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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

268 Scopus citations


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 languageAmerican English
Pages (from-to)1909-1917
Number of pages9
JournalCurrent Biology
Issue number16
StatePublished - 18 Aug 2014
Externally publishedYes

Bibliographical note

Funding Information:
We are grateful for support from the US NIH (grants R01HL062352, P01DK032094, R01EB007049, P30DK090969, and NCATS-8UL1TR000003), the US National Science Foundation (grant 1200834), an American Heart Association Grant in Aid (14GRNT20490285), the Human Frontier Science Program, and the University of Pennsylvania’s research centers (Materials Research Science and Engineering; Nano Science and Engineering; Nano/Bio Interface).


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