1. PIP4Ks Suppress Insulin Signaling through a Catalytic-Independent Mechanism.
- Author
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Wang DG, Paddock MN, Lundquist MR, Sun JY, Mashadova O, Amadiume S, Bumpus TW, Hodakoski C, Hopkins BD, Fine M, Hill A, Yang TJ, Baskin JM, Dow LE, and Cantley LC
- Subjects
- Animals, Humans, Phosphatidylinositol 4,5-Diphosphate genetics, Phosphotransferases (Alcohol Group Acceptor) genetics, Insulin metabolism, Phosphatidylinositol 4,5-Diphosphate metabolism, Phosphotransferases (Alcohol Group Acceptor) metabolism, Signal Transduction
- Abstract
Insulin stimulates the conversion of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P
2 ) 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., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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