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Lianggong Ding, Ye Lei, Yanping Han, Yuhong Li, Xunming Ji, Lei Liu
As fundamental processes in mitochondrial dynamics, mitochondrial fusion, fission and transport are regulated by several core components, including Miro. As an atypical Rho-like small GTPase with high molecular mass, the exchange of GDP/GTP in Miro may require assistance from a guanine nucleotide exchange factor (GEF). However, the GEF for Miro has not been identified. While studying mitochondrial morphology in Drosophila, we incidentally observed that the loss of vimar, a gene encoding an atypical GEF, enhanced mitochondrial fission under normal physiological conditions...
October 2016: PLoS Genetics
Anna Bagnato, Laura Rosanò
Metastatization is a complex multistep process requiring fine-tuned regulated cytoskeleton re-modeling, mediated by the cross-talk of actin with interacting partners, such as the Rho GTPases. Our expanding knowledge of invadopodia, small invasive membrane protrusions composed of a core of F-actin, actin regulators and actin-binding proteins, and hotspots for secretion of extracellular matrix (ECM) proteinases, contributes to clarify critical steps of the metastatic program. Growth factor receptors and their intermediate signaling molecules, along with matrix adhesion and rigidity, pH and hypoxia, act as drivers of cytoskeleton changes and invadopodia formation...
October 3, 2016: Small GTPases
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
Y Komiya, Y Onodera, M Kuroiwa, S Nomimura, Y Kubo, J-M Nam, K Kajiwara, S Nada, C Oneyama, H Sabe, M Okada
Epithelial tumor cells often acquire malignant properties, such as invasion/metastasis and uncontrolled cell growth, by undergoing epithelial-mesenchymal transition (EMT). However, the mechanisms by which EMT contributes to malignant progression remain elusive. Here we show that the Rho guanine nucleotide exchange factor (GEF) ARHGEF5 promotes tumor malignancy in a manner dependent on EMT status. We previously identified ARHGEF5, a member of the Dbl family of GEFs, as a multifunctional mediator of Src-induced cell invasion and tumor growth...
2016: Oncogenesis
Yufeng Tian, Grzegorz Gawlak, Xinyong Tian, Alok S Shah, Nicolene Sarich, Sandra Citi, Anna A Birukova
Agonist-induced activation of Rho GTPase signaling leads to endothelial cell (EC) permeability and may culminate to pulmonary edema, a devastating complication of acute lung injury. Cingulin is an adaptor protein first discovered in epithelium and involved in the organization of the tight junctions. This study investigated the role of cingulin in control of agonist-induced lung EC permeability via interaction with RhoA-specific activator GEF-H1. SiRNA-induced cingulin knockdown augmented thrombin-induced EC permeability monitored by measurements of transendothelial electrical resistance and endothelial cell permeability for macromolecules...
September 2, 2016: Journal of Biological Chemistry
Ru-Feng Wu, Chengxu Liao, Guosheng Fu, Heather N Hayenga, Kejia Yang, Zhenyi Ma, Zhe Liu, Lance S Terada
Tissue cells respond to changes in tensional forces with proliferation or death through the control of RhoA. However, the response coupling mechanisms that link force with RhoA activation are poorly understood. We found that tension applied to fibronectin-coated microbeads caused recruitment of all three isoforms of the Shc adapter (p66(Shc), p52(Shc), and p46(Shc)) to adhesion complexes. The Shc PTB domain was necessary and sufficient for this recruitment, and screening studies revealed direct interactions with the FERM domain of FAK that were required for Shc translocation to adhesion complexes...
August 29, 2016: Molecular and Cellular Biology
W Ba, N Nadif Kasri
Activity-dependent modifications in the strength of excitatory synapses are considered to be major cellular mechanisms that contribute to the plasticity of neuronal networks underlying learning and memory. Key mechanisms for the regulation of synaptic efficacy involve the dynamic changes in size and number of dendritic spines, as well as the synaptic incorporation and removal of AMPA-type glutamate receptors (AMPAr). As key regulators of the actin cytoskeleton, the Rho subfamily of GTP-binding proteins play a critical role in synaptic development and plasticity...
August 5, 2016: Small GTPases
Melanie J Grubisha, Chien-Wei Lin, George C Tseng, Peter Penzes, Etienne Sibille, Robert A Sweet
KALRN (KAL) is a Rho GEF that is highly involved in regulation of the actin cytoskeleton within dendrites. There are several isoforms of the protein that arise from differential splicing of KALRN's 66 exons. KAL isoforms have different functions in development. For example, overexpression of the KAL9 and KAL12 isoforms induce dendritic elongation in early development. However, in mature neurons KAL9 overexpression reduces dendritic length, a phenotype also observed in normal human ageing. We therefore hypothesized that KAL9 would have increased expression with age, and undertook to evaluate the expression of individual KALRN exons throughout the adult lifespan...
