Matrix elasticity regulates lamin-A,C phosphorylation and turnover with feedback to actomyosin

Curr Biol. 2014 Aug 18;24(16):1909-17. doi: 10.1016/j.cub.2014.07.001. Epub 2014 Aug 7.


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. 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. 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 downstream of matrix mechanics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Differentiation
  • Elasticity
  • Extracellular Matrix / metabolism*
  • Feedback, Physiological
  • Humans
  • Lamin Type A / genetics*
  • Lamin Type A / metabolism
  • Mesenchymal Stem Cells / metabolism*
  • Nonmuscle Myosin Type IIA / genetics*
  • Nonmuscle Myosin Type IIA / metabolism
  • Phosphorylation
  • Single-Cell Analysis


  • Lamin Type A
  • Nonmuscle Myosin Type IIA