to the mitochondria, release cytochrome c through a Bcl-x L -suppressible mechanism, and induce caspase-dependent apoptosis. Importantly, the 47 and 25 kDa HER-2 cleavage products share a functional BH3-like domain which is required for cytochrome c release and apoptosis. Moreover, addition of a peptide containing the HER-2 BH3 domain, but not a mutant BH3 domain, induces cytochrome c release from isolated mitochondria. Collectively, our results indicate that caspases activate a previously unrecognized pro-apoptotic function of HER-2 by releasing a BH3 domain containing product, which translocates to the mitochondria and triggers cytochrome c release and apoptosis. We propose that the physiological role of HER-2 cleavage is to amplify the cell death signal.