Mitogen-activated protein kinase (ERK1/2) activation by shear stress and adhesion in endothelial cells. Essential role for a herbimycin-sensitive kinase.
Mitogen-activated protein kinase (ERK1/2) activation by shear stress and adhesion in endothelial cells. Essential role for a herbimycin-sensitive kinase.
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内皮细胞中剪切应力和粘附作用激活丝裂原激活蛋白激酶 (ERK1/2)。
DOI：
10.1172/jci119083
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Berk,BC
中科院分区：
文献类型：
--
作者：
Takahashi,M;Berk,BC
流体剪切应力通过刺激机械敏感的内皮细胞信号事件来调节血管功能和结构。由整合素-基质相互作用介导的细胞粘附也通过机械敏感事件调节细胞内信号。为了深入了解整合素基质相互作用的作用，我们比较了粘连和剪切应力刺激的人脐静脉内皮细胞（HUVEC）中酪氨酸磷酸化和细胞外信号调节激酶（ERK1/2）的激活。HUVEC与纤维连接蛋白的粘附，而不是与聚l -赖氨酸的粘附，迅速激活了ERK1/2。流体剪切应力（12 dyn/cm2）增强了粘附刺激的ERK1/2激活，表明存在单独的途径。在信号转导上发现了两个差异：黏附使黏附激酶磷酸化迅速增加，而剪切应力没有增加；当肌动蛋白丝被细胞松弛素d破坏时，ERK1/2对粘附反应的激活受到更大程度的抑制。ERK1/2的激活有两个相似之处：PKC下调时，PKC的活性被完全抑制；需要一种对红霉素敏感（染料木素和酪氨酸不敏感）的酪氨酸激酶。c-Src被确定为候选酪氨酸激酶，因为它可以被剪切应力和粘附激活。这些发现表明，粘附和剪切应力通过一个涉及herbimycin敏感酪氨酸激酶和PKC的共享途径激活ERK1/2。此外，剪切应力通过另一种部分独立于细胞骨架完整性的途径激活ERK1/2。
Fluid shear stress modulates vascular function and structure by stimulating mechanosensitive endothelial cell signal events. Cell adhesion, mediated by integrin-matrix interactions, also regulates intracellular signaling by mechanosensitive events. To gain insight into the role of integrin-matrix interactions, we compared tyrosine phosphorylation and extracellular signal-regulated kinase (ERK1/2) activation in adhesion- and shear stress-stimulated human umbilical vein endothelial cells (HUVEC). Adhesion of HUVEC to fibronectin, but not to poly-L-lysine, rapidly activated ERK1/2. Fluid shear stress (12 dyn/cm2) enhanced ERK1/2 activation stimulated by adhesion, suggesting the presence of a separate pathway. Two differences in signal transduction were identified: focal adhesion kinase phosphorylation was increased rapidly by adhesion but not by shear stress; and ERK1/2 activation in response to adhesion was inhibited to a significantly greater extent when actin filaments were disrupted by cytochalasin D. Two similarities in activation of ERK1/2 were observed: protein kinase C (PKC) activity was necessary as shown by complete inhibition when PKC was downregulated; and an herbimycin-sensitive (genistein- and tyrphostin-insensitive) tyrosine kinase was required. c-Src was identified as a candidate tyrosine kinase as it was activated by both shear stress and adhesion. These findings suggest that adhesion and shear stress activate ERK1/2 via a shared pathway that involves an herbimycin-sensitive tyrosine kinase and PKC. In addition, shear stress activates ERK1/2 through another pathway that is partially independent of cytoskeletal integrity.