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(Circulation Research. 2003;93:221.)
© 2003 American Heart Association, Inc.

Cellular Biology

Activation of gp130 Transduces Hypertrophic Signal Through Interaction of Scaffolding/Docking Protein Gab1 With Tyrosine Phosphatase SHP2 in Cardiomyocytes

Yoshikazu Nakaoka, Keigo Nishida, Yasushi Fujio, Masahiro Izumi, Kazuo Terai, Yuichi Oshima, Shoko Sugiyama, Satoshi Matsuda, Shigeo Koyasu, Keiko Yamauchi-Takihara, Toshio Hirano, Ichiro Kawase, Hisao Hirota

From the Departments of Molecular Medicine (Y.N., M.I., K.T., Y.O., S.S., K.Y.-T., I.K., H.H.) and Molecular Oncology (T.H.), Osaka University Graduate School of Medicine, Osaka, Japan; Laboratory for Cytokine Signaling (K.N., T.H.), RIKEN Research Center for Allergy and Immunology, Kanagawa, Japan; Department of Clinical Evaluation of Medicines and Therapeutics (Y.F.), Osaka University Graduate School of Pharmaceutical Sciences, Osaka, Japan; Department of Microbiology and Immunology (S.M., S.K.), Keio University School of Medicine, Tokyo, Japan; Core Research for Evolutional Science and Technology (CREST) (S.M., S.K.), Japan Science and Technology Corporation, Saitama, Japan; and Laboratory for Developmental Immunology (T.H.), Osaka University Graduate School of Frontier Bioscience, Osaka, Japan.

Correspondence to Hisao Hirota, MD, PhD, Assistant Professor, Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita City, Osaka, 565-0871, Japan. E-mail hirota{at}imed3.med.osaka-u.ac.jp

Grb2-associated binder-1 (Gab1) is a scaffolding/docking protein and contains a Pleckstrin homology domain and potential binding sites for Src homology (SH) 2 and SH3 domains. Gab1 is tyrosine phosphorylated and associates with protein tyrosine phosphatase SHP2 and p85 phosphatidylinositol 3-kinase on stimulation with various cytokines and growth factors, including interleukin-6. We previously demonstrated that interleukin-6–related cytokine, leukemia inhibitory factor (LIF), induced cardiac hypertrophy through gp130. In this study, we report the role of Gab1 in gp130-mediated cardiac hypertrophy. Stimulation with LIF induced tyrosine phosphorylation of Gab1, and phosphorylated Gab1 interacted with SHP2 and p85 in cultured cardiomyocytes. We constructed three kinds of adenovirus vectors, those carrying wild-type Gab1 (AdGab1^WT), mutated Gab1 lacking SHP2 binding site (AdGab1^F627/659), and ß-galactosidase (Adß-gal). Compared with cardiomyocytes infected with Adß-gal, longitudinal elongation of cardiomyocytes induced by LIF was enhanced in cardiomyocytes infected with AdGab1^WT but inhibited in cardiomyocytes infected with AdGab1^F627/659. Upregulation of BNP mRNA expression by LIF was evoked in cardiomyocytes infected with Adß-gal and AdGab1^WT but not in cardiomyocytes infected with AdGab1^F627/659. In contrast, Gab1 repressed skeletal -actin mRNA expression through interaction with SHP2. Furthermore, activation of extracellular signal–regulated kinase 5 (ERK5) was enhanced in cardiomyocytes infected with AdGab1^WT compared with cardiomyocytes infected with Adß-gal but repressed in cardiomyocytes infected with AdGab1^F627/659. Coinfection of AdGab1^WT with adenovirus vector carrying dominant-negative ERK5 abrogated longitudinal elongation of cardiomyocytes induced by LIF. Taken together, these findings indicate that Gab1-SHP2 interaction plays a crucial role in gp130-dependent longitudinal elongation of cardiomyoctes through activation of ERK5.

Key Words: hypertrophy • Gab1 • SHP2 • gp130 • ERK5

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