Cited by 591PI3K/AKT/mTOR signaling in cancerProtein Tyrosine PhosphatasesProtein Kinase Regulation and GTPase Signaling

PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms

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Brognard, John, Sierecki, Emma, Gao, Tianyan, Newton, Alexandra C.·2007·Molecular Cell

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-3alpha 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.

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Crossref · 10.1016/j.molcel.2007.02.017

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Authors
Brognard, J., Sierecki, E., Gao, T., & Newton, A. C.
Affiliations
University of California San Diego (US)
Corresponding author
Newton, Alexandra C.
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2007-03
Volume
25
Issue
6
Pages
917-931
ISSN
1097-2765 (ISSN-L)
OpenAlex
W1984879511
Cited by
591
References
42
Citations by year
2026: 16 · 2025: 19 · 2024: 15 · 2023: 18 · 2022: 34 · 2021: 35 · 2020: 25 · 2019: 30 · 2018: 30 · 2017: 30 · 2016: 28 · 2015: 45 · 2014: 38 · 2013: 40 · 2012: 38
FWCI
15.22
Type
journal article
Language
en
Open access
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion)
Funders
  • U.S. Department of Defense
  • National Institutes of Health
  • University of California, San Diego
  • National Cancer Institute (2P30 CA 23100-18, K01CA10209, P30CA023100)
  • National Institute of General Medical Sciences (R01GM067946, 5 T32 GM07752-26, T32GM007752, GM067946)
  • U.S. Army Medical Research Acquisition Activity
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
PHLPP, PHLPP2, Akt signaling, Akt isoforms, Akt dephosphorylation, AKT2, AKT3, MDM2, GSK3α, p27, cell cycle progression, apoptosis
MeSH terms
Amino Acid Sequence, Cell Division, Cell Line, Cloning, Molecular, Humans, Isoenzymes, Molecular Sequence Data, Nuclear Proteins, Phosphoprotein Phosphatases, Recombinant Proteins, Transfection, Signal Transduction, Sequence Alignment, Apoptosis, Sequence Homology, Amino Acid, Proto-Oncogene Proteins c-akt

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