SHP2 mediates gp130-dependent cardiomyocyte hypertrophy via negative regulation of skeletal alpha-actin gene.
Morphological and biochemical phenotypes of cardiomyocyte hypertrophy are determined by neurohumoral factors. Stimulation of G protein-coupled receptor (GPCR) results in uniform cell enlargement in all directions with an increase in skeletal alpha-actin (alpha-SKA) gene expression, while stimulation of gp130 receptor by interleukin-6 (IL-6)-related cytokines induces longitudinal elongation with no increase in alpha-SKA gene expression. Thus, alpha-SKA is a discriminating marker for hypertrophic phenotypes; however, regulatory mechanisms of alpha-SKA gene expression remain unknown. Here, we clarified the role of SH2-containing protein tyrosine phosphatase 2 (SHP2) in alpha-SKA gene expression. In neonatal rat cardiomyocytes, endothelin-1 (ET-1), a GPCR agonist, but not leukemia inhibitory factor (LIF), an IL-6-related cytokine, induced RhoA activation and promotes alpha-SKA gene expression via RhoA. In contrast, LIF, but not ET-1, induced activation of SHP2 in cardiomyocytes, suggesting that SHP2 might negatively regulate alpha-SKA gene expression downstream of gp130. Therefore, we examined the effect of adenovirus-mediated overexpression of wild-type SHP2 (SHP2(WT)), dominant-negative SHP2 (SHP2(C/S)), or beta-galactosidase (beta-gal), on alpha-SKA gene expression. LIF did not upregulate alpha-SKA mRNA in cardiomyocytes overexpressing either beta-gal or SHP2(WT). In cardiomyocytes overexpressing SHP2(C/S), LIF induced upregulation of alpha-SKA mRNA, which was abrogated by concomitant overexpression of either C3-toxin or dominant-negative RhoA. RhoA was activated after LIF stimulation in the cardiomyocytes overexpressing SHP2(C/S), but not in myocytes overexpressing beta-gal. Furthermore, SHP2 mediates LIF-induced longitudinal elongation of cardiomyocytes via ERK5 activation. Collectively, these findings indicate that SHP2 negatively regulates alpha-SKA expression via RhoA inactivation and suggest that SHP2 implicates ERK5 in cardiomyocyte elongation downstream of gp130.
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Yamadaoka, Osaka, Japan. ynakaoka@imed3.med.osaka-u.ac.jp
Yoshikazu
Y
Nakaoka
Wataru
W
Shioyama
Satoshi
S
Kunimoto
Yoh
Y
Arita
Kaori
K
Higuchi
Kaori
K
Yamamoto
Yasushi
Y
Fujio
Keigo
K
Nishida
Tadashi
T
Kuroda
Hisao
H
Hirota
Keiko
K
Yamauchi-Takihara
Toshio
T
Hirano
Issei
I
Komuro
Naoki
N
Mochizuki
D000199:Actins / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics*; D048430:Cell Shape / Q000187:drug effects; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D019332:Endothelin-1 / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000199:Actins; D019332:Endothelin-1; D053605:Leukemia Inhibitory Factor; D012333:RNA, Messenger; D050822:Cytokine Receptor gp130; D048054:Mitogen-Activated Protein Kinase 7; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D020742:rhoA GTP-Binding Protein