The mammalian Ste20-like kinase 2 (Mst2) modulates stress-induced cardiac hypertrophy

J Biol Chem. 2014 Aug 29;289(35):24275-88. doi: 10.1074/jbc.M114.562405. Epub 2014 Jul 17.


The Hippo signaling pathway has recently moved to center stage in cardiac research because of its key role in cardiomyocyte proliferation and regeneration of the embryonic and newborn heart. However, its role in the adult heart is incompletely understood. We investigate here the role of mammalian Ste20-like kinase 2 (Mst2), one of the central regulators of this pathway. Mst2(-/-) mice showed no alteration in cardiomyocyte proliferation. However, Mst2(-/-) mice exhibited a significant reduction of hypertrophy and fibrosis in response to pressure overload. Consistently, overexpression of MST2 in neonatal rat cardiomyocytes significantly enhanced phenylephrine-induced cellular hypertrophy. Mechanistically, Mst2 positively modulated the prohypertrophic Raf1-ERK1/2 pathway. However, activation of the downstream effectors of the Hippo pathway (Yes-associated protein) was not affected by Mst2 ablation. An initial genetic study in mitral valve prolapse patients revealed an association between a polymorphism in the human MST2 gene and adverse cardiac remodeling. These results reveal a novel role of Mst2 in stress-dependent cardiac hypertrophy and remodeling in the adult mouse and likely human heart.

Keywords: Cardiac Hypertrophy; Cardiovascular Disease; Genetic Polymorphism; Signal Transduction; Transgenic Mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cardiomegaly / enzymology
  • Cardiomegaly / pathology
  • Cardiomegaly / physiopathology*
  • Cell Proliferation
  • Humans
  • In Situ Nick-End Labeling
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phenylephrine / adverse effects
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-raf / metabolism
  • Serine-Threonine Kinase 3
  • Stress, Physiological*


  • Phenylephrine
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-raf
  • Serine-Threonine Kinase 3
  • Stk3 protein, mouse