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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.