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Amy L Stiegler, Titus J Boggon
The two p190RhoGAP proteins, p190RhoGAP-A and -B, are key regulators of Rho GTPase signaling and are essential for actin cytoskeletal structure and contractility. Here we report the discovery of two evolutionarily conserved GTPase-like domains located in the 'middle domain', previously thought to be unstructured. Deletion of these domains reduces RhoGAP activity. Crystal structures, MANT-GTPγS binding, thermal denaturation, biochemical assays and sequence homology analysis all strongly support defects in nucleotide-binding activity...
September 11, 2017: Nature Communications
Lixia Yu, Jianming Ye, Qifeng Liu, Jianhua Feng, Xiaoxia Gu, Qiang Sun, Guoyuan Lu
The glomerular visceral epithelial cells, also termed podocytes, are key in maintaining the normal renal filtration barrier. Although it has been demonstrated that stimulation of c‑Maf inducing protein (CMIP) expression is involved in podocyte damage, the molecular events during this process remain unclear. In the current study, CMIP‑induced proximal signaling was investigated by focusing on its effect on cofilin‑1 activity in puromycin aminonucleoside (PA)‑damaged podocytes. An obvious elevation of CMIP expression and phosphorylated (p) cofilin‑1 levels was detected in cultured podocytes treated with PA and in glomeruli isolated from PA‑induced nephropathy rats...
October 2017: Molecular Medicine Reports
Jiang Li, Akane Yoshikawa, Herbert Y Meltzer
The aim of this study was to determine if three biomarkers for suicide attempts previously identified and replicated in a genome-wide association (GWAS) study of bipolar disorder (BD) suicide attempters also predicted suicide attempts in patients prospectively diagnosed with schizophrenia (SCZ) or schizoaffective disorder (SAD). 162 genetically-verified Caucasian patients with SCZ or SAD were phenotyped for presence (45.7%) or absence of a lifetime suicide attempt. Three single nucleotide polymorphisms (SNPs) were genotyped or partially imputed from a GWAS dataset...
June 16, 2017: Journal of Psychiatric Research
Hee-Jun Kim, Hong-Seok Choi, Jeong-Ho Park, Mo-Jong Kim, Hyoung-Gon Lee, Robert Bob Petersen, Yong-Sun Kim, Jae-Bong Park, Eun-Kyoung Choi
The cellular prion protein (PrP(C)) is a highly conserved glycosylphosphatidylinositol (GPI)-anchored membrane protein that is involved in the signal transduction during the initial phase of neurite outgrowth. The Ras homolog gene family member A (RhoA) is a small GTPase that is known to have an essential role in regulating the development, differentiation, survival, and death of neurons in the central nervous system. Although recent studies have shown the dysregulation of RhoA in a variety of neurodegenerative diseases, the role of RhoA in prion pathogenesis remains unclear...
March 16, 2017: Cell Death & Disease
Aurélien Bidaud-Meynard, Fabien Binamé, Valérie Lagrée, Violaine Moreau
Cell migration, a key feature of embryonic development, immunity, angiogenesis, and tumor metastasis, is based on the coordinated regulation of actin dynamics and integrin-mediated adhesion. Rho GTPases play a major role in this phenomenon by regulating the onset and maintenance of actin-based protruding structures at cell leading edges (i.e. lamellipodia and filopodia) and contractile structures (i.e., stress fibers) at their trailing edge. While spatio-temporal analysis demonstrated the tight regulation of Rho GTPases at the migration front during cell locomotion, little is known about how the main regulators of Rho GTPase activity, such as GAPs, GEFs and GDIs, play a role in this process...
March 13, 2017: Small GTPases
Li Li, Yong-Min Li, Ping Zhou, Xi-Shan Wang, Gui-Yu Wang, Xu-Hai Zhao, Bin-Bin Cui, Yan-Lu Ren, Xin-Shu Dong, Zhi-Qi Chen
PURPOSE: This study aims to investigate the expression and clinical significance of p190RhoGAP, a member of the RhoGAP family, in colorectal cancer (CRC). METHODS: The expression p190RhoGAP was detected by RT-PCR, western blot (WB) and immunohistochemistry (IHC) in 14 paired CRCs and matched non-cancerous mucosal tissues. The protein content of p190RhoGAP was identified in 114 CRCs by IHC. In addition, the association of the expression of p190RhoGAP with carcinogenesis, distant metastasis and prognosis was further evaluated...
2016: American Journal of Translational Research
Fabien Binamé, Aurélien Bidaud-Meynard, Laure Magnan, Léo Piquet, Bertille Montibus, Anne Chabadel, Frédéric Saltel, Valérie Lagrée, Violaine Moreau
Spatiotemporal regulation of RhoGTPases such as RhoA is required at the cell leading edge to achieve cell migration. p190RhoGAP (p190A) is the main negative regulator of RhoA and localizes to membrane protrusions, where its GTPase-activating protein (GAP) activity is required for directional migration. In this study, we investigated the molecular processes responsible for p190A targeting to actin protrusions. By analyzing the subcellular localization of truncated versions of p190A in hepatocellular carcinoma cells, we identified a novel functional p190A domain: the protrusion localization sequence (PLS) necessary and sufficient for p190A targeting to leading edges...
