Fluid shear stress activation of focal adhesion kinase - Linking to mitogen-activated protein kinases
Fluid shear stress activation of focal adhesion kinase - Linking to mitogen-activated protein kinases
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DOI：
10.1074/jbc.272.48.30455
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发表时间：
1997-11-28
影响因子：
4.8
通讯作者：
Shyy, JYJ
中科院分区：
文献类型：
--
作者：
Li, S;Kim, M;Shyy, JYJ
剪切应力作为血流动力学力的切向分量，激活培养血管内皮细胞胞外信号调节激酶（ERK）和c-Jun nh2末端激酶（JNK）信号转导通路，诱导许多即时早期基因的转录激活。整合素、蛋白酪氨酸激酶和肌动蛋白的结构完整性似乎是参与这些剪切应力诱导反应的重要因素。通过对牛主动脉内皮细胞（BAEC）施加12 dyn/cm(2)的剪切应力，研究了潜在的分子事件，我们发现这种剪切应力以快速和短暂的方式增加了酪氨酸磷酸化和focal adhesion kinase （FAK）的激酶活性及其与生长因子受体结合蛋白2 （Grb2）的关联，表明FAK可能通过Grb2与这些丝裂原激活的蛋白激酶信号通路相关。7 - less （Sos）复合物之子FAK（F397Y）编码FAK的显性负突变体，减弱剪切应力诱导的Myc表位标记的ERK2和血凝素表位标记的JNK1的激酶活性。Delta mSos1编码的Sos显性负突变体鸟嘌核苷酸交换结构域被删除，也能减弱剪切应激对Myc-ERK2和血凝素- jnk1的激活。用阻断型抗粘连蛋白受体单克隆抗体预处理融合BAEC单层，对这些剪切应激激活的ERKs和JNKs具有类似的抑制作用。共聚焦显微镜观察进一步表明，FAK倾向于与玻璃体连接蛋白受体聚集在剪切BAEC的腔侧附近。这些结果表明FAK信号在剪切应力诱导的ERK和JNK的双重激活中起着关键作用。
Shear stress, the tangential component of hemodynamic forces, activates the extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) signal transduction pathways in cultured vascular endothelial cells to induce the transcriptional activation of many immediate early genes. It appears that integrins, protein-tyrosine kinases, and the structural integrity of actin are important factors involved in these shear stress-induced responses. The underlying molecular events were investigated by the application of a shear stress of 12 dyn/cm(2) on bovine aortic endothelial cells (BAEC), We found that such a shear stress increased the tyrosine phosphorylation and the kinase activity of focal adhesion kinase (FAK) and its association with growth factor receptor binding protein 2 (Grb2) in a rapid and transient manner, suggesting that FAK may be linked to these mitogen-activated protein kinase signaling pathways through a Grb2.Son of sevenless (Sos) complex, FAK(F397Y), which encodes a dominant negative mutant of FAK, attenuated the shear stress-induced kinase activity of Myc epitope-tagged ERK2 and hemagglutinin epitope-tagged JNK1. Delta mSos1, encoding a dominant negative mutant of Sos in which the guanine nucleotide exchange domain has been deleted, also attenuated shear stress activation of Myc-ERK2 and hemagglutinin-JNK1, Pretreating the confluent BAEC monolayers with a blocking type antivitronectin receptor monoclonal antibody had similar inhibitory effects in these shear stress-activated ERKs and JNKs. Confocal microscopic observation further demonstrated that FAK tended to cluster with vitronectin receptor near the abluminal side of the sheared BAEC. These results demonstrate that FAK signaling is critical in the shear stress-induced dual activation of ERK and JNK.