October 2016: European Journal of Neuroscience
Megan B Miller, Yan Yan, Yi Wu, Bing Hao, Richard E Mains, Betty A Eipper
Kalirin (Kal), a dual Rho GDP/GTP exchange factor (GEF), plays essential roles within and outside the nervous system. Tissue-specific, developmentally regulated alternative splicing generates isoforms with one (Kal7) or two (Kal9, Kal12) GEF domains along with a kinase (Kal12) domain; while Kal9 and Kal12 are crucial for neurite outgrowth, Kal7 plays important roles in spine maintenance and synaptic plasticity. Tissue-specific usage of alternate Kalrn promoters (A, B, C, D) places four different peptides before the Sec14 domain...
July 28, 2016: Journal of Neurochemistry
Huibo Ren, Xie Dang, Yanqiu Yang, Dingquan Huang, Mengting Liu, Xiaowei Gao, Deshu Lin
Plant organ growth and final shape rely on cell proliferation and, particularly, on cell expansion that largely determines the visible growth of plant organs. Arabidopsis (Arabidopsis thaliana) petals serve as an excellent model for dissecting the coordinated regulation of patterns of cell expansion and organ growth, but the molecular signaling mechanisms underlying this regulation remain largely unknown. Here, we demonstrate that during the late petal development stages, SPIKE1 (SPK1), encoding a guanine nucleotide exchange factor, activates Rho of Plants (ROP) GTPase proteins (ROP2, ROP4, and ROP6) to affect anisotropic expansion of epidermal cells in both petal blades and claws, thereby affecting anisotropic growth of the petal and the final characteristic organ shape...
September 2016: Plant Physiology
Pauline Croisé, Laurent Brunaud, Petra Tóth, Stéphane Gasman, Stéphane Ory
Altered Rho GTPase signaling has been linked to many types of cancer. As many small G proteins, Rho GTPases cycle between an active and inactive state thanks to specific regulators that catalyse exchange of GDP into GTP (Rho-GEF) or hydrolysis of GTP into GDP (Rho-GAP). Recent studies have shown that alteration takes place either at the level of Rho proteins themselves (expression levels, point mutations) or at the level of their regulators, mostly RhoGEFs and RhoGAPs. Most reports describe Rho GTPases gain of function that may participate to the tumorigenesis processes...
June 29, 2016: Small GTPases
Mariam Mansour, Sue Haupt, Ai-Leen Chan, Nathan Godde, Alexandra Rizzitelli, Sherene Loi, Franco Caramia, Siddhartha Deb, Elena A Takano, Mark Bishton, Cameron Johnstone, Brendon Monahan, Yarra Levav-Cohen, Yong-Hui Jiang, Alpha S Yap, Stephen Fox, Ora Bernard, Robin Anderson, Ygal Haupt
Metastatic disease is the major cause of breast cancer-related death and despite many advances, current therapies are rarely curative. Tumor cell migration and invasion require actin cytoskeletal reorganization to endow cells with capacity to disseminate and initiate the formation of secondary tumors. However, it is still unclear how these migratory cells colonize distant tissues to form macrometastases. The E6-associated protein, E6AP, acts both as an E3 ubiquitin-protein ligase and as a coactivator of steroid hormone receptors...
July 15, 2016: Cancer Research
Fernanda B M Priviero, Haroldo A F Toque, Kenia Pedrosa Nunes, Denise G Priolli, Cleber E Teixeira, R Clinton Webb
Basal release of nitric oxide from endothelial cells modulates contractile activity in the corpus cavernosum via inhibition of the RhoA/Rho-kinase signaling pathway. We aimed to investigate nitric oxide bioavailability, oxidative stress and the Rho-kinase pathway in the relaxation of the corpus cavernosum of an obese and diabetic model of mice (db/db mice). We hypothesized that in db/db mice impaired relaxation induced by Rho-kinase inhibitor is accompanied by diminished NO bioavailability, increased oxidative stress and upregulation of the RhoA/Rho-kinase signalling pathway...
2016: PloS One
Nancy G Pedigo, Danielle Van Delden, Laura Walters, Christopher L Farrell
The FGD1 gene encodes for a guanine exchange factor (GEF) protein that specifically activates the Rho GTPase Cdc42. For cellular migration, Cdc42 is a key molecular switch that regulates cytoskeleton restructuring, gene transcription, cellular morphology, extension, and cell adhesion. In the past decade, germline mutations in the FGD1 gene have been associated with a rare X-linked disorder known as faciogenital dysplasia (FGDY). Malformations are consistent with a loss of cellular migration during embryonic development...
