TY - JOUR
T1 - Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling
AU - Nakaoka, Yoshikazu
AU - Nishida, Keigo
AU - Narimatsu, Masahiro
AU - Kamiya, Atsunori
AU - Minami, Takashi
AU - Sawa, Hirofumi
AU - Okawa, Katsuya
AU - Fujio, Yasushi
AU - Koyama, Tatsuya
AU - Maeda, Makiko
AU - Sone, Manami
AU - Yamasaki, Satoru
AU - Arai, Yuji
AU - Gou, Young Koh
AU - Kodama, Tatsuhiko
AU - Hirota, Hisao
AU - Otsu, Kinya
AU - Hirano, Toshio
AU - Mochizuki, Naoki
PY - 2007/7/2
Y1 - 2007/7/2
N2 - 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-1β (NRG-1β, 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-1β/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-1β 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-1β 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-1β/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.
AB - 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-1β (NRG-1β, 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-1β/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-1β 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-1β 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-1β/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.
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U2 - 10.1172/JCI30651
DO - 10.1172/JCI30651
M3 - Article
C2 - 17571162
AN - SCOPUS:34447134047
SN - 0021-9738
VL - 117
SP - 1771
EP - 1781
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 7
ER -