TY - JOUR
T1 - Compartmentalized Phosphorylation of IAP by Protein Kinase A Regulates Cytoprotection
AU - Dohi, Takehiko
AU - Xia, Fang
AU - Altieri, Dario C.
N1 - Funding Information:
We thank Dr. P. Fortugno for kinase assays with survivin peptides, Dr. S. Grossman for the Mdm2 cDNA, and Dr. S. Ghosh for the PKA-DN cDNA. This work was supported by NIH grants CA78810, CA90917, and HL54131.
PY - 2007/7/6
Y1 - 2007/7/6
N2 - 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.
AB - 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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U2 - 10.1016/j.molcel.2007.06.004
DO - 10.1016/j.molcel.2007.06.004
M3 - Article
C2 - 17612487
AN - SCOPUS:34250892539
VL - 27
SP - 17
EP - 28
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 1
ER -