mTORC2 regulates cardiac response to stress by inhibiting MST1.

Sciarretta S, Zhai P, Maejima Y, Del Re DP, Nagarajan N, Yee D, Liu T, Magnuson MA, Volpe M, Frati G, Li H, Sadoshima J
Cell Rep. 2015 11 (1): 125-36

PMID: 25843706 · PMCID: PMC4417361 · DOI:10.1016/j.celrep.2015.03.010

The mTOR and Hippo pathways have recently emerged as the major signaling transduction cascades regulating organ size and cellular homeostasis. However, direct crosstalk between two pathways is yet to be determined. Here, we demonstrate that mTORC2 is a direct negative regulator of the MST1 kinase, a key component of the Hippo pathway. mTORC2 phosphorylates MST1 at serine 438 in the SARAH domain, thereby reducing its homodimerization and activity. We found that Rictor/mTORC2 preserves cardiac structure and function by restraining the activity of MST1 kinase. Cardiac-specific mTORC2 disruption through Rictor deletion leads to a marked activation of MST1 that, in turn, promotes cardiac dysfunction and dilation, impairing cardiac growth and adaptation in response to pressure overload. In conclusion, our study demonstrates the existence of a direct crosstalk between mTORC2 and MST1 that is critical for cardiac cell survival and growth.

Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

MeSH Terms (18)

Animals Carrier Proteins Cell Proliferation Cell Survival Heart Hepatocyte Growth Factor Humans Mechanistic Target of Rapamycin Complex 2 Mice Mice, Knockout Multiprotein Complexes Myocardium Protein Multimerization Proto-Oncogene Proteins Rapamycin-Insensitive Companion of mTOR Protein Signal Transduction Stress, Mechanical TOR Serine-Threonine Kinases

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