Related Experiment Video
Updated: Jan 24, 2026

Studying the Hypothalamic Insulin Signal to Peripheral Glucose Intolerance with a Continuous Drug Infusion System into the Mouse Brain
Published on: January 4, 2018
PIP4Ks Suppress Insulin Signaling through a Catalytic-Independent Mechanism
Diana G Wang1, Marcia N Paddock2, Mark R Lundquist3
1Meyer 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.
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.
Related Concept Videos
Insulin: The Receptor and Signaling Pathways
Introduction to Test of Independence
The test statistic for a test of independence is similar to that of a goodness-of-fit test:
Hypothesis Test for Test of Independence
H0: The two variables (factors)...
Turnover Number and Catalytic Efficiency
Chymotrypsin is a pancreatic enzyme that breaks down proteins during digestion....
Catalytically Perfect Enzymes
Most enzymes...
Law of Independent Assortment

