ROCK and JAK1 Signaling Cooperate to Control Actomyosin Contractility in Tumor Cells and Stroma

Sanz-Moreno, Victoria; Gaggioli, Cédric; Yeo, Maggie; Albrengues, Jean; Wållberg, Fredrik; Virós, Amaya; Hooper, Steven; Mitter, Richard; Feral, Chloé C.; Cook, Martin; Larkin, James; Marais, Richard; Meneguzzi, Guerríno; Sahai, Erik; Marshall, Chris

doi:10.1016/j.ccr.2011.06.018

Cited by 357 publications

(473 citation statements)

References 65 publications

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“…Notably, activation of ROCK pathways can partially activate STAT3, and through the participation of other effectors, such as mDia, ROCK activity is required to fully promote the RhoA-mediated STAT3 activation (35). Because ROCK is a serine/threonine kinase and cannot directly mediate STAT3 phosphorylation on Tyr-705, it is likely that tyrosine kinases such JAK and Src or other intracellular signaling components, which may interface between ROCK and STAT3, are also engaged in this ROCK-dependent activation of STAT3 (36).…”

Section: Discussionmentioning

confidence: 99%

Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism

Zanin-Zhorov¹,

Weiss²,

Nyuydzefe³

et al. 2014

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

196

214

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Rho-associated kinase 2 (ROCK2) regulates the secretion of proinflammatory cytokines and the development of autoimmunity in mice. Data from a phase 1 clinical trial demonstrate that oral administration of KD025, a selective ROCK2 inhibitor, to healthy human subjects down-regulates the ability of T cells to secrete IL-21 and IL-17 by 90% and 60%, respectively, but not IFN-γ in response to T-cell receptor stimulation in vitro. Pharmacological inhibition with KD025 or siRNA-mediated inhibition of ROCK2, but not ROCK1, significantly diminished STAT3 phosphorylation and binding to IL-17 and IL-21 promoters and reduced IFN regulatory factor 4 and nuclear hormone RAR-related orphan receptor γt protein levels in T cells derived from healthy subjects or rheumatoid arthritis patients. Simultaneously, treatment with KD025 also promotes the suppressive function of regulatory T cells through up-regulation of STAT5 phosphorylation and positive regulation of forkhead box p3 expression. The administration of KD025 in vivo down-regulates the progression of collagen-induced arthritis in mice via targeting of the Th17-mediated pathway. Thus, ROCK2 signaling appears to be instrumental in regulating the balance between proinflammatory and regulatory T-cell subsets. Targeting of ROCK2 in man may therefore restore disrupted immune homeostasis and have a role in the treatment of autoimmunity.T he immune response is a delicate balancing act, protecting the integrity of the host organism from foreign invaders while not causing autoimmune reactivity (1). IL-21 and IL-17 are proinflammatory cytokines produced by T-helper 17 (Th17) cells that are involved in the pathogenesis of many autoimmune diseases (2-5). The generation of Th17 cells is induced by a combination of several cytokines including transforming growth factor-β (TGF-β1), IL-1β, IL-6, and IL-23, and involves the activation of transcription factors, such as RAR-related orphan receptor (ROR) γt, RORα, IFN regulatory factor (IRF) 4, and signal transducer and activator of transcription 3 (STAT3) (2, 6, 7). However, the signaling pathways that lead to activation of this transcriptional profile are poorly understood and remain unclear.Rho GTPase-mediated signaling pathways play a central role in the coordination and balancing of T-cell-mediated immune responses, including T-cell receptor (TCR)-mediated signaling, cytoskeletal reorganization, and the acquisition of the appropriate T-cell effector program (8). The Rho kinase family members, consisting of Rho-associated kinase 1 (ROCK1) and ROCK2, are serine-threonine kinases that are activated by Rho GTPases and mediate the phosphorylation of downstream targets in cells (9). Recent studies have demonstrated that ROCK2 regulates the production of both IL-21 and IL-17 and plays an essential role in the development of autoimmunity in mice (10, 11). Indeed, pan ROCK inhibition was reported to effectively down-regulate ongoing autoimmune response in animal models (11,12). Additionally, ROCK activity was found to be up-regulated in patients w...

