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Rac1 RhoA

Duncan Hieu M Dam, Xiao-Qi Wang, Sarah Sheu, Mahima Vijay, Desmond Shipp, Luke Miller, Amy S Paller
Activation of insulin-like growth factor-1 (IGF-1) receptor (IGF1R) signaling induces keratinocyte migration, but little is known about its regulation, including in diabetic wounds. GM3, a lipid raft ganglioside synthesized by GM3 synthase (GM3S), regulates receptor signaling. In diabetic mice, knockout or topically-applied nanoconstruct-mediated knockdown of GM3S promotes wound edge IGF1R phosphorylation and re-epithelialization. Through modulating GM3 expression, we explored the role of GM3 in regulating human keratinocyte IGF1R signaling...
October 8, 2016: Journal of Investigative Dermatology
Weiliang Lu, Xixi Wang, Jingjing Liu, Yu He, Ziwei Liang, Zijing Xia, Ying Cai, Liangxue Zhou, Hongxia Zhu, Shufang Liang
The protein ARHGDIA has been found to play distinct roles in cancer progression for several tumors. However, it remains elusive whether and how ARHGDIA plays functions in human glioma. In this study, we discovered that ARHGDIA is much downregulated in human glioma; meanwhile, its expression negatively correlates with glioma malignancy and positively relates to prognosis of glioma patients. It has independent predictive value of ARHGDIA expression level for overall survival of human glioma patients. Glioma patients with ARHGDIA-positive expression have a longer overall survival time than ARHGDIA-negative patients...
October 10, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Daria R Bulanova, Yevhen A Akimov, Anne Rokka, Teemu D Laajala, Tero Aittokallio, Petri Kouvonen, Teijo Pellinen, Sergey G Kuznetsov
G-Protein Coupled Receptor (GPCR), Class C, Group 5, Member A (GPRC5A) has been implicated in several malignancies. The underlying mechanisms, however, remain poorly understood. Using a panel of human cell lines, we demonstrate that CRISPR/Cas9-mediated knockout and RNAi-mediated depletion of GPRC5A impairs cell adhesion to integrin substrates: collagens I and IV, fibronectin, as well as to extracellular matrix proteins derived from the Engelbreth-Holm-Swarm (EHS) mouse sarcoma (Matrigel). Consistent with the phenotype, knock-out of GPRC5A correlated with a reduced integrin β1 (ITGB1) protein expression, impaired phosphorylation of the focal adhesion kinase (FAK), and lower activity of small GTPases RhoA and Rac1...
October 7, 2016: Cell Adhesion & Migration
Chen Feng, Wei-Kiat Wee, Huizhi Chen, Li-Teng Ong, Jing Qu, Hui-Foon Tan, Suet-Mien Tan
Kindlins are a small family of 4.1-ezrin-radixin-moesin (FERM)-containing cytoplasmic proteins. Kindlin-3 is expressed in platelets, hematopoietic cells, and endothelial cells. Kindlin-3 promotes integrin activation, clustering and outside-in signaling. Aberrant expression of kindlin-3 was reported in melanoma and breast cancer. Intriguingly, kindlin-3 has been reported to either positively or negatively regulate cancer cell metastasis. In this study, we sought to clarify the expression of kindlin-3 in melanoma cells and its role in melanoma metastasis...
October 7, 2016: Cell Adhesion & Migration
Diana Santander-García, Maria Cristina Ortega, Silvia Benito-Martínez, Susana Barroso, Ignacio Jiménez-Alfaro, Jaime Millán
Correct corneal endothelial barrier function is essential for maintaining corneal transparency. However, research on cell signaling pathways mediating corneal endothelial barrier dysfunction has progressed more slowly than that involving other cellular barriers because of the lack of human corneal endothelial cell models. Here we have optimized the culture of the human corneal endothelial cell (HCEC) line B4G12 as a model for studying paracellular permeability. We show that B4G12-HCECs form confluent monolayers with stable cell-cell junctions when cultured on plastic, but not glass, surfaces precoated with various extracellular matrix components...
September 30, 2016: Experimental Eye Research
Dan-Dan Dong, Hui Zhou, Gao Li
GPR78 is an orphan G-protein coupled receptor (GPCR) that is predominantly expressed in human brain tissues. Currently, the function of GPR78 is unknown. In this study, we found that GPR78 was expressed in lung cancer cells and functioned as a novel regulator of lung cancer cell migration and metastasis. We found that knockdown of GPR78 in lung cancer cells suppressed cell migration. Moreover, GPR78 modulated the formation of actin stress fibers in A549 cells in a RhoA- and Rac1-dependent manner. At a molecular level, GPR78 regulated cell motility through the activation of Gαq-RhoA/Rac1 pathway...
