scholarly journals A mechanosensitive RhoA pathway that protects epithelia against acute tensile stress

2018 ◽  
Author(s):  
Bipul R Acharya ◽  
Alexander Nestor-Bergmann ◽  
Xuan Liang ◽  
Srikanth Budnar ◽  
Oliver E. Jensen ◽  
...  
Keyword(s):  
Tensile Stress ◽  
Signaling Pathway ◽  
Contractile Response ◽  
Tensile Load ◽  
Actin Assembly ◽  
Epithelial Integrity ◽  
Tissue Movement ◽  
Intrinsic Capacity ◽  
Rhoa Signaling ◽  
E Cadherin

AbstractAdherens junctions are tensile structures that couple epithelial cells together. Junctional tension can arise from cell-intrinsic application of contractility or from the cell-extrinsic forces of tissue movement. In all these circumstances, it is essential that epithelial integrity be preserved despite the application of tensile stress. In this study, we identify junctional RhoA as a mechanosensitive signaling pathway that responds to epithelial stress. The junctional specificity of this response is mediated by the heterotrimeric protein Gα12, which is recruited by E-cadherin and, in turn, recruits p114 RhoGEF to activate RhoA. Further, we identify Myosin VI as a key mechanosensor, based on its intrinsic capacity to anchor E-cadherin to F-actin when exposed to tensile load. Tension-activated RhoA signaling was necessary to preserve epithelial integrity, which otherwise undergoes fracture when monolayer stress is acutely increased by calyculin. Paradoxically, this homeostatic RhoA signaling pathway increases junctional actomyosin, a contractile response that might be expected to itself promote fracture. Simulations of a vertex-based model revealed that the protective effect of RhoA signaling can be explained through increased yield limit at multicellular vertices, where experiments showed p114 RhoGEF was necessary to increase E-cadherin and promote actin assembly and organization.

Rac is a dominant regulator of cadherin-directed actin assembly that is activated by adhesive ligation independently of Tiam1

2007 ◽  
Vol 292 (3) ◽  
pp. C1061-C1069 ◽  
Author(s):  
Astrid Kraemer ◽  
Marita Goodwin ◽  
Suzie Verma ◽  
Alpha S. Yap ◽  
Radiya G. Ali
Keyword(s):  
Signaling Pathway ◽  
Dominant Negative ◽  
Signaling Cascades ◽  
Potential Contribution ◽  
Actin Assembly ◽  
Rho Family Gtpases ◽  
Rho Family ◽  
Signaling Receptors ◽  
The Impact ◽  
E Cadherin

Classic cadherins function as adhesion-activated cell signaling receptors. On adhesive ligation, cadherins induce signaling cascades leading to actin cytoskeletal reorganization that is imperative for cadherin function. In particular, cadherin ligation activates actin assembly by the actin-related protein (Arp)2/3 complex, a process that critically affects the ability of cells to form and extend cadherin-based contacts. However, the signaling pathway(s) that activate Arp2/3 downstream of cadherin adhesion remain poorly understood. In this report we focused on the Rho family GTPases Rac and Cdc42, which can signal to Arp2/3. We found that homophilic engagement of E-cadherin simultaneously activates both Rac1 and Cdc42. However, by comparing the impact of dominant-negative Rac1 and Cdc42 mutants, we show that Rac1 is the dominant regulator of cadherin-directed actin assembly and homophilic contact formation. To pursue upstream elements of the Rac1 signaling pathway, we focused on the potential contribution of Tiam1 to cadherin-activated Rac signaling. We found that Tiam1 or the closely-related Tiam2/STEF1 was recruited to cell-cell contacts in an E-cadherin-dependent fashion. Moreover, a dominant-negative Tiam1 mutant perturbed cell spreading on cadherin-coated substrata. However, disruption of Tiam1 activity with dominant-negative mutants or RNA interference did not affect the ability of E-cadherin ligation to activate Rac1. We conclude that Rac1 critically influences cadherin-directed actin assembly as part of a signaling pathway independent of Tiam1.

scholarly journals Microvesicles releasing by oral cancer cells enhance endothelial cell angiogenesis via Shh/RhoA signaling pathway

