Microtubules regulate GEF-H1 in response to extracellular matrix stiffness.
Microtubules regulate GEF-H1 in response to extracellular matrix stiffness.
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DOI：
10.1091/mbc.e11-10-0876
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发表时间：
2012-07
影响因子：
3.3
通讯作者：
Keely PJ
中科院分区：
文献类型：
--
作者：
Heck JN;Ponik SM;Garcia-Mendoza MG;Pehlke CA;Inman DR;Eliceiri KW;Keely PJ
Rho GTP酶在机械感觉中起作用，乳腺上皮细胞通过Rho介导的收缩来感知细胞外基质的硬度。刚性基质降低了微管的稳定性，从而导致Rho交换因子gef-h1的激活。乳腺上皮细胞通过Rho介导的收缩作用感受细胞外基质的硬度。反过来，基质刚性调节RhoA的活性。然而，上游信令机制的定义并不明确。在这里，我们证明了Rho交换因子gef-h1介导了RhoA的激活，以响应细胞外基质的刚性。我们证明了这一新发现，即僵硬的三维(3D)细胞外基质降低了微管的稳定性，从而导致全球环境基金-H1的激活。令人惊讶的是，丝裂原激活的蛋白激酶/细胞外信号调节的激酶通路的激活并不有助于僵硬诱导的全球环境基金-H1的激活。全球环境基金-H1的缺失减少了细胞对3D基质的收缩和侵袭。这些数据支持一个模型，在该模型中，基质硬度通过微管失稳以及随后全球环境基金-H1的释放和激活来调节RhoA。
Rho GTPase plays a role in mechanosensing, and breast epithelial cells sense the stiffness of the extracellular matrix through Rho-mediated contractility. Microtubule stability is reduced by a stiff matrix, which leads to the activation of the Rho exchange factor GEF-H1. Breast epithelial cells sense the stiffness of the extracellular matrix through Rho-mediated contractility. In turn, matrix stiffness regulates RhoA activity. However, the upstream signaling mechanisms are poorly defined. Here we demonstrate that the Rho exchange factor GEF-H1 mediates RhoA activation in response to extracellular matrix stiffness. We demonstrate the novel finding that microtubule stability is diminished by a stiff three-dimensional (3D) extracellular matrix, which leads to the activation of GEF-H1. Surprisingly, activation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway did not contribute to stiffness-induced GEF-H1 activation. Loss of GEF-H1 decreases cell contraction of and invasion through 3D matrices. These data support a model in which matrix stiffness regulates RhoA through microtubule destabilization and the subsequent release and activation of GEF-H1.