Biophysical Society Thematic Meeting | Singapore

Mechanobiology of Disease

Poster Abstracts

55-POS Board 55 Matrix Mechanics Controls FHL2 Movement to the Nucleus to Activate P21 Expression Naotaka Nakazawa 1 , Aneesh R. Sathe 1 , G.V. Shivashankar 1,2,3 , Michael P. Sheetz 1,2,4 . 1 Mechanobiology Institute, Singapore, Singapore, 2 National University of Singapore, Singapore, Singapore, 3 FIRC Institute of Molecular Oncology, Milan, Italy, 4 Columbia University, New York, NY, USA. Substrate rigidity affects many physiological processes through mechano-chemical signals from focal adhesion (FA) complexes that subsequently modulate gene expression. We find that shuttling of the LIM domain protein, four and a half LIM domain (FHL2) protein, between focal adhesions (FAs) and the nucleus depends upon matrix mechanics. In particular, on soft surfaces or after the loss of force, FHL2 moves from FAs into the nucleus, and concentrates at RNA Pol II sites, where it acts as a transcriptional co-factor, 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 focal adhesion 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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