title: Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling.
abstract: Grb2-associated binder (Gab) family of scaffolding adaptor proteins coordinate signaling cascades downstream of growth factor and cytokine receptors. In the heart, among EGF family members, neuregulin-1beta (NRG-1beta, a paracrine factor produced from endothelium) induced remarkable tyrosine phosphorylation of Gab1 and Gab2 via erythroblastic leukemia viral oncogene (ErbB) receptors. We examined the role of Gab family proteins in NRG-1beta/ErbB-mediated signal in the heart by creating cardiomyocyte-specific Gab1/Gab2 double knockout mice (DKO mice). Although DKO mice were viable, they exhibited marked ventricular dilatation and reduced contractility with aging. DKO mice showed high mortality after birth because of heart failure. In addition, we noticed remarkable endocardial fibroelastosis and increase of abnormally dilated vessels in the ventricles of DKO mice. NRG-1beta induced activation of both ERK and AKT in the hearts of control mice but not in those of DKO mice. Using DNA microarray analysis, we found that stimulation with NRG-1beta upregulated expression of an endothelium-stabilizing factor, angiopoietin 1, in the hearts of control mice but not in those of DKO mice, which accounted for the pathological abnormalities in the DKO hearts. Taken together, our observations indicated that in the NRG-1beta/ErbB signaling, Gab1 and Gab2 of the myocardium are essential for both maintenance of myocardial function and stabilization of cardiac capillary and endocardial endothelium in the postnatal heart.
authors.affiliation: Department of Structural Analysis, National Cardiovascular Center Research Institute, Osaka, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Nakaoka
authors.forename: Keigo
authors.initials: K
authors.lastname: Nishida
authors.forename: Masahiro
authors.initials: M
authors.lastname: Narimatsu
authors.forename: Atsunori
authors.initials: A
authors.lastname: Kamiya
authors.forename: Takashi
authors.initials: T
authors.lastname: Minami
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sawa
authors.forename: Katsuya
authors.initials: K
authors.lastname: Okawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fujio
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Koyama
authors.forename: Makiko
authors.initials: M
authors.lastname: Maeda
authors.forename: Manami
authors.initials: M
authors.lastname: Sone
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamasaki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Arai
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Hisao
authors.initials: H
authors.lastname: Hirota
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
authors.forename: Toshio
authors.initials: T
authors.lastname: Hirano
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018376:Cardiovascular Abnormalities / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D006321:Heart / Q000502:physiology*; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D020890:Neuregulin-1 / Q000378:metabolism*; D018739:Oncogene Proteins v-erbB / Q000378:metabolism*; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D042683:Angiopoietin-1; C490897:Gab1 protein, mouse; C490894:Gab2 protein, mouse; D020890:Neuregulin-1; D018739:Oncogene Proteins v-erbB; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases