Title | PIP4Ks Suppress Insulin Signaling through a Catalytic-Independent Mechanism. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Wang DG, Paddock MN, Lundquist MR, Sun JY, Mashadova O, Amadiume S, Bumpus TW, Hodakoski C, Hopkins BD, Fine M, Hill A, T Yang J, Baskin JM, Dow LE, Cantley LC |
Journal | Cell Rep |
Volume | 27 |
Issue | 7 |
Pagination | 1991-2001.e5 |
Date Published | 2019 May 14 |
ISSN | 2211-1247 |
Abstract | Insulin stimulates the conversion of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P) to phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P), which mediates downstream cellular responses. PI(4,5)P 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 and a concomitant increase in insulin-stimulated production of PI(3,4,5)P. The reintroduction of either wild-type or kinase-dead mutants of the PIP4Ks restored cellular PI(4,5)P levels and insulin stimulation of the PI3K pathway, suggesting a catalytic-independent role of PIP4Ks in regulating PI(4,5)P 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 synthesis and insulin-dependent conversion to PI(3,4,5)P and suggests that the pharmacological depletion of PIP4K enzymes could represent a strategy for enhancing insulin signaling. |
DOI | 10.1016/j.celrep.2019.04.070 |
Alternate Journal | Cell Rep |
PubMed ID | 31091439 |
PubMed Central ID | PMC6619495 |
Grant List | K22 CA181280 / CA / NCI NIH HHS / United States U54 CA210184 / CA / NCI NIH HHS / United States R35 CA197588 / CA / NCI NIH HHS / United States S10 OD019986 / OD / NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States R00 GM110121 / GM / NIGMS NIH HHS / United States |
Submitted by bel2021 on December 2, 2019 - 10:19am