Matrix Elasticity Regulates Lamin-A,C Phosphorylation and Turnover with Feedback to Actomyosin

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

doi:10.1016/j.cub.2014.07.001

Cited by 333 publications

(423 citation statements)

References 35 publications

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“…Consistent with the results reported here indicating that cyclic stretch may posttranslationally regulate lamin A/C, a 40-kDa lower band of lamin A/C (Fig. S4) indicates cleavage of lamin A/C that is regulated by adhesion and cell mechanics, as shown by Buxboim et al (28). Furthermore, our current study demonstrates that, in addition to lamin A/C, the expression of emerin in VSMCs also is modulated by mechanical cyclic stretch and subsequently induces VSMC proliferation.…”

Section: Discussionsupporting

confidence: 79%

Nuclear envelope proteins modulate proliferation of vascular smooth muscle cells during cyclic stretch application

Yao

Huang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cyclic stretch is an important inducer of vascular smooth muscle cell (VSMC) proliferation, which is crucial in vascular remodeling during hypertension. However, the molecular mechanism remains unclear. We studied the effects of emerin and lamin A/C, two important nuclear envelope proteins, on VSMC proliferation in hypertension and the underlying mechano-mechanisms. In common carotid artery of hypertensive rats in vivo and in cultured cells subjected to high (15%) cyclic stretch in vitro, VSMC proliferation was increased significantly, and the expression of emerin and lamin A/C was repressed compared with normotensive or normal (5%) cyclic stretch controls. Using targeted siRNA to mimic the repressed expression of emerin or lamin A/C induced by 15% stretch, we found that VSMC proliferation was enhanced under static and 5%-stretch conditions. Overexpression of emerin or lamin A/C reversed VSMC proliferation induced by 15% stretch. Hence, emerin and lamin A/C play critical roles in suppressing VSMC hyperproliferation induced by hyperstretch. ChIP-on-chip and MOTIF analyses showed that the DNAs binding with emerin contain three transcription factor motifs: CCNGGA, CCMGCC, and ABTTCCG; DNAs binding with lamin A/C contain the motifs CVGGAA, GCCGCYGC, and DAAGAAA. Protein/DNA array proved that altered emerin or lamin A/C expression modulated the activation of various transcription factors. Furthermore, accelerating local expression of emerin or lamin A/C reversed cell proliferation in the carotid artery of hypertensive rats in vivo. Our findings establish the pathogenetic role of emerin and lamin A/C repression in stretch-induced VSMC proliferation and suggest mechanobiological mechanism underlying this process that involves the sequencespecific binding of emerin and lamin A/C to specific transcription factor motifs.T he cyclic stretch caused by the rhythmical distention and relaxation of the arterial wall during the cardiac cycle is an important factor in the regulation of vascular modeling and remodeling (1, 2). There is growing evidence that mechanical cyclic stretch modulates the functions (e.g., apoptosis, proliferation, and migration) of vascular smooth muscle cells (VSMCs) in the media of the arterial wall (2) and that chronically elevated cyclic stretch stimulates VSMC functions to mediate vascular remodeling during hypertension (3, 4).It has been shown that there are various mechano-sensors in the vascular cell membrane, including lipids (5), glycocalyx (6), and proteins such as integrins (7), G proteins and G protein-coupled receptors (8), receptor tyrosine kinase (9), and Ca 2+ channel (10) and intercellular junction proteins (2, 11). In recent years, it has been suggested that nuclear envelope (NE) proteins, a hallmark of eukaryotic cells, participate in the mechano-transduction networks. Our previous proteomic analysis revealed that lamin A/C, one kind of NE protein, is mechano-responsive and may contribute to the shear stress-induced proliferation and migration of VSMCs (12). Recently, Swift et al. (13) ...

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Section: Discussionsupporting

confidence: 79%

Nuclear envelope proteins modulate proliferation of vascular smooth muscle cells during cyclic stretch application

Yao

Huang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…It has been shown that the cell can respond to the mechanical characteristics of its microenvironment by stabilizing lamin A/C and regulating changes in lamin protein composition and nuclear morphology (44). The timescale of this process is significantly slower than that of the perinuclear actin polymerization described in this study (tens of minutes vs. tens of seconds).…”

Section: Discussionmentioning

confidence: 51%

Mechanical stimulation induces formin-dependent assembly of a perinuclear actin rim

