Proto-oncogene CT10-regulated kinase (CRK) is a pro-apoptotic transducer of endoplasmic reticulum stress

Excessive demands on the protein folding capacity of the endoplasmic reticulum (ER) cause irremediable ER stress and contribute to cell loss in a number of cell degenerative diseases, including type 2 diabetes and neurodegeneration1,2. The signals communicating catastrophic ER damage to the mitochondrial apoptotic machinery remain poorly understood3-6. We used a biochemical approach to purify a cytosolic activity induced by ER stress that causes release of cytochrome c from isolated mitochondria. We discovered that the principal component of the purified pro-apoptotic activity is proto-oncogene CT10-regulated kinase (CRK), an adaptor protein with no known catalytic activity7. Crk-/- cells are strongly resistant to ER stress-induced apoptosis. Moreover, CRK is cleaved in response to ER stress to generate an N-terminal ~14kD fragment with greatly enhanced cytotoxic potential. We identified a putative BCL2 homology-3 (BH3) domain within this N-terminal CRK fragment, which sensitizes isolated mitochondria to cytochrome c release and when mutated significantly reduces CRK's apoptotic activity in vivo. Together these results identify CRK as a pro-apoptotic protein that signals irremediable ER stress to the mitochondrial execution machinery