July 1, 2016: Physiological Genomics
Ricardo Usategui-Martín, Ismael Calero-Paniagua, Judith García-Aparicio, Luis Corral-Gudino, Javier Del Pino Montes, Rogelio González Sarmiento
BACKGROUND AND AIMS: Paget's disease of bone (PDB) is a focal bone disorder affecting the skeleton segmentally. The disease affects osteoclasts which increase in size, number, and activity. One of the etiopathogenic hypotheses is that the disease is genetic. It has been reported that Rho GEF Vav3 is an essential factor in the regulation of osteoclast function, and alteration of the VAV3 gene could influence the development of the disease. The aim of our study was to perform an association study between variants of the VAV3 gene and the risk of developing Paget's disease of bone...
June 2016: Genetic Testing and Molecular Biomarkers
Justin R King, Nadine Kabbani
Nicotinic acetylcholine receptors (nAChRs) modulate the growth and structure of neurons throughout the nervous system. Ligand stimulation of the α7 nAChR has been shown to regulate the large heterotrimeric GTP-binding protein (G protein) signaling in various types of cells. Here, we demonstrate a role for α7 nAChR/G protein interaction in the activation of the small (monomeric) RhoA GTPase leading to cytoskeletal changes during neurite growth. Treatment of PC12 cells with the α7 nAChR agonist choline or PNU-282987 was associated with an increase in RhoA activity and an inhibition in neurite growth...
August 2016: Journal of Neurochemistry
Hiroto Fukushima, Makiko Yasumoto, Sachiko Ogasawara, Jun Akiba, Yuhei Kitasato, Masamichi Nakayama, Yoshiki Naito, Yusuke Ishida, Yoshinobu Okabe, Masafumi Yasunaga, Hiroyuki Horiuchi, Etsuko Sakamoto, Hiraku Itadani, Shinji Mizuarai, Shinji Oie, Hirohisa Yano
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive neoplastic diseases, associated with a remarkably poor prognosis. However, the molecular mechanisms underlying the development of PDAC remain elusive. The aim of this study was to identify genes whose expressions are correlated with a poor prognosis in PDAC patients, and to unravel the mechanisms underlying the involvement of these genes in the development of the cancer. METHODS: Global gene expression profiling was conducted in 39 specimens obtained from Japanese patients with PDAC to identify genes whose expressions were correlated with a shorter overall survival...
2016: Molecular Cancer
Yufeng Tian, Grzegorz Gawlak, James J O'Donnell, Isa Mambetsariev, Anna A Birukova
Excessive mechanical ventilation exerts pathologic mechanical strain on lung vascular endothelium and promotes endothelial cell (EC) inflammatory activation; however, the specific mechanisms underlying EC inflammatory response caused by mechanical ventilation related cyclic stretch (CS) remain unclear. This study investigated the effects of chronic exposure to CS at physiologic (5%) and pathologic (18%) magnitude on pulmonary EC inflammatory status in control conditions and bacterial lipopolysacharide (LPS)-stimulated conditions...
2016: PloS One
Arzu Ulu, Jeffrey A Frost
Rho GTPases regulate cell motility in a large part through control of actin cytoskeletal organization. The activation state of Rho proteins is regulated by a wide variety of guanine nucleotide exchange factors (GEFs) and GTPase activating proteins that are differentially expressed among cell types and disease states. The RhoA specific GEF neuroepithelial transforming gene 1 (Net1) is highly expressed in many cancer cells and stimulates cell motility, invasion and cell spreading in response to a variety of ligands...
April 2, 2016: Small GTPases
Geetha Chittoor, Jack W Kent, Marcio Almeida, Sobha Puppala, Vidya S Farook, Shelley A Cole, Karin Haack, Harald H H Göring, Jean W MacCluer, Joanne E Curran, Melanie A Carless, Matthew P Johnson, Eric K Moses, Laura Almasy, Michael C Mahaney, Donna M Lehman, Ravindranath Duggirala, Anthony G Comuzzie, John Blangero, Venkata Saroja Voruganti
BACKGROUND: The variation in serum uric acid concentrations is under significant genetic influence. Elevated SUA concentrations have been linked to increased risk for gout, kidney stones, chronic kidney disease, and cardiovascular disease whereas reduced serum uric acid concentrations have been linked to multiple sclerosis, Parkinson's disease and Alzheimer's disease. Previously, we identified a novel locus on chromosome 3p26 affecting serum uric acid concentrations in Mexican Americans from San Antonio Family Heart Study...
2016: BMC Genomics
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