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


    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. © 2014 Elsevier Ltd.
    Original languageEnglish
    Pages (from-to)1909-1917
    Number of pages8
    JournalCurrent Biology
    Issue number16
    Publication statusPublished - 18 Aug 2014


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