Non-muscle myosin IIB is critical for nuclear translocation during 3D invasion

Thomas, Dustin; Yenepalli, Aishwarya; Denais, Céline; Rape, Andrew D.; Beach, Jordan R.; Wang, Yuli; Schiemann, William P.; Baskaran, Harihara; Lammerding, Jan; Egelhoff, Thomas

doi:10.1083/jcb.201502039

Cited by 123 publications

(155 citation statements)

References 49 publications

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“…This is also consistent with a previous report showing a NMIIC to NMIIB isoform switch, and a reduced mesenchymal cell invasion following siRNA knockdown of NMIIB during EMT in mouse mammary epithelial cells (NMuMG) in response to TGFβ (Beach et al, 2011). Recently, NMIIB was shown to generate tension for nuclear translocation during migration in 3D collagen gels (Thomas et al, 2015).…”

Section: Nmiib Function In Myocardial Growthsupporting

confidence: 81%

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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Section: Nmiib Function In Myocardial Growthsupporting

confidence: 81%

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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“…2 c) and estimated the minimal actomyosin contraction force required for transmigration of the nucleus. Indeed, recent experiments suggest that the cells are not able to transmigrate either when contractility (41,42) is abolished or when nesprin links (42) and/or integrins (4) are inhibited. Cells also deform the endothelium and create larger openings to facilitate transmigration (Fig.…”

Section: Discussionmentioning

confidence: 99%

A Chemomechanical Model for Nuclear Morphology and Stresses during Cell Transendothelial Migration

Cao

Moeendarbary

Isermann

et al. 2016

Biophysical Journal

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116

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It is now evident that the cell nucleus undergoes dramatic shape changes during important cellular processes such as cell transmigration through extracellular matrix and endothelium. Recent experimental data suggest that during cell transmigration the deformability of the nucleus could be a limiting factor, and the morphological and structural alterations that the nucleus encounters can perturb genomic organization that in turn influences cellular behavior. Despite its importance, a biophysical model that connects the experimentally observed nuclear morphological changes to the underlying biophysical factors during transmigration through small constrictions is still lacking. Here, we developed a universal chemomechanical model that describes nuclear strains and shapes and predicts thresholds for the rupture of the nuclear envelope and for nuclear plastic deformation during transmigration through small constrictions. The model includes actin contraction and cytosolic back pressure that squeeze the nucleus through constrictions and overcome the mechanical resistance from deformation of the nucleus and the constrictions. The nucleus is treated as an elastic shell encompassing a poroelastic material representing the nuclear envelope and inner nucleoplasm, respectively. Tuning the chemomechanical parameters of different components such as cell contractility and nuclear and matrix stiffnesses, our model predicts the lower bounds of constriction size for successful transmigration. Furthermore, treating the chromatin as a plastic material, our model faithfully reproduced the experimentally observed irreversible nuclear deformations after transmigration in lamin-A/C-deficient cells, whereas the wild-type cells show much less plastic deformation. Along with making testable predictions, which are in accord with our experiments and existing literature, our work provides a realistic framework to assess the biophysical modulators of nuclear deformation during cell transmigration.

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“…6A). As we recently reported (16), NMIIB is expressed in 4T1 cells and has critical roles in long term traction force maintenance and in nuclear translocation through tight spaces during invasive migration. We performed time-lapse phase-contrast imaging of the engineered NMIIA and NMIIB 4T1 cell lines and compared their protrusion dynamics on 2D surfaces versus when embedded in 3D collagen gels.…”

Section: C-terminal Phosphorylation Sites Mediate Nmiia Recruitment Tmentioning

confidence: 99%

“…To test this idea, we switched to the mouse basal-like mammary gland cancer line 4T1 that displays robust 3D invasive behavior (16). Lentivirus-based shRNA, directed against the 3Ј-untranslated region of the MYH9 transcript, was used to deplete endogenous NMIIA.…”

Section: C-terminal Phosphorylation Sites Mediate Nmiia Recruitment Tmentioning

confidence: 99%

“…For example, during mesenchymal migration in 2D settings, NMIIA activity stabilizes anterior focal adhesions via unknown mechanisms, facilitating attachment of the anterior portion of the cell to the extracellular environment (13,14). In both amoeboid and mesenchymal modes of migration, as well as a recently reported "piston" mode of migration, NMII activity is critical for anterior translocation of the nucleus through tight spaces (15)(16)(17).…”

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confidence: 99%

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Myosin IIA Heavy Chain Phosphorylation Mediates Adhesion Maturation and Protrusion in Three Dimensions

Rai

Thomas

Beach

et al. 2017

Journal of Biological Chemistry

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Non-muscle myosin II (NMII) is a conserved force-producing cytoskeletal enzyme with important but poorly understood roles in cell migration. To investigate myosin heavy chain (MHC) phosphorylation roles in 3D migration, we expressed GFP-tagged NMIIA wild-type or mutant constructs in cells depleted of endogenous NMIIA protein. We find that individual mutation or double mutation of Ser-1916 or Ser-1943 to alanine potently blocks recruitment of GFP-NM-IIA filaments to leading edge protrusions in 2D, and this in turn blocks maturation of anterior focal adhesions. When placed in 3D collagen gels, cells expressing wild-type GFP MHC-IIA behave like parental cells, displaying robust and active formation and retraction of protrusions. However, cells depleted of NMIIA or cells expressing the mutant GFP MHC-IIA display severe defects in invasion and in stabilizing protrusions in 3D. These studies reveal an NMIIA-specific role in 3D invasion that requires competence for NMIIA phosphorylation at Ser-1916 and Ser-1943. In sum, these results demonstrate a critical and previously unrecognized role for NMIIA phosphorylation in 3D invasion.

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Non-muscle myosin IIB is critical for nuclear translocation during 3D invasion

Abstract: Non-muscle myosin IIB plays a major role in applying force on the nucleus to facilitate nuclear translocation through tight spaces during 3D invasive migration, while non-muscle myosin IIA is critical for generating force during active protrusion.

Cited by 123 publications

References 49 publications

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

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

A Chemomechanical Model for Nuclear Morphology and Stresses during Cell Transendothelial Migration

Myosin IIA Heavy Chain Phosphorylation Mediates Adhesion Maturation and Protrusion in Three Dimensions

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