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

Naotaka Nakazawa, Aneesh R. Sathe, G. V. Shivashankar, Michael Sheetz

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)E6813-E6822
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number44
DOIs
StatePublished - Nov 1 2016
Externally publishedYes

Fingerprint

Mechanics
Phosphorylation
Physiological Phenomena
Gene Expression
Focal Adhesion Protein-Tyrosine Kinases
Focal Adhesions
RNA Polymerase II
Tyrosine
Proteins
Phosphotransferases
Cell Proliferation
Growth

Keywords

  • Focal adhesion kinase
  • Four-and-a-half LIM domains 2
  • Gene expression
  • Mechanotransduction
  • Substrate rigidity

ASJC Scopus subject areas

  • General

Cite this

Matrix mechanics controls FHL2 movement to the nucleus to activate p21 expression. / Nakazawa, Naotaka; Sathe, Aneesh R.; Shivashankar, G. V.; Sheetz, Michael.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 44, 01.11.2016, p. E6813-E6822.

Research output: Contribution to journalArticle

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AU - Shivashankar, G. V.

AU - Sheetz, Michael

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AB - 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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