title: 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.affiliation: Mechanobiology Institute, National University of Singapore, Singapore 117411.
authors.forename: Naotaka
authors.initials: N
authors.lastname: Nakazawa
authors.affiliation: Mechanobiology Institute, National University of Singapore, Singapore 117411.
authors.forename: Aneesh R
authors.initials: AR
authors.lastname: Sathe
authors.affiliation: Mechanobiology Institute, National University of Singapore, Singapore 117411.|Department of Biological Sciences, National University of Singapore, Singapore 117543.|Institute of Molecular Oncology, Italian Foundation for Cancer Research, Milan 20139, Italy.
authors.forename: G V
authors.initials: GV
authors.lastname: Shivashankar
authors.affiliation: Mechanobiology Institute, National University of Singapore, Singapore 117411; ms2001@columbia.edu.|Department of Biological Sciences, National University of Singapore, Singapore 117543.|Department of Biological Sciences, Columbia University, New York, NY 10027.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Sheetz
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000502:physiology*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D024462:Myosin Type II / Q000378:metabolism; D010766:Phosphorylation; D017354:Point Mutation; D012319:RNA Polymerase II; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003598:Cytoskeletal Proteins; C105987:FHL2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D014157:Transcription Factors; D014443:Tyrosine; D051416:Focal Adhesion Protein-Tyrosine Kinases; D012319:RNA Polymerase II; D024462:Myosin Type II
keywords: focal adhesion kinase; four-and-a-half LIM domains 2; gene expression; mechanotransduction; substrate rigidity