Shao

Mogilner

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

121

129

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Cells constantly sense and respond to mechanical signals by reorganizing their actin cytoskeleton. Although a number of studies have explored the effects of mechanical stimuli on actin dynamics, the immediate response of actin after force application has not been studied. We designed a method to monitor the spatiotemporal reorganization of actin after cell stimulation by local force application. We found that force could induce transient actin accumulation in the perinuclear region within ∼2 min. This actin reorganization was triggered by an intracellular Ca 2+ burst induced by force application. Treatment with the calcium ionophore A23187 recapitulated the force-induced perinuclear actin remodeling. Blocking of actin polymerization abolished this process. Overexpression of Klarsicht, ANC-1, Syne Homology (KASH) domain to displace nesprins from the nuclear envelope did not abolish Ca 2+ -dependent perinuclear actin assembly. However, the endoplasmic reticulum-and nuclear membrane-associated inverted formin-2 (INF2), a potent actin polymerization activator (mutations of which are associated with several genetic diseases), was found to be important for perinuclear actin assembly. The perinuclear actin rim structure colocalized with INF2 on stimulation, and INF2 depletion resulted in attenuation of the rim formation. Our study suggests that cells can respond rapidly to external force by remodeling perinuclear actin in a unique Ca 2+ -and INF2-dependent manner.force | mechanotransduction | calcium | formin | perinuclear actin rim C ells can sense and adapt to their physical microenvironment through specific mechanosensing mechanisms. These properties are often mediated by the actin cytoskeleton, which can be modulated by a wide range of forces. Fluid shear stress, for example, induces actin stress fiber assembly and realignment along the direction of flow (1-4), whereas the cyclic stretch of an elastic substrate induces a reorientation of stress fibers under some angle to the direction of stretch (5-8). Applying mechanical force to cells by a microneedle results in focal adhesion growth and activation of formin-type actin nucleators (9, 10). Similarly, local application of force through fibronectin or collagen-coated beads trapped by optical or magnetic tweezers leads to the local reorganization of the actin cytoskeleton. This response is associated with reinforcement of bead attachment (11), recruitment of additional actin-associated proteins (12), and activation of a variety of signaling pathways (13)(14)(15)(16)(17). Most studies to date have explored the effects of force on actin structures directly associated with the sites of force application, such as focal adhesions and stress fibers. However, the immediate effect of force on the assembly of actin structures distal from the sites of force application has not been assessed. Such process is despite distal effects having potential implications in the transduction of local forces from the cell periphery to nuclear events (18).In this study, we used a local mecha...

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“…Third, inhibition of NMII activity affects the behavior of neural crest cells generated during neuroepithelial EMT in vivo in zebrafish brain development (Berndt et al, 2008). Moreover, fourth, NMII activity has been shown to affect stem cell lineage specification (Buxboim et al, 2014;Engler et al, 2006;Kim et al, 2015;Wang et al, 2012). All of these findings suggest that NMII may be involved in regulating epicardial EMT.…”

Section: Introductionmentioning

confidence: 72%

Nonmuscle myosin IIB regulates epicardial integrity and epicardium-derived mesenchymal cell maturation

Sung

Yang

et al. 2017

Journal of Cell Science

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Nonmuscle myosin IIB (NMIIB; heavy chain encoded by MYH10) is essential for cardiac myocyte cytokinesis. The role of NMIIB in other cardiac cells is not known. Here, we show that NMIIB is required in epicardial formation and functions to support myocardial proliferation and coronary vessel development. Ablation of NMIIB in epicardial cells results in disruption of epicardial integrity with a loss of E-cadherin at cell-cell junctions and a focal detachment of epicardial cells from the myocardium. NMIIB-knockout and blebbistatin-treated epicardial explants demonstrate impaired mesenchymal cell maturation during epicardial epithelial-mesenchymal transition. This is manifested by an impaired invasion of collagen gels by the epicardium-derived mesenchymal cells and the reorganization of the cytoskeletal structure. Although there is a marked decrease in the expression of mesenchymal genes, there is no change in Snail (also known as Snai1) or E-cadherin expression. Studies from epicardiumspecific NMIIB-knockout mice confirm the importance of NMIIB for epicardial integrity and epicardial functions in promoting cardiac myocyte proliferation and coronary vessel formation during heart development. Our findings provide a novel mechanism linking epicardial formation and epicardial function to the activity of the cytoplasmic motor protein NMIIB.

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Matrix Elasticity Regulates Lamin-A,C Phosphorylation and Turnover with Feedback to Actomyosin

Cited by 333 publications

References 35 publications

Nuclear envelope proteins modulate proliferation of vascular smooth muscle cells during cyclic stretch application

Nuclear envelope proteins modulate proliferation of vascular smooth muscle cells during cyclic stretch application

Mechanical stimulation induces formin-dependent assembly of a perinuclear actin rim

Nonmuscle myosin IIB regulates epicardial integrity and epicardium-derived mesenchymal cell maturation

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