Epinephrine inhibits PI3K alpha via the Hippo kinases

The phosphoinositide 3-kinase, p110α, is an essential mediator of insulin signaling and glucose homeostasis. We systematically interrogated the human serine, threonine, and tyrosine kinome to search for novel regulators of p110α and found that the Hippo kinases phosphorylate and completely inhibit its activity. This inhibitory state corresponds to a conformational change of a membrane binding domain on p110α, which impairs its ability to engage membranes. In human primary hepatocytes, cancer cell lines, and rodent tissues, activation of the Hippo kinases, MST1/2, using forskolin or epinephrine is associated with phosphorylation and inhibition of p110α, impairment of downstream insulin signaling, and suppression of glycolysis and glycogen synthesis. These changes are abrogated when MST1/2 are genetically deleted or inhibited with small molecules. Our study reveals a novel inhibitory pathway of PI3K signaling and a previously unappreciated link between epinephrine and insulin signaling. ### Competing Interest Statement L.C.C. is a founder and member of the board of directors of Agios Pharmaceuticals and is a founder and receives research support from Petra Pharmaceuticals. N.V. reports consulting activities for Novartis, Reactive Biosciences, and Magnet Biomedicine, and is on the scientific advisory board of Heligenics. E.A.K. is a shareholder of Eli Lilly and Company and E.A.K. and K.K. are employees of Loxo Oncology at Lilly. J.L.J. reports consultant activities for Petra Pharmaceuticals. M.D.G. reports personal fees from Novartis, Petra Pharmaceuticals, and Scorpion Therapeutics. L.C.C., B.D.H. and M.D.G. are inventors on patents (pending) for Combination Therapy for PI3K-associated Disease or Disorder, and The Identification of Therapeutic Interventions to Improve Response to PI3K Inhibitors for Cancer Treatment unrelated to this work. B.D.H., L.C.C., and M.D.G. are co-founders and shareholders in Faeth Therapeutics. R.E.S. is on the sponsored advisory board for Miromatrix Inc. T.M.Y is a stockholder and on the board of directors of DESTROKE, Inc., an early-stage start-up developing mobile technology for automated clinical stroke detection. All other authors declare no competing interests.