Key result
Soft surfaces or loss of force induced FHL2 movement from focal adhesions to the nucleus, increasing p21 expression and inhibiting cell growth via FAK phosphorylation.
Demonstrates a mechanochemical signaling pathway where matrix softness induces FHL2 nuclear translocation via FAK phosphorylation to upregulate p21 and inhibit cell proliferation.
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May link matrix stiffness to gene regulation in cardiac cells; leaves open in vivo relevance and therapeutic targeting in fibrosis.
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.
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Nakazawa et al. (2016) studied this question. Soft surfaces or loss of force was evaluated on FHL2 movement to the nucleus and p21 gene expression. Soft surfaces or loss of force induced FHL2 movement from focal adhesions to the nucleus, increasing p21 expression and inhibiting cell growth via FAK phosphorylation.
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