Author: ["Kathryn Austgen","Emily T. Johnson","Tae-Ju Park","Tom Curran","Scott A. Oakes"]
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Abstract
The signalling pathway by which ER damage triggers apoptosis remains unclear. Oakes and colleagues identify CT10-regulated kinase (CRK) as a pro-apoptotic protein induced by ER stress. Such stress leads to the accumulation of cleaved CRK fragments at mitochondria, sensitizing them to cytochrome c release in a cell-free system. 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 understood3,4,5,6. 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 the proto-oncoprotein CRK (CT10-regulated kinase), an adaptor protein with no known catalytic activity7. C r k−/− cells are strongly resistant to ER-stress-induced apoptosis. Moreover, CRK is cleaved in response to ER stress to generate an amino-terminal Mr∼14K fragment with greatly enhanced cytotoxic potential. We identified a putative BH3 (BCL2 homology 3) domain within this N-terminal CRK fragment, which sensitizes isolated mitochondria to cytochrome c release and when mutated significantly reduces the apoptotic activity of CRK in vivo. Together these results identify CRK as a pro-apoptotic protein that signals irremediable ER stress to the mitochondrial execution machinery.Cite this article
Austgen, K., Johnson, E., Park, TJ. et al. The adaptor protein CRK is a pro-apoptotic transducer of endoplasmic reticulum stress. Nat Cell Biol 14, 87–92 (2012). https://doi.org/10.1038/ncb2395 