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Publication

PIP4Ks Suppress Insulin Signaling through a Catalytic-Independent Mechanism.

Cell reports | 2019

Insulin stimulates the conversion of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) to phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3), which mediates downstream cellular responses. PI(4,5)P2 is produced by phosphatidylinositol-4-phosphate 5-kinases (PIP5Ks) and by phosphatidylinositol-5-phosphate 4-kinases (PIP4Ks). Here, we show that the loss of PIP4Ks (PIP4K2A, PIP4K2B, and PIP4K2C) in vitro results in a paradoxical increase in PI(4,5)P2 and a concomitant increase in insulin-stimulated production of PI(3,4,5)P3. The reintroduction of either wild-type or kinase-dead mutants of the PIP4Ks restored cellular PI(4,5)P2 levels and insulin stimulation of the PI3K pathway, suggesting a catalytic-independent role of PIP4Ks in regulating PI(4,5)P2 levels. These effects are explained by an increase in PIP5K activity upon the deletion of PIP4Ks, which normally suppresses PIP5K activity through a direct binding interaction mediated by the N-terminal motif VMLΦPDD of PIP4K. Our work uncovers an allosteric function of PIP4Ks in suppressing PIP5K-mediated PI(4,5)P2 synthesis and insulin-dependent conversion to PI(3,4,5)P3 and suggests that the pharmacological depletion of PIP4K enzymes could represent a strategy for enhancing insulin signaling.

Pubmed ID: 31091439 RIS Download

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Associated grants

Agency: NCI NIH HHS, United States
Id: K22 CA181280
Agency: NCI NIH HHS, United States
Id: U54 CA210184
Agency: NCI NIH HHS, United States
Id: P30 CA008748
Agency: NCI NIH HHS, United States
Id: R35 CA197588
Agency: NIGMS NIH HHS, United States
Id: R00 GM110121
Agency: NIH HHS, United States
Id: S10 OD019986
Agency: NIGMS NIH HHS, United States
Id: T32 GM007739

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