ROCK1 but not ROCK2 contributes to RhoA signaling and NMIIA-mediated contractility at the epithelial zonula adherens

Priya, Rashmi; Liang, Xuan; Teo, Jessica L.; Duszyc, Kinga; Yap, Alpha S.; Gómez, Guillermo A.

doi:10.1091/mbc.e16-04-0262

Cited by 32 publications

(22 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, its loss leads to a lesscompact cortical actin rim and low cell-cell tension, while its overactivation upon ROCK2 loss generates more ventral stress fibers and increased cell-cell tension. This is in good agreement with its higher capacity than ROCK2 to phosphorylate myosin II light chain (Newell-Litwa et al, 2015;Yoneda et al, 2005) and its reported role on junctional tension in epithelial cells (Priya et al, 2017).…”

Section: Rock1 and Rock2 Are Both Required To Organize The Actomyosinsupporting

confidence: 90%

The CCM1–CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity

Lisowska

Rödel

Manet

et al. 2018

Journal of Cell Science

View full text Add to dashboard Cite

Endothelial integrity relies on a mechanical crosstalk between intercellular and cell-matrix interactions. This crosstalk is compromised in hemorrhagic vascular lesions of patients carrying loss-of-function mutations in cerebral cavernous malformation (CCM) genes. RhoA/ROCK-dependent cytoskeletal remodeling is central to the disease, as it causes unbalanced cell adhesion towards increased cell-extracellular matrix adhesions and destabilized cell-cell junctions. This study reveals that CCM proteins directly orchestrate ROCK1 and ROCK2 complementary roles on the mechanics of the endothelium. CCM proteins act as a scaffold, promoting ROCK2 interactions with VE-cadherin and limiting ROCK1 kinase activity. Loss of CCM1 (also known as KRIT1) produces excessive ROCK1-dependent actin stress fibers and destabilizes intercellular junctions. Silencing of ROCK1 but not ROCK2 restores the adhesive and mechanical homeostasis of CCM1 and CCM2-depleted endothelial monolayers, and rescues the cardiovascular defects of mutant zebrafish embryos. Conversely, knocking down Rock2 but not Rock1 in wild-type zebrafish embryos generates defects reminiscent of the mutant phenotypes. Our study uncovers the role of the CCM1-CCM2 complex in controlling ROCK1 and ROCK2 to preserve endothelial integrity and drive heart morphogenesis. Moreover, it solely identifies the ROCK1 isoform as a potential therapeutic target for the CCM disease.

show abstract

Section: Rock1 and Rock2 Are Both Required To Organize The Actomyosinsupporting

confidence: 90%

The CCM1–CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity

Lisowska

Rödel

Manet

et al. 2018

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…, 2015 ). Moreover, ROCK1 knockdown in MCF-7 cells specifically reduced p-RLC localization to adherens junctions suggesting that ROCK1 preferentially regulates contractility in adherens junctions ( Priya et al. , 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Activation of ROCK and MLCK tunes regional stress fiber formation and mechanics via preferential myosin light chain phosphorylation

Kassianidou

Hughes

Kumar

2017

MBoC

View full text Add to dashboard Cite

MBoC | ARTICLE Activation of ROCK and MLCK tunes regional stress fiber formation and mechanics via preferential myosin light chain phosphorylation ABSTRACT The assembly and mechanics of actomyosin stress fibers (SFs) depend on myosin regulatory light chain (RLC) phosphorylation, which is driven by myosin light chain kinase (MLCK) and Rho-associated kinase (ROCK). Although previous work suggests that MLCK and ROCK control distinct pools of cellular SFs, it remains unclear how these kinases differ in their regulation of RLC phosphorylation or how phosphorylation influences individual SF mechanics. Here, we combine genetic approaches with biophysical tools to explore relationships between kinase activity, RLC phosphorylation, SF localization, and SF mechanics. We show that graded MLCK overexpression increases RLC monophosphorylation (p-RLC) in a graded manner and that this p-RLC localizes to peripheral SFs. Conversely, graded ROCK overexpression preferentially increases RLC diphosphorylation (pp-RLC), with pp-RLC localizing to central SFs. Interrogation of single SFs with subcellular laser ablation reveals that MLCK and ROCK quantitatively regulate the viscoelastic properties of peripheral and central SFs, respectively. The effects of MLCK and ROCK on single-SF mechanics may be correspondingly phenocopied by overexpression of mono-and diphosphomimetic RLC mutants. Our results point to a model in which MLCK and ROCK regulate peripheral and central SF viscoelastic properties through mono-and diphosphorylation of RLC, offering new quantitative connections between kinase activity, RLC phosphorylation, and SF viscoelasticity.

show abstract

“…For example, Myosin IIA functions as a scaffold that promotes RhoA-GTP output at junctions; Myosin IIA scaffolds ROCK1 at the ZA, and ROCK1 works through Rnd3 to prevent the accumulation of the Rho GAP p190RhoGAP-B, which would negatively regulate RhoA signaling at the ZA (Priya et al, 2015; Priya et al, 2017). Additionally, Myosin II filaments can serve as an F-actin bundling proteins.…”

Section: Junctional Roles For Myosin IImentioning

confidence: 99%

Rho GTPases and actomyosin: Partners in regulating epithelial cell-cell junction structure and function

Arnold

Stephenson

Miller

2017

Experimental Cell Research

121

118

View full text Add to dashboard Cite

Epithelial tissues are defined by polarized epithelial cells that are integrated into tissues and exhibit barrier function in order to regulate what is allowed to pass between cells. Cell-cell junctions must be stable enough to promote barrier function and tissue integrity, yet plastic enough to remodel when necessary. This remarkable ability to dynamically sense and respond to changes in cell shape and tissue tension allows cell-cell junctions to remain functional during events that disrupt epithelial homeostasis including morphogenesis, wound healing, and cell division. In order to achieve this plasticity, both tight junctions and adherens junctions are coupled to the underlying actomyosin cytoskeleton. Here, we discuss the importance of the junctional linkage to actomyosin and how a localized zone of active RhoA along with other Rho GTPases work together to orchestrate junctional actomyosin dynamics. We focus on how scaffold proteins help coordinate Rho GTPases, their upstream regulators, and their downstream effectors for efficient, localized Rho GTPase signaling output. Additionally, we highlight important roles junctional actin-binding proteins play in addition to their traditional roles in organizing actin. Together, Rho GTPases, their regulators, and effectors form compartmentalized signaling modules that regulate actomyosin structure and contractility to achieve proper cell-cell adhesion and tissue barriers.

show abstract

ROCK1 but not ROCK2 contributes to RhoA signaling and NMIIA-mediated contractility at the epithelial zonula adherens

Cited by 32 publications

References 46 publications

The CCM1–CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity

The CCM1–CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity

Activation of ROCK and MLCK tunes regional stress fiber formation and mechanics via preferential myosin light chain phosphorylation

Rho GTPases and actomyosin: Partners in regulating epithelial cell-cell junction structure and function

Contact Info

Product

Resources

About