title: Crosstalk between ERK1/2 and STAT3 in the modulation of cardiomyocyte hypertrophy induced by cardiotrophin-1.
abstract: BACKGROUND
  The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway and the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway are the two major independent signal transduction pathways. However, it has recently been found that STAT3 may be negatively regulated by ERK1/2 in gp130-dependent signaling. Cardiotrophin-1 (CT-1), a potent novel hypertrophic cytokine, depends on gp130 to induce signaling and depends on STAT3 to exert hypertrophic effect. In this study, we examined whether STAT3 activity was negatively regulated by ERK1/2 during CT-1-induced signaling in rat cardiomyocytes and, if so, whether such crosstalk interfered with the hypertrophic effect of CT-1 and, furthermore, whether the mechanism underlying the crosstalk involved phosphorylation of serine 727 (S727) in STAT3.
  
  
  METHODS
  The activities of ERK1/2 and STAT3 were assessed by in-gel kinase assay and Western blot analysis, respectively. The role of S727 phosphorylation in the crosstalk between ERK1/2 and STAT3 was determined by a transient transfection study using a STAT3S727A mutant. Cardiomyocyte hypertrophy was evaluated by the cellular protein-to-DNA ratio and [(3)H]-leucine incorporation.
  
  
  RESULTS
  CT-1 simultaneously activated both ERK1/2 and STAT3 in rat cardiomyocytes. Inhibition of ERK1/2 by U0126 resulted in an increase of CT-1-induced tyrosine phosphorylation of STAT3 and, consequently, the protein-to-DNA ratio and [(3)H]-leucine incorporation. Transient transfection of the cells with STAT3S727A had no significant effect on CT-1-induced tyrosine phosphorylation of STAT3.
  
  
  CONCLUSIONS
  STAT3 is activated by CT-1 in rat cardiomyocytes, but full activation is mitigated by the simultaneous activation of ERK1/2. The inhibition of ERK1/2 increases the activity of STAT3, which, in turn, enhances the hypertrophic effect of CT-1. The crosstalk between ERK1/2 and STAT3 is independent of the phosphorylation of the S727 in STAT3. Such crosstalk may contribute to the development of adequate cardiac hypertrophy.
authors.affiliation: Hebei Institute of Cardiovascular & Cerebrovascular Diseases, Shijiazhuang 050000, China.
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Ze-Jun
authors.initials: ZJ
authors.lastname: Tian
authors.forename: Yu-ming
authors.initials: YM
authors.lastname: Hao
authors.forename: Jun
authors.initials: J
authors.lastname: Du
authors.forename: Fan
authors.initials: F
authors.lastname: Liu
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiu-guang
authors.initials: XG
authors.lastname: Zu
authors.forename: Su-yun
authors.initials: SY
authors.lastname: Liu
authors.forename: Rui-qin
authors.initials: RQ
authors.lastname: Xie
authors.forename: Xiao-hong
authors.initials: XH
authors.lastname: Yang
authors.forename: Yu-zhou
authors.initials: YZ
authors.lastname: Wu
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: An
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D006332:Cardiomegaly / Q000139:chemically induced* / Q000378:metabolism; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000633:toxicity*; D004268:DNA-Binding Proteins / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D004268:DNA-Binding Proteins; C494201:Il6st protein, rat; D008562:Membrane Glycoproteins; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D050822:Cytokine Receptor gp130; D014443:Tyrosine; C092073:cardiotrophin 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3