PHLPP: A phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth

Tianyan Gao, Frank Furnari, Alexandra C. Newton

Research output: Contribution to journalArticlepeer-review

752 Scopus citations

Abstract

Akt/protein kinase B critically regulates the balance between cell survival and apoptosis. Phosphorylation of Akt at two key sites, the activation loop and the hydrophobic motif, activates the kinase and promotes cell survival. The mechanism of dephosphorylation and signal termination is unknown. Here, we identify a protein phosphatase, PH domain leucine-rich repeat protein phosphatase (PHLPP), that specifically dephosphorylates the hydrophobic motif of Akt (Ser473 in Akt1), triggering apoptosis and suppressing tumor growth. The effects of PHLPP on apoptosis are prevented in cells expressing an S473D construct of Akt, revealing that the hydrophobic motif is the primary cellular target of PHLPP. PHLPP levels are markedly reduced in several colon cancer and glioblastoma cell lines that have elevated Akt phosphorylation. Reintroduction of PHLPP into a glioblastoma cell line causes a dramatic suppression of tumor growth. These data are consistent with PHLPP terminating Akt signaling by directly dephosphorylating and inactivating Akt.

Original languageEnglish
Pages (from-to)13-24
Number of pages12
JournalMolecular Cell
Volume18
Issue number1
DOIs
StatePublished - Apr 1 2005

Bibliographical note

Funding Information:
We thank John Brognard for assistance with the flow cytometry, Dr. Phillip A. Dennis at the National Cancer Institute for the gift of H157 cells, Drs. Carolyn Worby and Jack Dixon for providing the dsRNA against dPTEN and help with Drosophila cell culture, and Dr John Carethers for the colon cancer cell lines. This work was supported by National Institutes of Health (NIH) K01 CA10209-01 (T.G.), NIH NCI PO1 CA95616 (F.F.), and NIH GM 43154 (A.C.N.).

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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