Nanoscale integrin cluster dynamics controls cellular mechanosensing via FAKY397 phosphorylation

Bo Cheng, Wanting Wan, Guoyou Huang, Yuhui Li, Guy M. Genin, Mohammad R.K. Mofrad, Tian Jian Lu, Feng Xu, Min Lin

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

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.

Original languageEnglish
Article numbereaax1909
JournalScience Advances
Volume6
Issue number10
DOIs
StatePublished - 2020

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