Akt Phosphorylation and Stabilization of X-linked Inhibitor of Apoptosis Protein (XIAP)

Han C. Dan, Mei Sun, Satoshi Kaneko, Richard I. Feldman, Santo V. Nicosia, Hong Gang Wang, Benjamin K. Tsang, Jin Q. Cheng

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356 Scopus citations

Abstract

Akt negatively regulates apoptotic pathways at a pre-mitochondrial level through phosphorylation and modulation of proteins such as Bad, Forkhead proteins, and GSK-3β. Akt has also been shown to protect cell death at a post-mitochondrial level, although its downstream targets have not been well documented. Here, we demonstrate that Akt, including AKT1 and AKT2, interacts with and phosphorylates X-linked inhibitor of apoptosis protein (XIAP) at residue serine-87 in vitro and in vivo. Phosphorylation of XIAP by Akt protects XIAP from ubiquitination and degradation in response to cisplatin. Moreover, autoubiquitination of XIAP is also inhibited by Akt. Consistent with this, an XIAP mutant introduced into cells which mimics the Akt-phosphorylated form (i.e. XIAP-S87D) displays reduced ubiquitination and degradation as compared with wild type XIAP. The greater stability of XIAP-S87D in cells translated to increased cell survival after cisplatin treatment. Conversely, a mutant that could not be phosphorylated by Akt (XIAP-S87A) was more rapidly degraded and showed increased cisplatin-induced apoptosis. Furthermore, suppression of XIAP by either siRNA or adenovirus of antisense of XIAP induced programmed cell death and inhibited Akt-stimulated cell survival in ovarian cancer cells. These data identify XIAP as a new downstream target of Akt and a potentially important mediator of the effect of Akt on cell survival.

Original languageEnglish (US)
Pages (from-to)5405-5412
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number7
DOIs
StatePublished - Feb 13 2004

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Dan, H. C., Sun, M., Kaneko, S., Feldman, R. I., Nicosia, S. V., Wang, H. G., Tsang, B. K., & Cheng, J. Q. (2004). Akt Phosphorylation and Stabilization of X-linked Inhibitor of Apoptosis Protein (XIAP). Journal of Biological Chemistry, 279(7), 5405-5412. https://doi.org/10.1074/jbc.M312044200