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

Amnon Buxboim, Joe Swift, Jerome Irianto, Kyle R. Spinler, P. C.Dave P. Dingal, Avathamsa Athirasala, Yun Ruei C. Kao, Sangkyun Cho, Takamasa Harada, Jae Won Shin, Dennis E. Discher

Research output: Contribution to journalArticlepeer-review

181 Scopus citations

Abstract

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 downstream of matrix mechanics.

Original languageEnglish (US)
Pages (from-to)1909-1917
Number of pages9
JournalCurrent Biology
Volume24
Issue number16
DOIs
StatePublished - Aug 18 2014
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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