Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling
Yoshikazu Nakaoka, … , Toshio Hirano, Naoki Mochizuki
Yoshikazu Nakaoka, … , Toshio Hirano, Naoki Mochizuki
Published July 2, 2007
Citation Information: J Clin Invest. 2007;117(7):1771-1781. https://doi.org/10.1172/JCI30651.
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Research Article Cardiology

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-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.

Authors

Yoshikazu Nakaoka, Keigo Nishida, Masahiro Narimatsu, Atsunori Kamiya, Takashi Minami, Hirofumi Sawa, Katsuya Okawa, Yasushi Fujio, Tatsuya Koyama, Makiko Maeda, Manami Sone, Satoru Yamasaki, Yuji Arai, Gou Young Koh, Tatsuhiko Kodama, Hisao Hirota, Kinya Otsu, Toshio Hirano, Naoki Mochizuki

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Figure 7

Gab1 and Gab2 are required for NRG-1β–dependent ERK and AKT activation in the heart.

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Gab1 and Gab2 are required for NRG-1β–dependent ERK and AKT activation i...
(A) NRG-1β–induced activation of ERK and AKT in the hearts from the indicated mice was assessed using phospho-specific Abs. Activation of ERK and AKT was exclusively attenuated in DKO hearts compared with the other 3 groups. Representative blots of 4 experiments are shown. (B) Phosphorylation of ERK was quantified against total ERK (n = 4). (C) Phosphorylation of AKT was quantified against total AKT (n = 4). *P < 0.05, **P < 0.01 for the indicated groups. Tyrosine phosphorylation of Gab1 (D) and Gab2 (E) and their association with SHP2 and p85 in hearts from the 4 groups of mice after injection with NRG-1β was examined as in Figure 1, A and B. Arrows in D denote the 2 isoforms of Gab1. (F) Tyrosine phosphorylation of ErbB2 (upper panels) and ErbB4 (lower panels) in hearts from the 4 groups were assessed at 5 minutes after NRG-1β injection. Tyrosine phosphorylation of ErbB receptors in the murine hearts upon NRG-1β stimulation was examined by IP with anti-ErbB2 or anti-ErbB4 Ab, followed by IB with the Abs indicated at the left.