title: Molecular Characterization of Striated Muscle-Specific Gab1 Isoform as a Critical Signal Transducer for Neuregulin-1/ErbB Signaling in Cardiomyocytes.
abstract: Grb2-associated binder (Gab) docking proteins regulate signals downstream of a variety of growth factors and receptor tyrosine kinases. Neuregulin-1 (NRG-1), a member of epidermal growth factor family, plays a critical role for cardiomyocyte proliferation and prevention of heart failure via ErbB receptors. We previously reported that Gab1 and Gab2 in the myocardium are essential for maintenance of myocardial function in the postnatal heart via transmission of NRG-1/ErbB-signaling through analysis of Gab1/Gab2 cardiomyocyte-specific double knockout mice. In that study, we also found that there is an unknown high-molecular weight (high-MW) Gab1 isoform (120 kDa) expressed exclusively in the heart, in addition to the ubiquitously expressed low-MW (100 kDa) Gab1. However, the high-MW Gab1 has been molecularly ill-defined to date. Here, we identified the high-MW Gab1 as a striated muscle-specific isoform. The high-MW Gab1 has an extra exon encoding 27 amino acid residues between the already-known 3rd and 4th exons of the ubiquitously expressed low-MW Gab1. Expression analysis by RT-PCR and immunostaining with the antibody specific for the high-MW Gab1 demonstrate that the high-MW Gab1 isoform is exclusively expressed in striated muscle including heart and skeletal muscle. The ratio of high-MW Gab1/ total Gab1 mRNAs increased along with heart development. The high-MW Gab1 isoform in heart underwent tyrosine-phosphorylation exclusively after intravenous administration of NRG-1, among several growth factors. Adenovirus-mediated overexpression of the high-MW Gab1 induces more sustained activation of AKT after stimulation with NRG-1 in cardiomyocytes compared with that of β-galactosidase. On the contrary, siRNA-mediated knockdown of the high-MW Gab1 significantly attenuated AKT activation after stimulation with NRG-1 in cardiomyocytes. Taken together, these findings suggest that the striated muscle-specific high-MW isoform of Gab1 has a crucial role for NRG-1/ErbB signaling in cardiomyocytes.
authors.affiliation: Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.|Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Yasui
authors.affiliation: Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.|Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Masaki
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yoh
authors.initials: Y
authors.lastname: Arita
authors.affiliation: Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ishibashi
authors.affiliation: Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
authors.forename: Tadakatsu
authors.initials: T
authors.lastname: Inagaki
authors.affiliation: Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Okazawa
authors.affiliation: Department of Cardiology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Oka
authors.affiliation: Department of Cardiology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Shioyama
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamauchi-Takihara
authors.affiliation: Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sakata
authors.affiliation: Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.|Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.|Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science Technology Agency, Kawaguchi, Saitama, 332-0012, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Nakaoka
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017398:Alternative Splicing; D000818:Animals; D066246:ErbB Receptors / Q000378:metabolism*; D015870:Gene Expression; D051379:Mice; D008970:Molecular Weight; D032383:Myocytes, Cardiac / Q000378:metabolism*; D020890:Neuregulin-1 / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490897:Gab1 protein, mouse; D020890:Neuregulin-1; D010750:Phosphoproteins; D012333:RNA, Messenger; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt