Discovery of a novel ROCK2 inhibitor with anti-migration effects via docking and high-content drug screening

2016 ◽  
Vol 12 (9) ◽  
pp. 2713-2721 ◽  
Author(s):  
Cheong-Meng Chong ◽  
Man-Teng Kou ◽  
Peichen Pan ◽  
Hefeng Zhou ◽  
Nana Ai ◽  
...  
Keyword(s):  
Cell Migration ◽  
Drug Screening ◽  
Stress Fibers ◽  
Neurite Length ◽  
Actin Stress Fibers

Through the combined virtual and high content drug screening, BIPM was identified as a novel and potent ROCK2 inhibitor. Exposure of SH-SY5Y cells to BIPM led to significant changes in neurite length, cell migration and actin stress fibers via mediating ROCK2 downstream proteins.

scholarly journals Kank regulates RhoA-dependent formation of actin stress fibers and cell migration via 14-3-3 in PI3K–Akt signaling

2008 ◽  
Vol 181 (3) ◽  
pp. 537-549 ◽  
Author(s):  
Naoto Kakinuma ◽  
Badal Chandra Roy ◽  
Yun Zhu ◽  
Yong Wang ◽  
Ryoiti Kiyama
Keyword(s):  
Cell Migration ◽  
Growth Factors ◽  
Growth Factor ◽  
Akt Signaling ◽  
Stress Fibers ◽  
Nih3t3 Cells ◽  
Rhoa Activity ◽  
Epidermal Growth ◽  
Phosphoinositide 3 Kinase ◽  
Actin Stress Fibers

Phosphoinositide-3 kinase (PI3K)/Akt signaling is activated by growth factors such as insulin and epidermal growth factor (EGF) and regulates several functions such as cell cycling, apoptosis, cell growth, and cell migration. Here, we find that Kank is an Akt substrate located downstream of PI3K and a 14-3-3–binding protein. The interaction between Kank and 14-3-3 is regulated by insulin and EGF and is mediated through phosphorylation of Kank by Akt. In NIH3T3 cells expressing Kank, the amount of actin stress fibers is reduced, and the coexpression of 14-3-3 disrupted this effect. Kank also inhibits insulin-induced cell migration via 14-3-3 binding. Furthermore, Kank inhibits insulin and active Akt-dependent activation of RhoA through binding to 14-3-3. Based on these findings, we hypothesize that Kank negatively regulates the formation of actin stress fibers and cell migration through the inhibition of RhoA activity, which is controlled by binding of Kank to 14-3-3 in PI3K–Akt signaling.

scholarly journals Somatostatin, Acting at Receptor Subtype 1, Inhibits Rho Activity, the Assembly of Actin Stress Fibers, and Cell Migration

2002 ◽  
Vol 277 (32) ◽  
pp. 28431-28438 ◽  
Author(s):  
Alison M. J. Buchan ◽  
Chin-Yu Lin ◽  
Jimmy Choi ◽  
Diane L. Barber
Keyword(s):  
Cell Migration ◽  
Stress Fibers ◽  
Receptor Subtype ◽  
Actin Stress Fibers

scholarly journals Mechanically induced deformation and strain dynamics in actin stress fibers

2012 ◽  
Vol 5 (6) ◽  
pp. 627-630 ◽  
Author(s):  
Sebastian Hadjiantoniou ◽  
Louise Guolla ◽  
Andrew E. Pelling
Keyword(s):  
Stress Fibers ◽  
Actin Stress Fibers

scholarly journals Delayed stress fiber formation mediates pulmonary myofibroblast differentiation in response to TGF-β

2011 ◽  
Vol 301 (5) ◽  
pp. L656-L666 ◽  
Author(s):  
Nathan Sandbo ◽  
Andrew Lau ◽  
Jacob Kach ◽  
Caitlyn Ngam ◽  
Douglas Yau ◽  
...  
Keyword(s):  
Rho Kinase ◽  
Stress Fiber ◽  
Fiber Formation ◽  
Stress Fibers ◽  
Nuclear Accumulation ◽  
Myofibroblast Differentiation ◽  
Latrunculin B ◽  
Stress Fiber Formation ◽  
Actin Expression ◽  
Actin Stress Fibers

