title: mTORC2 regulates cardiac response to stress by inhibiting MST1.
abstract: 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.
authors.affiliation: Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA; IRCCS Neuromed, Pozzilli 86077, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Sciarretta
authors.affiliation: Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Peiyong
authors.initials: P
authors.lastname: Zhai
authors.affiliation: Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maejima
authors.affiliation: Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Del Re
authors.affiliation: Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Narayani
authors.initials: N
authors.lastname: Nagarajan
authors.affiliation: Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Yee
authors.affiliation: Center for Advanced Proteomics Research, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
authors.affiliation: Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.affiliation: IRCCS Neuromed, Pozzilli 86077, Italy; Division of Cardiology, Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome 00187, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Volpe
authors.affiliation: IRCCS Neuromed, Pozzilli 86077, Italy; Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina 04100, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Frati
authors.affiliation: Center for Advanced Proteomics Research, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA. Electronic address: sadoshju@njms.rutgers.edu.
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D006321:Heart / Q000503:physiopathology; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D055503:Protein Multimerization; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction; D013314:Stress, Mechanical; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D046912:Multiprotein Complexes; D011518:Proto-Oncogene Proteins; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C082332:macrophage stimulating protein; C525637:rictor protein, mouse; D017228:Hepatocyte Growth Factor; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
references.citation: Biochem J. 2008 Dec 15;416(3):375-85
references.pmid: 18925875
references.citation: Nat Med. 2004 Mar;10(3):248-54
references.pmid: 14966518
references.citation: Curr Biol. 2004 Jul 27;14(14):1296-302
references.pmid: 15268862
references.citation: Nat Cell Biol. 2004 Nov;6(11):1122-8
references.pmid: 15467718
references.citation: Science. 2004 Dec 24;306(5705):2267-70
references.pmid: 15618521
references.citation: Science. 2005 Feb 18;307(5712):1098-101
references.pmid: 15718470
references.citation: Cell. 2006 Feb 10;124(3):471-84
references.pmid: 16469695
references.citation: Mol Cell. 2006 Apr 21;22(2):159-68
references.pmid: 16603397
references.citation: Circulation. 2006 May 2;113(17):2097-104
references.pmid: 16636172
references.citation: Dev Cell. 2006 Oct;11(4):583-9
references.pmid: 16962829
references.citation: Cell. 2006 Oct 6;127(1):125-37
references.pmid: 16962653
references.citation: Genes Dev. 2006 Oct 15;20(20):2820-32
references.pmid: 17043309
references.citation: Dev Cell. 2006 Dec;11(6):859-71
references.pmid: 17141160
references.citation: Proc Natl Acad Sci U S A. 2007 May 29;104(22):9236-41
references.pmid: 17517604
references.citation: EMBO J. 2008 Jul 23;27(14):1932-43
references.pmid: 18566586
references.citation: EMBO J. 2008 Jul 23;27(14):1919-31
references.pmid: 18566587
references.citation: Science. 2012 Mar 30;335(6076):1638-43
references.pmid: 22461615
references.citation: Cell. 2012 Apr 13;149(2):274-93
references.pmid: 22500797
references.citation: J Biol Chem. 2012 Jul 6;287(28):23698-709
references.pmid: 22619175
references.citation: Circulation. 2012 Oct 30;126(18):2208-19
references.pmid: 23019294
references.citation: Nat Cell Biol. 2012 Dec;14(12):1322-9
references.pmid: 23143395
references.citation: PLoS One. 2013;8(1):e54221
references.pmid: 23342106
references.citation: J Biol Chem. 2013 Feb 8;288(6):3977-88
references.pmid: 23275380
references.citation: Genes Dev. 2013 Feb 15;27(4):355-71
references.pmid: 23431053
references.citation: J Biol Chem. 2013 Apr 5;288(14):10176-87
references.pmid: 23426372
references.citation: Cell. 2013 Aug 29;154(5):1047-59
references.pmid: 23954413
references.citation: Circulation. 2013 Nov 5;128(19):2132-44
references.pmid: 24008870
references.citation: Nat Med. 2013 Nov;19(11):1478-88
references.pmid: 24141421
references.citation: Circ Res. 2014 Jan 31;114(3):549-64
references.pmid: 24481845
references.citation: Dev Biol. 2014 Apr 1;388(1):57-67
references.pmid: 24491818
references.citation: Circ Res. 2014 Apr 11;114(8):1268-80
references.pmid: 24557881
references.citation: Mol Cell. 2014 May 22;54(4):639-50
references.pmid: 24813943
references.citation: J Biol Chem. 2014 Aug 29;289(35):24275-88
references.pmid: 25035424
references.citation: Aging Cell. 2014 Oct;13(5):911-7
references.pmid: 25059582
references.citation: Methods Enzymol. 2009;452:165-80
references.pmid: 19200882
references.citation: J Biol Chem. 2009 Mar 20;284(12):8023-32
references.pmid: 19150980
references.citation: Mol Cell Proteomics. 2009 Jul;8(7):1751-64
references.pmid: 19369195
references.citation: Mol Cell Biol. 2009 Nov;29(21):5657-70
references.pmid: 19720745
references.citation: Oncogene. 2010 Feb 18;29(7):1003-16
references.pmid: 19935711
references.citation: J Clin Invest. 2010 Aug;120(8):2805-16
references.pmid: 20644257
references.citation: J Clin Invest. 2010 Oct;120(10):3555-67
references.pmid: 20890045
references.citation: Dev Cell. 2010 Oct 19;19(4):491-505
references.pmid: 20951342
references.citation: Circulation. 2011 Mar 15;123(10):1073-82
references.pmid: 21357822
references.citation: Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6474-9
references.pmid: 21464307
references.citation: Development. 2011 Jun;138(11):2337-46
references.pmid: 21525075
references.citation: Cancer Res. 2011 Jun 15;71(12):4303-13
references.pmid: 21512132
references.citation: Biochem Biophys Res Commun. 2011 Sep 16;413(1):46-52
references.pmid: 21867682
references.citation: Genes Dev. 2012 Jan 1;26(1):54-68
references.pmid: 22215811
references.citation: J Biol Chem. 2001 Jul 27;276(30):28586-97
references.pmid: 11382772
references.citation: J Clin Invest. 2003 May;111(10):1463-74
references.pmid: 12750396
references.citation: Biochem J. 2004 Jul 15;381(Pt 2):453-62
references.pmid: 15109305