Expanding coincident signaling by PTEN through its inositol 1,3,4,5,6‐pentakisphosphate 3‐phosphatase activity
Abstract
PTEN, a tumor suppressor among the most commonly mutated proteins in human cancer, is recognized to be both a protein phosphatase and a phosphatidylinositol 3,4,5‐trisphosphate (PtdIns(3,4,5)P 3) 3‐phosphatase. Previous work [Maehama and Dixon, J. Biol. Chem. 273 (1998) 13375–13378] has led to a consensus that inositol phosphates are not physiologically relevant substrates for PTEN. In contrast, we demonstrate that PTEN is an active inositol 1,3,4,5,6‐pentakisphosphate (Ins(1,3,4,5,6)P 5) 3‐phosphatase when expressed and purified from bacteria or HEK cells. Kinetic data indicate Ins(1,3,4,5,6)P 5 (K m=7.1 μM) and PtdIns(3,4,5)P 3 (K m=26 μM) compete for PTEN in vivo. Transient transfection of HEK cells with PTEN decreased Ins(1,3,4,5,6)P 5 levels. We discuss the physiological significance of these studies in relation to recent work showing that dephosphorylation of Ins(1,3,4,5,6)P 5 to inositol 1,4,5,6‐tetrakisphosphate is a cell signaling event.
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The most likely enzyme to generate Ins(1,4,5,6)P4 is PTEN, a well-known tumour suppressor gene that is active in the nucleus and plays a role in chromosome stability.
“The most likely enzyme is the well-known tumour suppressor gene PTEN42,43, which is known to be active in the nucleus and to play a role in chromosome stability (reviewed in44).”
From Structure of Hdac3 Bound to Co-Repressor and Inositol Tetraphosphate (2012) · cites this paper as [43]
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Structure of Hdac3 Bound to Co-Repressor and Inositol Tetraphosphate
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“The most likely enzyme is the well-known tumour suppressor gene PTE”
Background
- Authors
- Caffrey, J. J., Darden, T., Wenk, M. R., & Shears, S. B.
- Affiliations
- National Institutes of Health (US)
- Yale University (US)
- Corresponding author
- Shears, Stephen B.
- Venue
- FEBS Letters
- Publisher
- Wiley
- Published
- 2001-06-14
- Volume
- 499
- Issue
- 1-2
- Pages
- 6-10
- ISSN
- 0014-5793 (ISSN-L)
- 1873-3468
- OpenAlex
- W2099519775
- Cited by
- 47
- References
- 26
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 2 · 2019: 1 · 2018: 2 · 2017: 3 · 2014: 2 · 2013: 2 · 2012: 2
- FWCI
- 1.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- FEBS Letters (publishedVersion)
- PubMed (publishedVersion)
- 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 Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- PTEN, inositol phosphates, substrate competition, enzyme kinetics, tumor suppressor, signal transduction, inositol polyphosphate metabolism
- MeSH terms
- Cell Line, Chromatography, High Pressure Liquid, Escherichia coli, Humans, Hydrolysis, Inositol Phosphates, Kinetics, Models, Molecular, Phosphoric Monoester Hydrolases, Phosphorylation, Protein Conformation, Recombinant Fusion Proteins, Transfection, Signal Transduction, Tumor Suppressor Proteins, PTEN Phosphohydrolase
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