Englander Institute for Precision Medicine

Epinephrine inhibits PI3Kα via the Hippo kinases.

TitleEpinephrine inhibits PI3Kα via the Hippo kinases.
Publication TypeJournal Article
Year of Publication2023
AuthorsLin T-Y, Ramsamooj S, Perrier T, Liberatore K, Lantier L, Vasan N, Karukurichi K, Hwang S-K, Kesicki EA, Kastenhuber ER, Wiederhold T, Yaron TM, Huntsman EM, Zhu M, Ma Y, Paddock MN, Zhang G, Hopkins BD, McGuinness O, Schwartz RE, Ersoy BA, Cantley LC, Johnson JL, Goncalves MD
JournalCell Rep
Date Published2023 Dec 26
KeywordsAnimals, Cell Line, Colforsin, Enzyme Activation, Epinephrine, Female, Gene Deletion, Hippo Signaling Pathway, Humans, Insulin, Male, Mice, Mice, Inbred C57BL, Phosphatidylinositols, Phosphorylation, Protein Serine-Threonine Kinases

The phosphoinositide 3-kinase p110α 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 p110α and found that the Hippo kinases phosphorylate p110α at T1061, which inhibits 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 of T1061 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 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.

Alternate JournalCell Rep
PubMed ID38060450
PubMed Central IDPMC10809223
Grant ListK08 CA230318 / CA / NCI NIH HHS / United States
R01 DK121072 / DK / NIDDK NIH HHS / United States
U24 DK059637 / DK / NIDDK NIH HHS / United States
R35 CA197588 / CA / NCI NIH HHS / United States
P30 DK020593 / DK / NIDDK NIH HHS / United States

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