PHLPP: A phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth
Open accessAbstract
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.
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With a high pLI score (0.92), PHLPP1 is a tumor suppressor in humans and mice.
“With a high pLI score (0.92), PHLPP1 is a tumor suppressor in humans and mice [30, 31].”
From Neandertal Introgression Sheds Light on Modern Human Endocranial Globularity (2019) · cites this paper as [30]
PHLPP dephosphorylates AKT at Thr473 and suppresses AKT-mediated survival.
“Moreover, the PH-domain-leucin-rich protein phosphatase, PHLPP, also dephosphorylates AKT Thr473, suppressing AKT-mediated survival (Gao et al., 2005).”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Gao et al., 2005
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- Authors
- Gao, T., Furnari, F., & Newton, A. C.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Newton, Alexandra C.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2005-04
- Volume
- 18
- Issue
- 1
- Pages
- 13-24
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2095304369
- Cited by
- 906
- References
- 40
- Citations by year
- 2026: 17 · 2025: 23 · 2024: 27 · 2023: 28 · 2022: 33 · 2021: 46 · 2020: 48 · 2019: 33 · 2018: 57 · 2017: 36 · 2016: 38 · 2015: 53 · 2014: 57 · 2013: 51 · 2012: 58
- FWCI
- 17.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P01 CA 95616, K01 CA10209-01, P01CA095616)
- National Institute of General Medical Sciences (GM 43154)
- 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, protein phosphatase, Akt dephosphorylation, apoptosis, tumor suppression, glioblastoma, colon cancer, cell survival
- MeSH terms
- Acid Phosphatase, Amino Acid Sequence, Cell Line, Cloning, Molecular, Humans, Molecular Sequence Data, Phosphoproteins, Plasmids, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Transfection, Apoptosis, Protein Serine-Threonine Kinases, DNA, Complementary, Cell Line, Tumor, Proto-Oncogene Proteins c-akt
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