Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55α regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt

Yi Chun Kuo, Kai Yun Huang, Chung Hsiang Yang, Yu San Yang, Wen Yu Lee, Chi Wu Chiang

研究成果: Article同行評審

299 引文 斯高帕斯(Scopus)

摘要

Akt is a protein serine/threonine kinase that is involved in the regulation of diverse cellular processes. Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural subunit (A), catalytic subunit (C), and a variable regulatory subunit (B). Here we report the identification of the specific B regulatory subunit that targets the PP2A holoenzyme to Akt. We found endogenous association of PP2A AB55C holoenzymes with Akt by co-immunoprecipitation analyses in pro-lymphoid FL5.12 cells. Akt was shown to associate with ectopically expressed B55α subunit in NIH3T3 cells. The direct interaction between B55α subunit and Akt was confirmed using in vitro pulldown analyses. Intriguingly, we found that overexpression of B55α subunit significantly impaired phosphorylation at Thr-308, but to a lesser extent at Ser-473 of Akt in both FL5.12 and NIH3T3 cells. Concomitantly, phosphorylation of a subset of Akt substrates, including FoxO3a, was substantially decreased by B55α overexpression in these cells. Silencing of B55α expression markedly increased phosphorylation at Thr-308 but not at Ser-473 in both FL5.12 cells and NIH3T3 cells. Consistently, PP2A AB55αC holoenzymes preferentially dephosphorylated phospho-Thr-308 rather than phospho-Ser-473 in in vitro dephosphorylation assays. Furthermore, B55α overexpression retarded proliferation of NIH3T3 cells, and knockdown of B55α expression increased survival of FL5.12 cells upon interleukin-3 deprivation. Together, our data demonstrate that B55α-dependent targeting of the PP2A holoenzyme to Akt selectively regulates Akt phosphorylation at Thr-308 to regulate cell proliferation and survival.

原文English
頁(從 - 到)1882-1892
頁數11
期刊Journal of Biological Chemistry
283
發行號4
DOIs
出版狀態Published - 2008 1月 25

All Science Journal Classification (ASJC) codes

  • 生物化學
  • 分子生物學
  • 細胞生物學

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