Matrix mechanics controls FHL2 movement to the nucleus to activate p21 expression
Matrix mechanics controls FHL2 movement to the nucleus to activate p21 expression
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DOI：
10.1073/pnas.1608210113
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发表时间：
2016-11-01
影响因子：
11.1
通讯作者：
Sheetz, Michael P.
中科院分区：
文献类型：
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作者：
Nakazawa, Naotaka;Sathe, Aneesh R.;Sheetz, Michael P.
底物刚性通过粘着斑复合物的机械化学信号影响许多生理过程，随后调节基因表达。我们发现，穿梭的LIM结构域（结构域中发现的蛋白质，Lin 11，Isl-1，和Mec-3）蛋白质四个半LIM结构域2（FHL 2）之间的脂肪酸和细胞核取决于矩阵力学。特别是，在软表面上或失去力后，FHL 2从FA移动到细胞核中并集中在RNA聚合酶（Pol）II位点，在那里它作为转录辅因子，导致p21基因表达增加，这将抑制软表面上的生长。在分子水平上，穿梭需要FHL 2中的特定酪氨酸，以及活性FA激酶（FAK）的磷酸化。因此，我们认为FAK对FHL 2的磷酸化是一个关键的、机械依赖的步骤，它通过增加p21的表达，从软基质向细胞核传递信号，从而抑制细胞增殖。
Substrate rigidity affects many physiological processes through mechanochemical signals from focal adhesion (FA) complexes that subsequently modulate gene expression. We find that shuttling of the LIM domain (domain discovered in the proteins, Lin11, Isl-1, and Mec-3) protein four-and-a-half LIM domains 2 (FHL2) between FAs and the nucleus depends on matrix mechanics. In particular, on soft surfaces or after the loss of force, FHL2 moves from FAs into the nucleus and concentrates at RNA polymerase (Pol) II sites, where it acts as a transcriptional cofactor, causing an increase in p21 gene expression that will inhibit growth on soft surfaces. At the molecular level, shuttling requires a specific tyrosine in FHL2, as well as phosphorylation by active FA kinase (FAK). Thus, we suggest that FHL2 phosphorylation by FAK is a critical, mechanically dependent step in signaling from soft matrices to the nucleus to inhibit cell proliferation by increasing p21 expression.