Cell Reports (Dec 2023)
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. Schwartz,
- Baran A. Ersoy,
- Lewis C. Cantley,
- Jared L. Johnson,
- Marcus D. Goncalves
Affiliations
- Ting-Yu Lin
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY 10021, USA
- Shakti Ramsamooj
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Division of Endocrinology, Weill Cornell Medicine, New York, NY 10021, USA
- Tiffany Perrier
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Division of Endocrinology, Weill Cornell Medicine, New York, NY 10021, USA
- Katarina Liberatore
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA
- Louise Lantier
- Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN 37232, USA
- Neil Vasan
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA
- Kannan Karukurichi
- Petra Pharma Corporation, New York, NY 10016, USA
- Seo-Kyoung Hwang
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Division of Endocrinology, Weill Cornell Medicine, New York, NY 10021, USA
- Edward A. Kesicki
- Petra Pharma Corporation, New York, NY 10016, USA
- Edward R. Kastenhuber
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA
- Thorsten Wiederhold
- Cell Signaling Technology, Beverly, MA 01915, USA
- Tomer M. Yaron
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, USA
- Emily M. Huntsman
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, USA
- Mengmeng Zhu
- Proteomics and Metabolomics Core Facility, Weill Cornell Medicine, New York, NY 10021, USA
- Yilun Ma
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA
- Marcia N. Paddock
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA
- Guoan Zhang
- Proteomics and Metabolomics Core Facility, Weill Cornell Medicine, New York, NY 10021, USA
- Benjamin D. Hopkins
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA
- Owen McGuinness
- Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN 37232, USA
- Robert E. Schwartz
- Division of Gastroenterology & Hepatology, Weill Cornell Medicine, New York, NY 10021, USA
- Baran A. Ersoy
- Division of Gastroenterology & Hepatology, Weill Cornell Medicine, New York, NY 10021, USA
- Lewis C. Cantley
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA
- Jared L. Johnson
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Corresponding author
- Marcus D. Goncalves
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Division of Endocrinology, Weill Cornell Medicine, New York, NY 10021, USA; Corresponding author
- Journal volume & issue
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Vol. 42,
no. 12
p. 113535
Abstract
Summary: 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.
