TY - JOUR
T1 - MTORC2 regulates cardiac response to stress by inhibiting MST1
AU - Sciarretta, Sebastiano
AU - Zhai, Peiyong
AU - Maejima, Yasuhiro
AU - DelRe, Dominic P.
AU - Nagarajan, Narayani
AU - Yee, Derek
AU - Liu, Tong
AU - Magnuson, Mark A.
AU - Volpe, Massimo
AU - Frati, Giacomo
AU - Li, Hong
AU - Sadoshima, Junichi
N1 - Funding Information:
The authors wish to thank Daniela Zablocki and Christopher D. Brady for critical reading of the manuscript. This work was supported in part by U.S. Public Health Service Grants HL102738, HL67724, HL91469, AG23039, and HL112330. This work was also supported by the Foundation Leducq Transatlantic Networks of Excellence. S.S. received support from a Postdoctoral Fellowship from the Founders Affiliate, American Heart Association and a grant from the Italian Society of Hypertension and the Italian Society of Cardiology.
Publisher Copyright:
© 2015 The Authors.
PY - 2015/4/7
Y1 - 2015/4/7
N2 - 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 theMST1 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. Inconclusion, our study demonstrates the existence of a direct crosstalk between mTORC2 and MST1 that is critical for cardiac cell survival and growth.
AB - 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 theMST1 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. Inconclusion, our study demonstrates the existence of a direct crosstalk between mTORC2 and MST1 that is critical for cardiac cell survival and growth.
UR - http://www.scopus.com/inward/record.url?scp=84927695687&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2015.03.010
DO - 10.1016/j.celrep.2015.03.010
M3 - Article
C2 - 25843706
AN - SCOPUS:84927695687
SN - 2211-1247
VL - 11
SP - 125
EP - 136
JO - Cell Reports
JF - Cell Reports
IS - 1
ER -