The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P.R. China.
Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, P.R. China.
Sci Adv. 2020 Mar 4;6(10):eaax1909. doi: 10.1126/sciadv.aax1909. eCollection 2020 Mar.
Transduction of extracellular matrix mechanics affects cell migration, proliferation, and differentiation. While this mechanotransduction is known to depend on the regulation of focal adhesion kinase phosphorylation on Y397 (FAKpY397), the mechanism remains elusive. To address this, we developed a mathematical model to test the hypothesis that FAKpY397-based mechanosensing arises from the dynamics of nanoscale integrin clustering, stiffness-dependent disassembly of integrin clusters, and FAKY397 phosphorylation within integrin clusters. Modeling results predicted that integrin clustering dynamics governs how cells convert substrate stiffness to FAKpY397, and hence governs how different cell types transduce mechanical signals. Existing experiments on MDCK cells and HT1080 cells, as well as our new experiments on 3T3 fibroblasts, confirmed our predictions and supported our model. Our results suggest a new pathway by which integrin clusters enable cells to calibrate responses to their mechanical microenvironment.
细胞外基质力学的转导影响细胞的迁移、增殖和分化。虽然已知这种力学转导依赖于黏着斑激酶磷酸化在 Y397 上的调节（FAKpY397），但机制仍不清楚。为了解决这个问题，我们开发了一个数学模型来检验这样一个假设，即基于 FAKpY397 的机械感觉源自纳米级整合素聚类的动力学、整合素簇的刚度依赖性解体以及整合素簇内的 FAKY397 磷酸化。模型结果预测，整合素聚类动力学控制着细胞如何将基质刚度转化为 FAKpY397，因此控制着不同类型的细胞如何传递机械信号。对 MDCK 细胞和 HT1080 细胞的现有实验，以及我们对 3T3 成纤维细胞的新实验，证实了我们的预测并支持了我们的模型。我们的结果表明了一种新的途径，即整合素簇使细胞能够校准对其机械微环境的反应。
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