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Section: Discussionmentioning

confidence: 99%

Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism

Zanin-Zhorov¹,

Weiss²,

Nyuydzefe³

et al. 2014

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

196

214

View full text Add to dashboard Cite

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“…Rho-kinase regulates stress fibre formation and cell-cell junctions in ECs in response to vascular endothelial derived growth factor (VEGF) (6). Members of the Rho family of GTPases have also emerged as key players in the regulation of a variety of biological activities involving cell motility and actin cytoskeleton reorganization (7). Several members of this family, including RhoA, Cdc42 and Rac1 are involved in focal adhesion complex assembly, cell polarity, gene transcription and cell-cycle progression (8).…”

Section: Introductionmentioning

confidence: 99%

Fasudil inhibits lung carcinoma-conditioned endothelial cell viability and migration

Zhang

Ren

et al. 2012

Oncol Rep

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Abstract. The aim of this study was to investigate the effect of fasudil on lung carcinoma-conditioned endothelial cells (LCc-ECs). To obtain LCc-ECs, human umbilical vein endothelial cells (HUVECs) were treated with conditioned cell culture media from human A549 lung adenocarcinoma cells. The effect of fasudil on the viability of LCc-ECs was assessed using the MTT assay, in vitro invasive ability was evaluated using the transwell chamber assay and cytoskeletal changes were detected using fluorescein-labelled phalloidin immunocytochemistry. RhoA mRNA and p-MLC protein expression were measured using RT-PCR and western blotting. Fasudil significantly and dose-dependently inhibited LCc-EC proliferation and in vitro invasive ability. Fasudil also led to stress fibre breakage and fracture in LCc-ECs, indicating that fasudil impacts polymerisation of the cytoskeletal actin filament network. Expression of RhoA mRNA and protein expression of the ROCK substrate p-MLC were reduced by fasudil, suggesting that fasudil can inhibit RhoA/ROCK signalling and attenuate angiogenesis in LCc-ECs. This study indicates that fasudil is an anti-angiogenic agent with potential application for the treatment of cancer, especially lung adenocarcinoma.

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“…The tumor cells then extravasate and colonize into a macrometastasis 12 . Progression through the epithelial to mesenchymal transition (EMT), tumor invasion, and metastasis has been enhanced by steroid hormones 13,14 , growth factors [15][16][17][18] , and cytokines [19][20][21] . These molecules are so critical to addressing the signaling pathway of tumor progression, that the development of an assay to address their role in tumor invasive potential is an important step toward deciphering the intricate signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

A Modified <em>In vitro</em> Invasion Assay to Determine the Potential Role of Hormones, Cytokines and/or Growth Factors in Mediating Cancer Cell Invasion

Bagati

Koch

Bofinger

et al. 2015

JoVE

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Blood serum serves as a chemoattractant towards which cancer cells migrate and invade, facilitating their intravasation into microvessels. However, the actual molecules towards which the cells migrate remain elusive. This modified invasion assay has been developed to identify targets which drive cell migration and invasion. This technique compares the invasion index under three conditions to determine whether a specific hormone, growth factor, or cytokine plays a role in mediating the invasive potential of a cancer cell. These conditions include i) normal fetal bovine serum (FBS), ii) charcoal-stripped FBS (CS-FBS), which removes hormones, growth factors, and cytokines and iii) CS-FBS + molecule (denoted "X"). A significant change in cell invasion with CS-FBS as compared to FBS, indicates the involvement of hormones, cytokines or growth factors in mediating the change. Individual molecules can then be added back to CS-FBS to assay their ability to reverse or rescue the invasion phenotype. Furthermore, two or more factors can be combined to evaluate the additive or synergistic effects of multiple molecules in driving or inhibiting invasion. Overall, this method enables the investigator to determine whether hormones, cytokines, and/or growth factors play a role in cell invasion by serving as chemoattractants or inhibitors of invasion for a particular type of cancer cell or a specific mutant. By identifying specific chemoattractants and inhibitors, this modified invasion assay may help to elucidate signaling pathways that direct cancer cell invasion. Video LinkThe video component of this article can be found at

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ROCK and JAK1 Signaling Cooperate to Control Actomyosin Contractility in Tumor Cells and Stroma

Cited by 357 publications

References 65 publications

Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism

Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism

Fasudil inhibits lung carcinoma-conditioned endothelial cell viability and migration

A Modified <em>In vitro</em> Invasion Assay to Determine the Potential Role of Hormones, Cytokines and/or Growth Factors in Mediating Cancer Cell Invasion

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