Epinephrine inhibits PI3Kα via the Hippo kinases

Ting Yu Lin, Shakti Ramsamooj, Tiffany Perrier, Katarina Liberatore, Louise Lantier, Neil Vasan, Kannan Karukurichi, Seo Kyoung Hwang, Edward A. Kesicki, Edward R. Kastenhuber, Thorsten Wiederhold, Tomer M. Yaron, Emily M. Huntsman, Mengmeng Zhu, Yilun Ma, Marcia N. Paddock, Guoan Zhang, Benjamin D. Hopkins, Owen McGuinness, Robert E. SchwartzBaran A. Ersoy, Lewis C. Cantley, Jared L. Johnson, Marcus D. Goncalves

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number113535
JournalCell Reports
Issue number12
StatePublished - 26 Dec 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 The Authors


  • CP: Metabolism
  • CP: Molecular biology
  • Hippo kinases
  • PI3K signaling
  • epinephrine signaling
  • glucose metabolism
  • glycogen metabolism
  • insulin sensitivity
  • liver


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