September 26, 2016: Journal of Cell Biology
Barbara Torsello, Cristina Bianchi, Chiara Meregalli, Vitalba Di Stefano, Lara Invernizzi, Sofia De Marco, Giorgio Bovo, Rinaldo Brivio, Guido Strada, Silvia Bombelli, Roberto A Perego
Renal tubular cells are involved in the tubular interstitial fibrosis observed in diabetic nephropathy. It is debated whether epithelial-mesenchymal transition (EMT) affects tubular cells, which under high-glucose conditions overproduce transforming growth factor-β (TGF-β), a fibrogenic cytokine involved in interstitial fibrosis development. Our study investigated the involvement of non-receptor tyrosine kinase Arg (also called Abl2) in TGF-β production. Human primary tubular cell cultures exposed to high-glucose conditions were used...
August 1, 2016: Journal of Cell Science
Thomas Daubon, Pirjo Spuul, Florian Alonso, Isabelle Fremaux, Elisabeth Génot
Podosomes are dynamic cell-matrix contact structures that combine several key abilities, including adhesion, matrix degradation and mechanosensing. These actin-based cytoskeletal structures have been mostly studied in monocytic cells, but much less is known about those formed in other lineages. In this study, we characterise podosomes in capillary-derived microvascular endothelial cells. We identify two types of podosomes: constitutive podosomes that form in the absence of specific stimulation and induced podosomes that arise in response to the angiogenic factor VEGF-A...
July 1, 2016: Journal of Cell Science
Johannes Elvin, Lisa Buvall, Annika Lindskog Jonsson, Anna Granqvist, Emelie Lassén, Lovisa Bergwall, Jenny Nyström, Börje Haraldsson
Drugs containing adrenocorticotropic hormone have been used as therapy for patients with nephrotic syndrome. We have previously shown that adrenocorticotropic hormone and a selective agonist for the melanocortin 1 receptor (MC1R) exert beneficial actions in experimental membranous nephropathy with reduced proteinuria, reduced oxidative stress, and improved glomerular morphology and function. Our hypothesis is that MC1R activation in podocytes elicits beneficial effects by promoting stress fibers and maintaining podocyte viability...
May 1, 2016: American Journal of Physiology. Renal Physiology
Damien Duval, Pauline Labbé, Léa Bureau, Thierry Le Tourneau, Russell A Norris, Roger R Markwald, Robert Levine, Jean-Jacques Schott, Jean Mérot
Although the genetic basis of mitral valve prolapse (MVP) has now been clearly established, the molecular and cellular mechanisms involved in the pathological processes associated to a specific mutation often remain to be determined. The FLNA gene (encoding Filamin A; FlnA) was the first gene associated to non-syndromic X-linked myxomatous valvular dystrophy, but the impacts of the mutations on its function remain un-elucidated. Here, using the first repeats (1-8) of FlnA as a bait in a yeast two-hybrid screen, we identified the tyrosine phosphatase PTPN12 (PTP-PEST) as a specific binding partner of this region of FlnA protein...
September 8, 2015: Journal of Cardiovascular Development and Disease
Mounira Krifa, Salah Edin El Meshri, Nawel Bentouati, Antonio Pizzi, Emilie Sick, Leila Chekir-Ghedira, Philippe Rondé
A large number of plants used in traditional medicines have been shown to possess antitumor activities. The aims of this study were to evaluate any anticancer effect of the essential oil (EO) extracted from P. tortuosus against B16F10 melanoma cancer cells in vitro as well as in vivo. In vitro, EO was shown to induce apoptosis and to inhibit migration and invasion processes. Further investigation revealed that EO decreased focal adhesion and invadopodia formation which was accompanied by a drastic downregulation of FAK, Src, ERK, p130Cas and paxillin...
May 2016: Journal of Cellular Biochemistry
Philipp Eberwein, Dougal Laird, Simon Schulz, Thomas Reinhard, Thorsten Steinberg, Pascal Tomakidi
Within the concept of integrin growth factor receptor (GFR) cross-talk, little is known about the effects of GFRs on focal adhesions (FAs). Therefore, we tested the hypothesis whether EGF can modulate constituents of FAs and subsequent down-stream events. To this end, EGF-treated keratinocytes were subjected to combined fluorescence imaging and western blotting, to quantify expression and/or activation of molecules, involved in integrin GFR cross-talk, and receptor proximal and distal signaling events. Generally, EGF response revealed an amplified redistribution or activation of molecules under study, which will be explained in detail from the plasma membrane to the cell interior...
