TY - JOUR
T1 - Matrix mechanics controls FHL2 movement to the nucleus to activate p21 expression
AU - Nakazawa, Naotaka
AU - Sathe, Aneesh R.
AU - Shivashankar, G. V.
AU - Sheetz, Michael P.
N1 - Funding Information:
We thank Dr. Keiko Kawauchi, Dr. Cheng-Han Yu, Dr. Shota Yamauchi, Dr. Hiroaki Hirata, Dr. Yukako N Motegi, Dr. Ichiro Harada, Dr. Prasuna Rao, and Ms. Yidan Cui for useful discussions; Dr. Chwee Teck Lim and Dr. Brenda Nai Mui Hoon for assistance with the AFM experiments; and Chun Xi Wong and Dr. Andrew Ming-shang Wong for scientific illustration and clarification. This work was supported by the National Research Foundation of Singapore and the Ministry of Education of Singapore through the Mechanobiology Institute, National University of Singapore.
PY - 2016/11/1
Y1 - 2016/11/1
N2 - 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.
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.
KW - Focal adhesion kinase
KW - Four-and-a-half LIM domains 2
KW - Gene expression
KW - Mechanotransduction
KW - Substrate rigidity
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U2 - 10.1073/pnas.1608210113
DO - 10.1073/pnas.1608210113
M3 - Article
C2 - 27742790
AN - SCOPUS:84994234540
SN - 0027-8424
VL - 113
SP - E6813-E6822
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 44
ER -