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Cell Rep. 2019 May 14;27(7):1991-2001.e5. doi: 10.1016/j.celrep.2019.04.070.

PIP4Ks Suppress Insulin Signaling through a Catalytic-Independent Mechanism.

Author information

1
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Weill Cornell Medicine/Rockefeller University/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY 10021, USA.
2
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Hematology and Oncology Division, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
3
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA.
4
Department of Chemistry and Chemical Biology and Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA.
5
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
6
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Hematology and Oncology Division, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA; Department of Biochemistry, Weill Cornell Medicine, New York, NY 10021, USA.
7
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA. Electronic address: lcantley@med.cornell.edu.

Abstract

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.

KEYWORDS:

Akt; PI(3,4,5)P(3); PI(4,5)P(2); PI3K; PI5P4K; PIP4K; PIP5K; RTK; insulin; signaling

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