title: RSK3 is required for concentric myocyte hypertrophy in an activated Raf1 model for Noonan syndrome.
abstract: Noonan syndrome (NS) is a congenital disorder resulting from mutations of the Ras-Raf signaling pathway. Hypertrophic cardiomyopathy associated with RAF1 "RASopathy" mutations is a major risk factor for heart failure and death in NS and has been attributed to activation of MEK1/2-ERK1/2 mitogen-activated protein kinases. We recently discovered that type 3 p90 ribosomal S6 kinase (RSK3) is an ERK effector that is required, like ERK1/2, for concentric myocyte hypertrophy in response to pathological stress such as pressure overload. In order to test whether RSK3 also contributes to NS-associated hypertrophic cardiomyopathy, RSK3 knock-out mice were crossed with mice bearing the Raf1(L613V) human NS mutation. We confirmed that Raf1(L613V) knock-in confers a NS-like phenotype, including cardiac hypertrophy. Active RSK3 was increased in Raf1(L613V) mice. Constitutive RSK3 gene deletion prevented the Raf1(L613V)-dependent concentric growth in width of the cardiac myocyte and attenuated cardiac hypertrophy in female mice. These results are consistent with RSK3 being an important mediator of ERK1/2-dependent growth in RASopathy. In conjunction with previously published data showing that RSK3 is important for pathological remodeling of the heart, these data suggest that targeting of this downstream MAP-kinase pathway effector should be considered in the treatment of RASopathy-associated hypertrophic cardiomyopathy.
authors.affiliation: Cardiac Signal Transduction and Cellular Biology Laboratory, Interdisciplinary Stem Cell Institute, Departments of Pediatrics and Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33101, United States.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Passariello
authors.affiliation: Cardiac Signal Transduction and Cellular Biology Laboratory, Interdisciplinary Stem Cell Institute, Departments of Pediatrics and Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33101, United States.
authors.forename: Eliana C
authors.initials: EC
authors.lastname: Martinez
authors.affiliation: Cardiac Signal Transduction and Cellular Biology Laboratory, Interdisciplinary Stem Cell Institute, Departments of Pediatrics and Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33101, United States.
authors.forename: Hrishikesh
authors.initials: H
authors.lastname: Thakur
authors.affiliation: Cardiac Signal Transduction and Cellular Biology Laboratory, Interdisciplinary Stem Cell Institute, Departments of Pediatrics and Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33101, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Cesareo
authors.affiliation: Cardiac Signal Transduction and Cellular Biology Laboratory, Interdisciplinary Stem Cell Institute, Departments of Pediatrics and Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33101, United States.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Li
authors.affiliation: Cardiac Signal Transduction and Cellular Biology Laboratory, Interdisciplinary Stem Cell Institute, Departments of Pediatrics and Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33101, United States. Electronic address: mkapiloff@med.miami.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kapiloff
mesh_terms: D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism; D004195:Disease Models, Animal; D004452:Echocardiography; D004789:Enzyme Activation; D005260:Female; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009634:Noonan Syndrome / Q000150:complications* / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics* / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics* / Q000378:metabolism; D020257:Ventricular Remodeling
chemical_list: D019908:Proto-Oncogene Proteins c-raf; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3
keywords: Heart failure; Hypertrophy; Noonan Syndrome; Remodeling; Signal transduction