Compartmentalized phosphorylation of IAP by protein kinase A regulates cytoprotection.
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.
Dohi
Takehiko
T
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Xia
Fang
F
Altieri
Dario C
DC
D000818:Animals; D017209:Apoptosis; D002451:Cell Compartmentation; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D019610:Cytoprotection; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D009369:Neoplasms / Q000473:pathology; D010766:Phosphorylation; D017433:Protein Structure, Secondary; D012694:Serine / Q000378:metabolism; D014183:Transplantation, Heterologous; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D012694:Serine; D017868:Cyclic AMP-Dependent Protein Kinases