67 / 129
Mechanobiology of Disease
Poster Abstracts
62
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.