2017 ◽  
Vol 18 (10) ◽  
pp. 783-791 ◽  
Author(s):  
Xiao Huaitong ◽  
Feng Yuanyong ◽  
Tao Yueqin ◽  
Zhao Peng ◽  
Shang Wei ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Oral Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Oral Cancer Cells ◽  
Rhoa Signaling

scholarly journals miRNA‑199b‑3p suppresses growth and progression of ovarian cancer via the CHK1/E‑cadherin/EMT signaling pathway by targeting ZEB1

2020 ◽  
Vol 45 (2) ◽  
pp. 569-581
Author(s):  
Liqun Wei ◽  
Yuanqi He ◽  
Shuhong Bi ◽  
Xiaoxiao Li ◽  
Jianzhong Zhang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Signaling Pathway ◽  
E Cadherin

scholarly journals The Role and Mechanism of AMIGO3 in the Formation of Aberrant Neural Circuits After Status Convulsion in Immature Mice

2021 ◽  
Vol 14 ◽  
Author(s):  
Xue Li ◽  
Yanan Pan ◽  
Jianxiong Gui ◽  
Zhixu Fang ◽  
Dishu Huang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Axonal Regeneration ◽  
Neural Circuits ◽  
Axon Growth ◽  
Demyelinating Diseases ◽  
Reading Frame ◽  
Myelin Sheaths ◽  
Transmission Electron ◽  
Rhoa Signaling ◽  
Myelin Basic Protein Expression

Leucine rich repeat and immunoglobulin-like domain-containing protein 1 (Lingo-1) has gained considerable interest as a potential therapy for demyelinating diseases since it inhibits axonal regeneration and myelin production. However, the results of clinical trials targeted at Lingo-1 have been unsatisfactory. Amphoterin-induced gene and open reading frame-3 (AMIGO3), which is an analog of Lingo-1, might be an alternative therapeutic target for brain damage. In the present study, we investigated the effects of AMIGO3 on neural circuits in immature mice after status convulsion (SC) induced by kainic acid. The expression of both AMIGO3 and Lingo-1 was significantly increased after SC, with levels maintained to 20 days after SC. Following SC, transmission electron microscopy revealed the impaired microstructure of myelin sheaths and Western blot analysis showed a decrease in myelin basic protein expression, and this damage was alleviated by downregulation of AMIGO3 expression. The ROCK/RhoA signaling pathway was inhibited at 20 days after SC by downregulating AMIGO3 expression. These results indicate that AMIGO3 plays important roles in seizure-induced damage of myelin sheaths as well as axon growth and synaptic plasticity via the ROCK/RhoA signaling pathway.

Red Raspberry Extracts Inhibit A549 Lung Cancer Cell Migration, Invasion, and Epithelial-Mesenchymal Transition Through the Epidermal Growth Factor Receptor/Signal Transducer and Activator of Transcription-3 Signaling Pathway

2021 ◽  
Vol 11 (3) ◽  
pp. 439-444
Author(s):  
Jiayi Ren ◽  
Lifang Wang ◽  
Jia Fu ◽  
Chunyang Wang ◽  
Yan Gong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Protein Expression ◽  
Cyclin D1 ◽  
Signaling Pathway ◽  
A549 Cells ◽  
Advanced Lung Cancer ◽  
Migration And Invasion ◽  
Red Raspberry ◽  
A549 Lung ◽  
E Cadherin

