Neuregulin activates erbB2-dependent Src/FAK signaling and cytoskeletal remodeling in isolated adult rat cardiac myocytes
Neuregulin activates erbB2-dependent Src/FAK signaling and cytoskeletal remodeling in isolated adult rat cardiac myocytes
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DOI：
10.1016/j.yjmcc.2006.04.007
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发表时间：
2006-08-01
影响因子：
5
通讯作者：
Sawyer, Douglas B.
中科院分区：
文献类型：
--
作者：
Kuramochi, Yukio;Guo, Xinxin;Sawyer, Douglas B.
心肌细胞erbB 2的表达是维持正常心脏结构和功能所必需的，尽管其在心脏细胞生理学中的作用还不完全清楚。我们测试的假设，erbB 2信号调节局灶性粘连形成通过激活src/FAK通路，使用成年大鼠心室肌细胞在原代培养。erbB配体神经调节蛋白-1 β（NRG-1 β）诱导Src在Y 416和Y215处以及FAK在Y861处的磷酸化。使用抗体和药物抑制剂策略，我们发现FAK激活是erbB 2和Src依赖的，但独立于PI 3激酶/Akt通路。此外，NRG-1 β刺激erbB 2，FAK，p130（CAS）和桩蛋白之间的多蛋白复合物的形成在30分钟内，并诱导板状伪足与纵向延长的心肌细胞在几天内。板状伪足的延伸导致分离的肌细胞之间的细胞间接触恢复，从而允许同步搏动。NRG-1 β的这些作用被src抑制剂以及erbB 2抗体阻止。这些结果表明，NRG-1 β/erbB 2/Src/FAK信号在心肌细胞的电和机械耦合的维持和修复中的潜在作用。(c)2006年爱思唯尔公司All rights reserved.
Cardiac myocyte erbB2 expression is required for maintenance of normal cardiac structure and function, though its role in cardiac cellular physiology is incompletely understood. We tested the hypothesis that erbB2 signaling modulates focal adhesion formation via activation of a src/FAK pathway using adult rat ventricular myocytes in primary culture. The erbB ligand neuregulin-1 beta (NRG-1 beta) induced phosphorylation of Src at Y416 and Y215, and FAK at Y861. Using antibody and pharmacological inhibitor strategies, we found that FAK activation was erbB2- and Src-dependent, but independent of PI3-kinase/Akt pathway. Furthermore, NRG-1 beta stimulated the formation of a multiprotein complex between erbB2, FAK, p130(CAS) and paxillin within 30 min, and induced lamellipodia with longitudinal elongation of the myocytes within days. The extension of lamellipodia resulted in restoration of cell-to-cell contact between isolated myocytes, allowing for synchronous beating. These effects of NRG-1 beta were prevented by a src inhibitor as well as an antibody to erbB2. These results suggest the potential role of NRG-1 beta/erbB2/Src/FAK signaling in the maintenance and repair of electrical and mechanical coupling in cardiomyocytes. (c) 2006 Elsevier Inc. All rights reserved.