Epinephrine inhibits PI3Ka via the Hippo kinases

The phosphoinositide 3-kinase p110a is an essential mediator of insulin signaling and glucose homeostasis. We interrogated the human serine, threonine, and tyrosine kinome to search for novel regulators of p110a and found that the Hippo kinases phosphorylate p110a at T1061, which inhibits its activity. This inhibitory state corresponds to a conformational change of a membrane-binding domain on p110a, 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 of T1061 and inhi-bition of p110a, 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 mole-cules or if the T1061 is mutated to alanine. Our study defines an inhibitory pathway of PI3K signaling and a link between epinephrine and insulin signaling.