The incidence and mortality of lung cancer ranks first among all malignant tumors in the world. Because it is relatively asymptomatic at early stages, most patients do not become aware of the disease until it has progressed to an advanced stage. Advanced lung cancer metastasis results in systemic cachexia and effective treatment becomes challenging, leading to poor response and outcome. Therefore, the development of new drugs for the treatment of lung cancer is paramount. In this study, A549 cells were treated with different concentrations of red raspberry extract and the proliferation, migration, and invasion of cells were evaluated. The results indicated that red raspberry extract reduced the proliferation, migration, and invasion of A549 cells. Western blot analysis was used to detect the expression of the cyclin D1, N-cadherin, vimentin, E-cadherin, EGFR, and STAT3 proteins. Treatment with red raspberry extract reduced the expression of cyclin D1, N-cadherin, vimentin, EGFR, and STAT3, whereas the expression of E-cadherin increased. Following transfection of an EGFR overexpression vector into A549 cells, we observed a reduced inhibitory effect of the red raspberry extract on the proliferation, migration, and invasion of A549 cells. In addition, EGFR overexpression abrogated the increased expression of cyclin D1, N-cadherin, vimentin, EGFR, and STAT3 protein expression in A549 cells following extract treatment. In contrast, E-cadherin protein expression was decreased under these treatment conditions. Overall, this study suggests that red raspberry extract may reduce the proliferation, migration, invasion, and epithelialmesenchymal transition of A549 lung cancer cells by inhibiting the activation of the EGFR/STAT3 signaling pathway. These findings may lead to the development of new strategies to treat advanced lung cancer.

Glutathione S-transferase omega 2 regulates cell growth and the expression of E-cadherin via post-transcriptional down-regulation of β-catenin in human esophageal squamous cells

2019 ◽  
Vol 41 (7) ◽  
pp. 875-886
Author(s):  
Masayoshi Terayama ◽  
Kazuhiko Yamada ◽  
Teruki Hagiwara ◽  
Fumika Inazuka ◽  
Takuhito Sezaki ◽  
...  
Keyword(s):  
Cell Growth ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Mapk Signaling ◽  
Membrane Localization ◽  
Esophageal Mucosa ◽  
Glutathione S Transferase ◽  
Down Regulation ◽  
Transfected Cells ◽  
E Cadherin

Abstract Glutathione S-transferase omega 2 (GSTO2), which belongs to the superfamily of GST omega class, lacks any appreciable GST activity. Although GSTO2 exhibits thioltransferase and glutathione dehydrogenase activities, its precise expression and physiological functions are still unclear. In the present study, we found that GSTO2 is exclusively expressed in the basal cell layer in Ki67-negative non-proliferative cells in the human esophageal mucosa. GSTO2 overexpression in esophageal squamous cell carcinoma (ESCC) cell lines inhibited cell growth and colony formation, and GSTO2-transfected cells formed smaller tumors in nude mice compared with mock-transfected cells. Interestingly, GSTO2 induction suppressed the expressions of E-cadherin and β-catenin at the cell–cell contact site. We quantified the phosphorylation levels of key proteins of MAPK signaling pathway and identified phosphorylation of p38. Additionally, HSP27, a downstream molecule of p38, was accelerated in GSTO2-transfected cells, unlike in mock-transfected cells. When GSTO2-transfected cells were treated with a p38 inhibitor, the expression of β-catenin and the membrane localization of E-cadherin was recovered. We next examined GSTO2 expression in 61 ESCC tissues using quantitative reverse transcription polymerase chain reaction and immunostaining. The results showed that GSTO2 mRNA and protein were significantly reduced in ESCC compared with normal tissues. When human ESCC cell lines were treated with 5-aza-2′-deoxycytidine, a DNA-methyltransferase inhibitor, GSTO2 transcription was induced, suggesting that aberrant hypermethylation is the cause of the down-regulated expression. Our results indicate that GSTO2 expression inhibits the membrane localization of E-cadherin, probably by modulation of the p38 signaling pathway. Down-regulation of GSTO2 by DNA hypermethylation contributes to the growth and progression of ESCC.

scholarly journals FAK regulates actin polymerization during sperm capacitation via the ERK2/GEF-H1/RhoA signaling pathway

2020 ◽  
Vol 133 (8) ◽  
pp. jcs239186 ◽  
Author(s):  
Monica L. Salgado-Lucio ◽  
Danelia Ramírez-Ramírez ◽  
Coral Y. Jorge-Cruz ◽  
Ana L. Roa-Espitia ◽  
Enrique O. Hernández-González
Keyword(s):  
Signaling Pathway ◽  
Actin Polymerization ◽  
Sperm Capacitation ◽  
Rhoa Signaling
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