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- W2912384184 abstract "PTEN counteracts the PI3-kinase signaling cascade by dephosphorylating the D3-site of PI(3,4,5)P3 and PI(3,4)P2, thereby regulating cell growth, proliferation and metabolism. Recently, the mutation p.A126G in the active site of PTEN was shown to be associated with an increase in PI(3,4)P2 levels in living cells. Cellular assays using the voltage-sensitive Ci-VSP-/PTEN chimera PTENCiV demonstrated D5-site activity of the mutant toward PI(3,4,5)P3, consequently leading to the production of PI(3,4)P2. Due to the accumulation of PI(3,4)P2 at the membrane, PTEN's activity toward this PIP-variant appeared to be strongly reduced, when the protein carried the p.A126G-mutation, although the reason for this alteration remained elusive. By performing phosphatase activity assays in vitro, we can now shed light on the molecular mechanism that is disturbed by the mutation. In comparison to wild type PTEN, the mutant was surprisingly more efficient in cleaving water-soluble and vesicle-bound PI(3,4)P2, in case the lipid was the only PIP-variant in the reaction mixture. Addition of PI(4,5)P2 allosterically activated wild type PTEN, but did not increase phosphatase activity of the mutant toward water-soluble PI(3,4)P2, and even inhibited the protein from cleaving vesicle-bound PI(3,4)P2. Since PI(4,5)P2 is the predominant PIP-variant at the plasma membrane, the PI(4,5)P2-mediated inhibition of PTEN(A126G) might cause the accumulation of PI(3,4)P2 in the cellular assays. In summary, the active site mutation p.A126G alters PTEN's function by interfering with the PI(4,5)P2-mediated allosteric activation mechanisms, turning it into an inhibition of the catalytic reaction toward PI(3,4)P2." @default.
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- W2912384184 date "2019-02-01" @default.
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- W2912384184 title "Active Site Mutation A126G Abrogates PI(4,5)P2-Mediated Allosteric Activation of the Tumor Suppressor PTEN" @default.
- W2912384184 doi "https://doi.org/10.1016/j.bpj.2018.11.2004" @default.
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