Matrix mechanics controls FHL2 movement to the nucleus to activate p21 expression.

Abstract:

: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.

authors

Nakazawa N,Sathe AR,Shivashankar GV,Sheetz MP

doi

10.1073/pnas.1608210113

subject

Has Abstract

pub_date

2016-11-01 00:00:00

pages

E6813-E6822

issue

44

eissn

0027-8424

issn

1091-6490

pii

1608210113

journal_volume

113

pub_type

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