September 29, 2016: BMB Reports
Huzoor Akbar, Xin Duan, Saima Saleem, Ashley K Davis, Yi Zheng
Agonist induced generation of reactive oxygen species (ROS) by NADPH oxidases (NOX) enhances platelet aggregation and hence the risk of thrombosis. RhoA and Rac1 GTPases are involved in ROS generation by NOX in a variety of cells, but their roles in platelet ROS production remain unclear. In this study we used platelets from RhoA and Rac1 conditional knockout mice as well as human platelets treated with Rhosin and NSC23767, rationally designed small molecule inhibitors of RhoA and Rac GTPases, respectively, to better define the contributions of RhoA and Rac1 signaling to ROS generation and platelet activation...
2016: PloS One
Nathan G Hedrick, Stephen C Harward, Charles E Hall, Hideji Murakoshi, James O McNamara, Ryohei Yasuda
The Rho GTPase proteins Rac1, RhoA and Cdc42 have a central role in regulating the actin cytoskeleton in dendritic spines, thereby exerting control over the structural and functional plasticity of spines and, ultimately, learning and memory. Although previous work has shown that precise spatiotemporal coordination of these GTPases is crucial for some forms of cell morphogenesis, the nature of such coordination during structural spine plasticity is unclear. Here we describe a three-molecule model of structural long-term potentiation (sLTP) of murine dendritic spines, implicating the localized, coincident activation of Rac1, RhoA and Cdc42 as a causal signal of sLTP...
September 28, 2016: Nature
Xinyong Tian, Tomomi Ohmura, Alok S Shah, Sophia Son, Yufeng Tian, Anna A Birukova
Rapid changes in microtubule (MT) polymerization dynamics affect regional activity of small GTPases RhoA and Rac1, which play a key role in the regulation of actin cytoskeleton and endothelial cell (EC) permeability. This study tested the role of End Binding Protein-1 (EB1) in the mechanisms of increased and decreased EC permeability caused by thrombin and hepatocyte growth factor (HGF) and mediated by RhoA and Rac1 GTPases, respectively. Stimulation of human lung EC with thrombin inhibited peripheral MT growth, which was monitored by morphological and biochemical evaluation of peripheral MT and the levels of stabilized MT...
September 23, 2016: Cellular Signalling
Robert Schierwagen, Lara Maybüchen, Kanishka Hittatiya, Sabine Klein, Frank E Uschner, Tarcio Teodoro Braga, Bernardo S Franklin, Georg Nickenig, Christian P Strassburg, Jogchum Plat, Tilman Sauerbruch, Eicke Latz, Dieter Lütjohann, Sebastian Zimmer, Jonel Trebicka
Non-alcoholic steatohepatitis (NASH), especially as part of the metabolic syndrome (MS), is an increasing burden in western countries. Statins are already used in metabolic syndrome and seem to be beneficial in liver diseases. The aim of this study was to investigate the molecular mechanisms underlying pleiotropic effects on small GTPases of statins in NASH. NASH within MS was induced in 12-week-old ApoE-/- mice after 7 weeks of western diet (NASH mice). Small GTPases were inhibited by activated simvastatin (SMV), NSC23766 (NSC) or Clostridium sordellii lethal toxin (LT) using subcutaneous osmotic mini-pumps...
September 15, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
Raquel B Haga, Anne J Ridley
Rho GTPases are well known for their roles in regulating cell migration, and also contribute to a variety of other cellular responses. They are subdivided into two groups: typical and atypical. The typical Rho family members, including RhoA, Rac1 and Cdc42, cycle between an active GTP-bound and inactive GDP-bound conformation, and are regulated by GEFs, GAPs and GDIs, whereas atypical Rho family members have amino acid substitutions that alter their ability to interact with GTP/GDP and hence are regulated by different mechanisms...
September 14, 2016: Small GTPases
Ting Lan, Ji Pang, Yan Wu, Miaolin Zhu, Xiaoyuan Yao, Min Wu, Hai Qian, Zhenyu Zhang, Jizong Gao, Yongchang Chen
Cross-linked hyaluronic acid gel (CHAG) has been used to prevent postoperative adhesion of abdominal tumorectomy. However, its effect on tumor cells is still unknown. This paper was designed to investigate the effect of CHAG on metastasis and growth of tumor cells. Migration and invasion assays, Western blotting, pull down assay, siRNA interference, and nude mice implantation tumor model were applied in this study. The results of in vitro experiments with gastric cancer cell line AGS and hepatic cancer cell line HepG2 showed that CHAG inhibited the migration and invasion activities, the MAPK and PI3K/Akt mediated signaling, the activation of small G proteins Rac1 and RhoA, and the expression of MMPs and PCNA initiated by EGF, through blocking the activation of EGFR...
August 31, 2016: Oncotarget
Jin-Man Kim, Mi Yeong Kim, Kyunghee Lee, Daewon Jeong
Cell migration during specialized stages of osteoclast precursors, mononuclear preosteoclasts, and multinucleated mature osteoclasts remain uncertain. M-CSF- and osteopontin-induced osteoclastic cell migration was inhibited by function-blocking monoclonal antibodies specific to the integrin αv and β3 subunits, suggesting that integrin αvβ3 mediates migratory signaling induced by M-CSF and osteopontin. M-CSF and osteopontin stimulation was shown to regulate two branched signaling processes, PI3K/PKCα/RhoA axis and PI3K/PKCδ/Rac1 axis...
