PIP4Ks suppress insulin signaling through a catalytic-independent mechanism Journal Article
| Authors: | Wang, D. G.; Paddock, M. N.; Lundquist, M. R.; Sun, J. Y.; Mashadova, O.; Amadiume, S.; Bumpus, T. W.; Hodakoski, C.; Hopkins, B. D.; Fine, M.; Hill, A.; Yang, T. J.; Baskin, J. M.; Dow, L. E.; Cantley, L. C. |
| Article Title: | PIP4Ks suppress insulin signaling through a catalytic-independent mechanism |
| 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)P 3 ), which mediates downstream cellular responses. PI(4,5)P 2 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 2 and a concomitant increase in insulin-stimulated production of PI(3,4,5)P 3 . The reintroduction of either wild-type or kinase-dead mutants of the PIP4Ks restored cellular PI(4,5)P 2 levels and insulin stimulation of the PI3K pathway, suggesting a catalytic-independent role of PIP4Ks in regulating PI(4,5)P 2 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 2 synthesis and insulin-dependent conversion to PI(3,4,5)P 3 and suggests that the pharmacological depletion of PIP4K enzymes could represent a strategy for enhancing insulin signaling. PI(4,5)P 2 is produced by both phosphatidylinositol-4-phosphate 5-kinases (PIP5Ks) and by phosphatidylinositol-5-phosphate 4-kinases (PIP4Ks). Wang et al. report an allosteric function of a conserved N-terminal motif of PIP4Ks in suppressing PIP5K-mediated PI(4,5)P 2 synthesis and insulin-dependent conversion to PI(3,4,5)P 3 . This non-catalytic role has implications for the development of PIP4K targeted therapies. © 2019 The Authors |
| Keywords: | signaling; insulin; akt; pi3k; pi(3,4,5)p 3; pi(4,5)p 2; pi5p4k; pip4k; pip5k; rtk |
| Journal Title: | Cell Reports |
| Volume: | 27 |
| Issue: | 7 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2019-05-14 |
| Start Page: | 1991 |
| End Page: | 2001.e5 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2019.04.070 |
| PROVIDER: | scopus |
| PUBMED: | 31091439 |
| PMCID: | PMC6619495 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 June 2019 -- Source: Scopus |
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