Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling
Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling
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DOI：
10.1172/jci30651
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发表时间：
2007-07-01
影响因子：
15.9
通讯作者：
Mochizuki, Naoki
中科院分区：
文献类型：
--
作者：
Nakaoka, Yoshikazu;Nishida, Keigo;Mochizuki, Naoki
Grb2相关结合蛋白(Gab)家族的支架连接蛋白协调生长因子和细胞因子受体下游的信号通路。在心脏，在EGF家族成员中，NRG-1β(一种内皮产生的旁分泌因子)通过红系白血病病毒癌基因(ErbB)受体诱导Gab1和Gab2的显著酪氨酸磷酸化。我们通过建立心肌细胞特异性GAB1/Gab2双基因敲除小鼠(DKO小鼠)，研究了Gab家族蛋白在NRG-1β/ErbB介导的心脏信号中的作用。虽然DKO小鼠是存活的，但它们表现出显著的脑室扩张和随着年龄的增长收缩能力降低。DKO小鼠出生后因心力衰竭表现出很高的死亡率。此外，我们注意到显著的心内膜弹力纤维增殖症和异常扩张的血管增加在DKO小鼠的脑室。NRG-1β可诱导对照组小鼠心脏ERK和AKT的激活，但不能激活DKO小鼠的心脏。利用DNA芯片分析，我们发现NRG-1β刺激上调了内皮稳定因子血管生成素1在对照组小鼠心脏中的表达，但在DKO小鼠的心脏中没有表达，这是DKO小鼠心脏病理异常的原因。综上所述，我们的观察结果表明，在NRG-1β/ErbB信号通路中，心肌的GAB1和Gab2对于维持心肌功能和心脏毛细血管和心内膜内皮细胞的稳定是必不可少的。
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-1 beta (NRG-1 beta, a paracrine factor produced from endothelium) induced remarkable tyrosine phosphorylation of Gab 1 and Gab2 via erythroblastic leukemia viral oncogene (ErbB) receptors. We examined the role of Gab family proteins in NRG-1 beta/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-1 beta 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-1 beta 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-1 beta/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.