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PIP4Ks Suppress Insulin Signaling through a Catalytic-Independent Mechanism.
- Source :
-
Cell reports [Cell Rep] 2019 May 14; Vol. 27 (7), pp. 1991-2001.e5. - Publication Year :
- 2019
-
Abstract
- Insulin stimulates the conversion of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P <subscript>2</subscript> ) to phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P <subscript>3</subscript> ), which mediates downstream cellular responses. PI(4,5)P <subscript>2</subscript> 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)P <subscript>2</subscript> and a concomitant increase in insulin-stimulated production of PI(3,4,5)P <subscript>3</subscript> . The reintroduction of either wild-type or kinase-dead mutants of the PIP4Ks restored cellular PI(4,5)P <subscript>2</subscript> levels and insulin stimulation of the PI3K pathway, suggesting a catalytic-independent role of PIP4Ks in regulating PI(4,5)P <subscript>2</subscript> 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)P <subscript>2</subscript> synthesis and insulin-dependent conversion to PI(3,4,5)P <subscript>3</subscript> and suggests that the pharmacological depletion of PIP4K enzymes could represent a strategy for enhancing insulin signaling.<br /> (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 27
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 31091439
- Full Text :
- https://doi.org/10.1016/j.celrep.2019.04.070