Myofibroblast differentiation induced by transforming growth factor-β (TGF-β) and characterized by de novo expression of smooth muscle (SM)-specific proteins is a key process in wound healing and in the pathogenesis of fibrosis. We have previously shown that TGF-β-induced expression and activation of serum response factor (SRF) is required for this process. In this study, we examined the signaling mechanism for SRF activation by TGF-β as it relates to pulmonary myofibroblast differentiation. TGF-β stimulated a profound, but delayed (18–24 h), activation of Rho kinase and formation of actin stress fibers, which paralleled SM α-actin expression. The translational inhibitor cycloheximide blocked these processes without affecting Smad-dependent gene transcription. Inhibition of Rho kinase by Y-27632 or depolymerization of actin by latrunculin B resulted in inhibition TGF-β-induced SRF activation and SM α-actin expression, having no effect on Smad signaling. Conversely, stabilization of actin stress fibers by jasplakinolide was sufficient to drive these processes in the absence of TGF-β. TGF-β promoted a delayed nuclear accumulation of the SRF coactivator megakaryoblastic leukemia-1 (MKL1)/myocardin-related transcription factor-A, which was inhibited by latrunculin B. Furthermore, TGF-β also induced MKL1 expression, which was inhibited by latrunculin B, by SRF inhibitor CCG-1423, or by SRF knockdown. Together, these data suggest a triphasic model for myofibroblast differentiation in response to TGF-β that involves 1) initial Smad-dependent expression of intermediate signaling molecules driving Rho activation and stress fiber formation, 2) nuclear accumulation of MKL1 and activation of SRF as a result of actin polymerization, and 3) SRF-dependent expression of MKL1, driving further myofibroblast differentiation.

Vascular-endothelial-cadherin modulates endothelial monolayer permeability

1999 ◽  
Vol 112 (12) ◽  
pp. 1915-1923 ◽  
Author(s):  
P.L. Hordijk ◽  
E. Anthony ◽  
F.P. Mul ◽  
R. Rientsma ◽  
L.C. Oomen ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Actin Cytoskeleton ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Transendothelial Migration ◽  
Stress Fibers ◽  
Vascular Endothelial ◽  
Monolayer Permeability ◽  
Actin Stress Fibers ◽  
Cell Cell

Vascular endothelial (VE)-cadherin is the endothelium-specific member of the cadherin family of homotypic cell adhesion molecules. VE-cadherin, but not the cell adhesion molecule platelet/endothelial cell adhesion molecule (PECAM-1), markedly colocalizes with actin stress fibers at cell-cell junctions between human umbilical vein endothelial cells. Inhibition of VE-cadherin-mediated, but not PECAM-1-mediated, adhesion induced reorganization of the actin cytoskeleton, loss of junctional VE-cadherin staining and loss of cell-cell adhesion. In functional assays, inhibition of VE-cadherin caused increased monolayer permeability and enhanced neutrophil transendothelial migration. In a complementary set of experiments, modulation of the actin cytoskeleton was found to strongly affect VE-cadherin distribution. Brief stimulation of the beta2-adrenergic receptor with isoproterenol induced a loss of actin stress fibers resulting in a linear, rather than ‘jagged’, VE-cadherin distribution. The concomitant, isoproterenol-induced, reduction in monolayer permeability was alleviated by a VE-cadherin-blocking antibody. Finally, cytoskeletal reorganization resulting from the inactivation of p21Rho caused a diffuse localization of VE-cadherin, which was accompanied by reduced cell-cell adhesion. Together, these data show that monolayer permeability and neutrophil transendothelial migration are modulated by VE-cadherin-mediated cell-cell adhesion, which is in turn controlled by the dynamics of the actin cytoskeleton.

Actin stress fibers are at a tipping point between conventional shortening and rapid disassembly at physiological levels of MgATP

2010 ◽  
Vol 395 (3) ◽  
pp. 301-306 ◽  
Author(s):  
Tsubasa S. Matsui ◽  
Kazushi Ito ◽  
Roland Kaunas ◽  
Masaaki Sato ◽  
Shinji Deguchi
Keyword(s):  
Tipping Point ◽  
Stress Fibers ◽  
Actin Stress Fibers
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