RSK3 is required for concentric myocyte hypertrophy in an activated Raf1 model for Noonan syndrome

Catherine L. Passariello, Eliana C. Martinez, Hrishikesh Thakur, Maria Cesareo, Jinliang Li, Michael S. Kapiloff

Research output: Contribution to journalArticle

2 Scopus citations

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 Raf1L613V human NS mutation. We confirmed that Raf1L613V knock-in confers a NS-like phenotype, including cardiac hypertrophy. Active RSK3 was increased in Raf1L613V mice. Constitutive RSK3 gene deletion prevented the Raf1L613V-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.

Original languageEnglish (US)
Pages (from-to)98-105
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume93
DOIs
StatePublished - Apr 1 2016

Keywords

  • Heart failure
  • Hypertrophy
  • Noonan Syndrome
  • Remodeling
  • Signal transduction

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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