Extracellular signal-regulated kinase and c-Jun NH2-terminal kinase activation by mechanical stretch is integrin-dependent and matrix-specific in rat cardiac fibroblasts
Extracellular signal-regulated kinase and c-Jun NH2-terminal kinase activation by mechanical stretch is integrin-dependent and matrix-specific in rat cardiac fibroblasts
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DOI：
10.1172/jci1026
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发表时间：
1998-01-15
影响因子：
15.9
通讯作者：
Ruoslahti, E
中科院分区：
文献类型：
--
作者：
MacKenna, DA;Dolfi, F;Ruoslahti, E
整合素连接细胞骨架和细胞外基质，介导多种信号级联反应，可将机械刺激转化为生化信号。我们研究了整合素和基质依赖性激活细胞外信号调节激酶（ERK 2），c-Jun氨基末端激酶（JNK 1），和p38在大鼠心脏成纤维细胞响应于4%的静态双轴拉伸。ERK 2和JNK 1，但不是p38，迅速激活拉伸时，成纤维细胞被允许合成自己的矩阵。当细胞被限制在特定的基质底物时，ERK 2和JNK 1被差异激活：ERK 2仅在细胞被接种在纤连蛋白上时被激活，而JNK 1在细胞被接种在纤连蛋白、玻连蛋白或层粘连蛋白上时被激活。在拉伸前将细胞接种在胶原蛋白上不会激活任何一种激酶。所有基质的粘附都是整合素依赖性的，因为它可以被特定整合素的抑制剂阻断。ERK 2活化可以用抗α 4和α 5抗体和精氨酸-甘氨酸-天冬氨酸（RGD）肽的组合阻断，而单独使用的抗体或肽不能阻断ERK 2活化。这一结果表明，至少有两种整合素，α 4 β 1和一种RGD导向的非α 5 β 1整合素，响应机械刺激激活ERK 2。JNK 1的激活不能被抑制剂阻断，这表明非RGD依赖性整联蛋白或α 4 β 1以外的整联蛋白可以激活粘附于纤连蛋白的细胞中的JNK 1。这项研究表明，整合素作为mechanotensors，提供洞察潜在的机制，在体内响应机械刺激。
Integrins, which connect the cytoskeleton to the extracellular matrix and mediate a variety of signaling cascades, may transduce mechanical stimuli into biochemical signals. We studied integrin-and matrix-dependent activation of extracellular signal-regulated kinase (ERK2), c-Jun NH2-terminal kinase (JNK1), and p38 in response to 4% static biaxial stretch in rat cardiac fibroblasts. ERK2 and JNK1, but not p38, were rapidly activated by stretch when the fibroblasts were allowed to synthesize their own matrices. When the cells were limited to specific matrix substrates, ERK2 and JNK1 were differentially activated: ERK2 was only activated when the cells were plated on fibronectin, while JNK1 was activated when the cells were plated on fibronectin, vitronectin, or laminin. Plating cells on collagen before stretching did not activate either kinase. Adhesion to all matrices was integrin-dependent because it could be blocked by inhibitors of specific integrins. ERK2 activation could be blocked with a combination of anti-alpha 4 and -alpha 5 antibodies and an arginine-glycine-aspartic acid (RGD) peptide, while the antibodies or peptide used separately failed to block ERK2 activation. This result suggests that at least two integrins, alpha 4 beta 1 and an RGD-directed, non-alpha 5 beta 1 integrin, activate ERK2 in response to mechanical stimulation. Activation of JNK1 could not be blocked with the inhibitors, suggesting that an RGD-independent integrin or integrins other than alpha 4 beta 1 can activate JNK1 in cells adherent to fibronectin. This study demonstrates that integrins act as mechanotransducers, providing insight into potential mechanisms for in vivo responses to mechanical stimuli.