Journal
MOLECULAR CELL
Volume 27, Issue 1, Pages 17-28Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2007.06.004
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Funding
- NCI NIH HHS [CA90917, R01 CA090917-08, CA78810, R01 CA078810, R01 CA078810-11, R01 CA090917] Funding Source: Medline
- NHLBI NIH HHS [R01 HL054131-15, R01 HL054131-11, R37 HL054131, R01 HL054131, HL54131] Funding Source: Medline
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Cell death pathways are likely regulated in specialized subcellular microdomains, but how this occurs is not understood. Here, we show that cyclic AMP-dependent protein kinase A (PKA) phosphorylates the inhibitor of apoptosis (IAP) protein survivin on Ser20 in the cytosol, but not in mitochondria. This phosphorylation event disrupts the binding interface between survivin and its antiapoptotic cofactor, XIAP. Conversely, mitochondrial survivin or a non-PKA phosphorylatable survivin mutant binds XIAP avidly, enhances XIAP stability, synergistically inhibits apoptosis, and accelerates tumor growth, in vivo. Therefore, differential phosphorylation of survivin by PKA in subcellular microdomains regulates tumor cell apoptosis via its interaction with XIAP.
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