Compartmentalized Phosphorylation of IAP by Protein Kinase A Regulates Cytoprotection

Takehiko Dohi, Fang Xia, Dario C. Altieri

Research output: Contribution to journalArticle

114 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 languageEnglish (US)
Pages (from-to)17-28
Number of pages12
JournalMolecular cell
Volume27
Issue number1
DOIs
StatePublished - Jul 6 2007

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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