The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins.
The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins.
复制标题
DOI：
10.1038/ncb2254
复制
发表时间：
2011-06
影响因子：
21.3
通讯作者：
中科院分区：
文献类型：
--
作者：
单个细胞如何对机械力作出反应是生物学家相当感兴趣的，因为力影响细胞行为的许多方面。对整联蛋白施加力会触发细胞骨架重排和相关粘附复合物的生长，导致细胞刚度增加，也称为强化。虽然RhoA已被证明在强化过程中发挥作用，但调节其活性的分子机制尚不清楚。通过结合生物化学和生物物理方法，我们确定了两个鸟嘌呤核苷酸交换因子（GEFs），LARG和GEF-H1，作为调节细胞适应力的关键分子。我们发现，刺激整合素与张力触发激活这两个GEFs和他们的招聘粘附复合物。令人惊讶的是，LARG和GEF-H1的激活涉及不同的信号通路。我们的研究结果表明，LARG被激活的Src家族酪氨酸激酶Fyn，而GEF-H1的催化活性增强ERK下游的信号级联，包括FAK和Ras。
How individual cells respond to mechanical forces is of considerable interest to biologists as force affects many aspects of cell behavior. Application of force on integrins triggers cytoskeletal rearrangements and growth of the associated adhesion complex, resulting in increased cellular stiffness, also known as reinforcement. While RhoA has been shown to play a role during reinforcement, the molecular mechanisms that regulate its activity are unknown. By combining biochemical and biophysical approaches, we identified two guanine nucleotide exchange factors (GEFs), LARG and GEF-H1, as key molecules that regulate the cellular adaptation to force. We show that stimulation of integrins with tensional force triggers activation of these two GEFs and their recruitment to adhesion complexes. Surprisingly, activation of LARG and GEF-H1 involves distinct signaling pathways. Our results reveal that LARG is activated by the Src family tyrosine kinase Fyn, whereas GEF-H1 catalytic activity is enhanced by ERK downstream of a signaling cascade that includes FAK and Ras.