Journal
CURRENT BIOLOGY
Volume 24, Issue 16, Pages 1909-1917Publisher
CELL PRESS
DOI: 10.1016/j.cub.2014.07.001
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Funding
- US NIH [R01HL062352, P01DK032094, R01EB007049, P30DK090969, NCATS-8UL1TR000003]
- US National Science Foundation [1200834]
- American Heart Association [14GRNT20490285]
- Human Frontier Science Program
- University of Pennsylvania's research center (Materials Research Science and Engineering)
- University of Pennsylvania's research center (Nano Science and Engineering)
- University of Pennsylvania's research center (Nano/Bio Interface)
- Div Of Civil, Mechanical, & Manufact Inn
- Directorate For Engineering [1200834] Funding Source: National Science Foundation
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Tissue microenvironments are characterized not only in terms of chemical composition but also by collective properties such as stiffness, which influences the contractility of a cell, its adherent morphology, and even differentiation [1-8]. The nucleoskeletal protein lamin-A,C increases with matrix stiffness, confers nuclear mechanical properties, and influences differentiation of mesenchymal stem cells (MSCs), whereas B-type lamins remain relatively constant [9]. Here we show in single-cell analyses that matrix stiffness couples to myosin-II activity to promote lamin-A,C dephosphorylation at Ser22, which regulates turnover, lamina physical properties, and actomyosin expression. Lamin-A,C phosphorylation is low in interphase versus dividing cells, and its levels rise with states of nuclear rounding in which myosin-II generates little to no tension. Phosphorylated lamin-A,C localizes to nucleoplasm, and phosphorylation is enriched on lamin-A,C fragments and is suppressed by a cyclin-dependent kinase (CDK) inhibitor. Lamin-A,C knockdown in primary MSCs suppresses transcripts predominantly among actomyosin genes, especially in the serum response factor (SRF) pathway. Levels of myosin-IIA thus parallel levels of lamin-A,C, with phosphosite mutants revealing a key role for phosphoregulation. In modeling the system as a parsimonious gene circuit, we show that tension-dependent stabilization of lamin-A,C and myosin-IIA can suitably couple nuclear and cell morphology down-stream of matrix mechanics.
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