December 5, 2016: Molecular and Cellular Endocrinology
Joseph H R Hetmanski, Jean-Marc Schwartz, Patrick T Caswell
Precise spatiotemporal dynamics of Rho GTPases are essential for efficient cell migration. Manipulating Rac1 and RhoA signaling is thus a potential intervention strategy to abrogate harmful cell invasion and subsequent metastasis; however GTPase signaling can be extremely complicated due to crosstalk and the multitude of upstream regulators and downstream effectors. Studying Rho GTPase networks in a formal mathematical setting can therefore be of great use. We recently built a predictive model based on Boolean logic which identified a negative feedback loop critical for RhoA and Rac1 activity...
August 30, 2016: Small GTPases
Nuria Socoro-Yuste, Marie-Claire Dagher, Anne Gonzalez De Peredo, Julie Mondet, Affif Zaccaria, Florence Roux Dalvai, Isabelle Plo, Jean Yves Cahn, Pascal Mossuz
Besides genetic abnormalities in MPN patients, several studies have reported alterations in protein expression that could contribute towards the clinical phenotype. However, little is known about protein modifications in Ph(-) MPN erythrocytes. In this context, we used a quantitative mass spectrometry proteomics approach to study the MPN erythrocyte proteome. LC-MS/MS (LTQ Orbitrap) analysis led to the identification of 51 and 86 overexpressed proteins in Polycythemia Vera and Essential Thrombocythemia respectively, compared with controls...
August 24, 2016: Biochimica et Biophysica Acta
Xiang Wang, Fang Zhao, Zhong-Ming Lv, Wei-Qin Shi, Lu-Yong Zhang, Ming Yan
Triptolide (TP), derived from the medicinal plant Triterygium wilfordii Hook. f. (TWHF), is a diterpene triepoxide with variety biological and pharmacological activities. However, TP has been restricted in clinical application due to its narrow therapeutic window especially in reproductive system. During spermatogenesis, Sertoli cell cytoskeleton plays an essential role in facilitating germ cell movement and cell-cell actin-based adherens junctions (AJ). At Sertoli cell-spermatid interface, the anchoring device is a kind of AJ, known as ectoplasmic specializations (ES)...
November 1, 2016: Toxicology and Applied Pharmacology
Lan K Nguyen, Boris N Kholodenko, Alex von Kriegsheim
Cell migration requires a precise temporal and spatial coordination of several processes which allow the cell to efficiently move. The extension and retraction of membrane protrusion, as well as adhesion are controlled by the Rho-family small GTPases. Two members of the family, Rac1 and RhoA, can show opposite behaviors and spatial localisations, with RhoA being active toward the rear of the cell and regulating its retraction during migration, whereas Rac1 is active toward the front of the cell. In addition to the spatial segregation, RhoA and Rac1 activity at the leading edge of the cells has an element of temporal segregation, with RhoA and Rac1 activities peaking at separate points during the migratory cycle of protrusion and retraction...
August 17, 2016: Small GTPases
Louis Hodgson, Désirée Spiering, Mohsen Sabouri-Ghomi, Onur Dagliyan, Céline DerMardirossian, Gaudenz Danuser, Klaus M Hahn
Guanine-nucleotide dissociation inhibitors (GDIs) are negative regulators of Rho family GTPases that sequester the GTPases away from the membrane. Here we ask how GDI-Cdc42 interaction regulates localized Cdc42 activation for cell motility. The sensitivity of cells to overexpression of Rho family pathway components led us to a new biosensor, GDI.Cdc42 FLARE, in which Cdc42 is modified with a fluorescence resonance energy transfer (FRET) 'binding antenna' that selectively reports Cdc42 binding to endogenous GDIs...
October 2016: Nature Chemical Biology
Dong-Liang Shi, Gui-Rong Shi, Jing Xie, Xu-Zhao Du, Hao Yang
Fibroblast-like synoviocytes (FLS) with aberrant expression of microRNA (miRNA) are critical pathogenic regulators in rheumatoid arthritis (RA). Previous studies have found that overexpression or silencing of miRNA can contribute to the development of miRNA-based therapeutics in arthritis models. In this study, we explored the effects of miR-27a on cell migration and invasion in cultured FLS from RA patients. We found that miR-27a was markedly downregulated in the serum, synovial tissue, and FLS of RA patients...
August 31, 2016: Molecules and Cells
Anne J Ridley
Rho GTPases have many and diverse roles in cell physiology, and some family members are very well studied, including RhoA, Rac1 and Cdc42. But many are relatively neglected, and fundamental questions about their mechanisms and functions remain open.
2016: BMC Biology
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