PHLPP and a Second Isoform, PHLPP2, Differentially Attenuate the Amplitude of Akt Signaling by Regulating Distinct Akt Isoforms

John Brognard, Emma Sierecki, Tianyan Gao, Alexandra C. Newton

Research output: Contribution to journalArticlepeer-review

457 Scopus citations

Abstract

Akt/protein kinase B controls cell growth, proliferation, and survival. We recently discovered a novel phosphatase PHLPP, for PH domain leucine-rich repeat protein phosphatase, which terminates Akt signaling by directly dephosphorylating and inactivating Akt. Here we describe a second family member, PHLPP2, which also inactivates Akt, inhibits cell-cycle progression, and promotes apoptosis. These phosphatases control the amplitude of Akt signaling: depletion of either isoform increases the magnitude of agonist-evoked Akt phosphorylation by almost two orders of magnitude. Although PHLPP1 and PHLPP2 both dephosphorylate the same residue (hydrophobic phosphorylation motif) on Akt, they differentially terminate Akt signaling by regulating distinct Akt isoforms. Knockdown studies reveal that PHLPP1 specifically modulates the phosphorylation of HDM2 and GSK-3α through Akt2, whereas PHLPP2 specifically modulates the phosphorylation of p27 through Akt3. Our data unveil a mechanism to selectively terminate Akt-signaling pathways through the differential inactivation of specific Akt isoforms by specific PHLPP isoforms.

Original languageEnglish
Pages (from-to)917-931
Number of pages15
JournalMolecular Cell
Volume25
Issue number6
DOIs
StatePublished - Mar 23 2007

Bibliographical note

Funding Information:
We thank Dr. Phillip Dennis for the H157 cell line. We thank Drs. Tony Hunter, Jack Dixon, Steve Dowdy, and Tony Wynshaw-Boris for helpful discussions. We thank Dr. Mark Lawson for guidance and help with statistical analysis. We thank Dr. Maya Kunkel for purified Akt used in phosphatase assays. DNA sequencing was performed by the DNA Sequencing Shared Resource, UCSD Cancer Center, which is funded in part by NCI Cancer Center Support Grant #2 P30 CA23100-18. This work was supported by DOD BCRP Predoctoral Grant BC043239 (J.B.), pharmacology training grant 5 T32 GM07752-26 (J.B.), and National Institutes of Health Grant K01CA10209 (T.G.) and GM067946 (A.C.N.). Regarding grant BC043239, the U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014, is the awarding and administering acquisition office. The content of this article does not necessarily reflect the position or the policy of the U.S. government.

Keywords

  • CELLCYCLE
  • SIGNALING

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'PHLPP and a Second Isoform, PHLPP2, Differentially Attenuate the Amplitude of Akt Signaling by Regulating Distinct Akt Isoforms'. Together they form a unique fingerprint.

Cite this