PIP4Ks Suppress Insulin Signaling through a Catalytic-Independent Mechanism
Diana G. Wang,
Marcia N. Paddock,
Mark R. Lundquist,
Janet Y. Sun,
Oksana Mashadova,
Solomon Amadiume,
Timothy W. Bumpus,
Cindy Hodakoski,
Benjamin D. Hopkins,
Matthew Fine,
Amanda Hill,
T. Jonathan Yang,
Jeremy M. Baskin,
Lukas E. Dow,
Lewis C. Cantley
Affiliations
Diana G. Wang
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
Marcia N. Paddock
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
Mark R. Lundquist
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA
Janet Y. Sun
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA
Oksana Mashadova
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA
Solomon Amadiume
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA
Timothy W. Bumpus
Department of Chemistry and Chemical Biology and Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA
Cindy Hodakoski
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA
Benjamin D. Hopkins
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA
Matthew Fine
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA
Amanda Hill
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA
T. Jonathan Yang
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
Jeremy M. Baskin
Department of Chemistry and Chemical Biology and Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA
Lukas E. Dow
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
Lewis C. Cantley
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Corresponding author
Summary: 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. : PI(4,5)P2 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)P2 synthesis and insulin-dependent conversion to PI(3,4,5)P3. This non-catalytic role has implications for the development of PIP4K targeted therapies. Keywords: PIP4K, PI5P4K, PIP5K, PI3K, Akt, insulin, signaling, PI(4,5)P2, PI(3,4,5)P3, RTK
