Protein phosphatase-1 regulates Akt1 signal transduction pathway to control gene expression, cell survival and differentiation

L. Xiao, L. L. Gong, D. Yuan, M. Deng, X. M. Zeng, L. L. Chen, L. Zhang, Q. Yan, J. P. Liu, X. H. Hu, S. M. Sun, J. Liu, H. L. Ma, C. B. Zheng, H. Fu, P. C. Chen, J. Q. Zhao, S. S. Xie, L. J. Zou, Y. M. XiaoW. B. Liu, J. Zhang, Y. Liu, D. W.C. Li

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62 Scopus citations


AKT pathway has a critical role in mediating signaling transductions for cell proliferation, differentiation and survival. Previous studies have shown that AKT activation is achieved through a series of phosphorylation steps: first, AKT is phosphorylated at Thr-450 by JNK kinases to prime its activation; then, phosphoinositide-dependent kinase 1 phosphorylates AKT at Thr-308 to expose the Ser-473 residue; and finally, AKT is phosphorylated at Ser-473 by several kinases (PKD2 and others) to achieve its full activation. For its inactivation, the PH-domain containing phosphatases dephosphorylate AKT at Ser-473, and protein serine/threonine phosphatase-2A (PP-2A) dephosphorylates it at Thr-308. However, it remains unknown regarding which phosphatase dephosphorylates AKT at Thr-450 during its inactivation. In this study, we present both in vitro and in vivo evidence to show that protein serine/threonine phosphatase-1 (PP-1) is a major phosphatase that directly dephosphorylates AKT to modulate its activation. First, purified PP-1 directly dephosphorylates AKT in vitro. Second, immunoprecipitation and immunocolocalization showed that PP-1 interacts with AKT. Third, stable knock down of PP-1α or PP-1Β but not PP-1γ, PP-2Aα or PP-2AΒ by shRNA leads to enhanced phosphorylation of AKT at Thr-450. Finally, overexpression of PP-1α or PP-1Β but not PP-1γ, PP-2Aα or PP-2AΒ results in attenuated phosphorylation of AKT at Thr-450. Moreover, our results also show that dephosphorylation of AKT by PP-1 significantly modulates its functions in regulating the expression of downstream genes, promoting cell survival and modulating differentiation. These results show that PP-1 acts as a major phosphatase to dephosphorylate AKT at Thr-450 and thus modulate its functions.

Original languageEnglish (US)
Pages (from-to)1448-1462
Number of pages15
JournalCell Death and Differentiation
Issue number9
Publication statusPublished - Sep 1 2010



  • Akt1
  • apoptosis
  • dephosphorylation
  • differentiation
  • PP-1

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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