Compartmentalized Phosphorylation of IAP by Protein Kinase A Regulates Cytoprotection

Takehiko Dohi; Fang Xia; Dario C. Altieri

doi:10.1016/j.molcel.2007.06.004

Compartmentalized Phosphorylation of IAP by Protein Kinase A Regulates Cytoprotection

Takehiko Dohi, Fang Xia, Dario C. Altieri

Department of Surgery

Research output: Contribution to journal › Article › peer-review

116 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	17-28
Number of pages	12
Journal	Molecular cell
Volume	27
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2007.06.004
State	Published - Jul 6 2007

All Science Journal Classification (ASJC) codes

Molecular Biology
Cell Biology

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title = "Compartmentalized Phosphorylation of IAP by Protein Kinase A Regulates Cytoprotection",

abstract = "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.",

author = "Takehiko Dohi and Fang Xia and Altieri, {Dario C.}",

note = "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. ",

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doi = "10.1016/j.molcel.2007.06.004",

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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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Compartmentalized Phosphorylation of IAP by Protein Kinase A Regulates Cytoprotection

Abstract

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