October 2015: Biochimica et Biophysica Acta
Mykhaylo V Artamonov, Li Jin, Aaron S Franke, Ko Momotani, Ruoya Ho, Xiu Rong Dong, Mark W Majesky, Avril V Somlyo
This study identifies signaling pathways that play key roles in the formation and maintenance of epicardial cells, a source of progenitors for coronary smooth muscle cells (SMCs). After epithelial to mesenchymal transition (EMT), mesenchymal cells invade the myocardium to form coronary SMCs. RhoA/Rho kinase activity is required for EMT and for differentiation into coronary SMCs, whereas cAMP activity is known to inhibit EMT in epithelial cells by an unknown mechanism. We use outgrowth of epicardial cells from E9...
April 17, 2015: Journal of Biological Chemistry
Lauren M DePoy, Riley E Perszyk, Kelsey S Zimmermann, Anthony J Koleske, Shannon L Gourley
Cocaine and amphetamine remodel dendritic spines within discrete cortico-limbic brain structures including the orbitofrontal cortex (oPFC). Whether dendrite structure is similarly affected, and whether pre-existing cellular characteristics influence behavioral vulnerabilities to drugs of abuse, remain unclear. Animal models provide an ideal venue to address these issues because neurobehavioral phenotypes can be defined both before, and following, drug exposure. We exposed mice to cocaine from postnatal days 31-35, corresponding to early adolescence, using a dosing protocol that causes impairments in an instrumental reversal task in adulthood...
2014: Frontiers in Pharmacology
Arkadi Manukyan, Kirsten Ludwig, Sergio Sanchez-Manchinelly, Sarah J Parsons, P Todd Stukenberg
The cytokinetic furrow is organized by the RhoA GTPase, which recruits actin and myosin II to the furrow and drives contractility. Here, we show that the RhoA GTPase-activting protein (GAP) p190RhoGAP-A (also known as ARHGAP35) has a role in cytokinesis and is involved in regulating levels of RhoA-GTP and contractility. Cells depleted of p190RhoGAP-A accumulate high levels of RhoA-GTP and markers of high RhoA activity in the furrow, resulting in failure of the cytokinetic furrow to progress to abscission. The loss of p190RhoGAP-A can be rescued by a low dose of the myosin II inhibitor blebbistatin, suggesting that cells fail cytokinesis because they have too much myosin activity...
January 1, 2015: Journal of Cell Science
David M Bryant, Julie Roignot, Anirban Datta, Arend W Overeem, Minji Kim, Wei Yu, Xiao Peng, Dennis J Eastburn, Andrew J Ewald, Zena Werb, Keith E Mostov
The formation of epithelial tissues containing lumens requires not only the apical-basolateral polarization of cells, but also the coordinated orientation of this polarity such that the apical surfaces of neighboring cells all point toward the central lumen. Defects in extracellular matrix (ECM) signaling lead to inverted polarity so that the apical surfaces face the surrounding ECM. We report a molecular switch mechanism controlling polarity orientation. ECM signals through a β1-integrin/FAK/p190RhoGAP complex to downregulate a RhoA/ROCK/Ezrin pathway at the ECM interface...
October 27, 2014: Developmental Cell
Elizabeth Kiwanuka, Cameron Cy Lee, Florian Hackl, Edward J Caterson, Johan Pe Junker, Bengt Gerdin, Elof Eriksson
Cell migration requires spatiotemporal integration of signals that regulate cytoskeletal dynamics. In response to a migration-promoting agent, cells begin to polarise and extend protrusions in the direction of migration. These cytoskeletal rearrangements are orchestrated by a variety of proteins, including focal adhesion kinase (FAK) and the Rho family of GTPases. CCN2, also known as connective tissue growth factor, has emerged as a regulator of cell migration but the mechanism by which CCN2 regulates keratinocyte function is not well understood...
June 2016: International Wound Journal
Elvira Bailón, Estefanía Ugarte-Berzal, Irene Amigo-Jiménez, Philippe Van den Steen, Ghislain Opdenakker, José A García-Marco, Angeles García-Pardo
This study addresses the role of (pro)MMP-9 overexpression in CLL cell migration. We have used primary CLL cells and CLL-derived MEC-1 cells transfected with empty (mock cells) or proMMP-9-encoding (MMP-9 cells) lentiviral vectors. The constitutive (pro)MMP-9 expression in mock cells and primary CLL cells was similar, whereas in MMP-9 cells, expression resembled that of CLL cells incubated with proMMP-9. In xenograft models, in NOD/SCID mice, MMP-9-MEC-1 transfectants showed significantly reduced homing to bone marrow and spleen compared with mock cells...
August 2014: Journal of Leukocyte Biology
Rubén A Bartolomé, Marta Díaz-Martínez, Georgina P Coló, Nohemí Arellano-Sánchez, Pedro Torres-Ayuso, Jan Willem Kleinovink, Isabel Mérida, Joaquin Teixidó
Activation of the GTPase RhoA linked to cell invasion can be tightly regulated following Gα13 stimulation. We have used a cellular model displaying Gα13-dependent inhibition of RhoA activation associated with defective cell invasion to the chemokine CXCL12 to characterize the molecular players regulating these processes. Using both RNAi transfection approaches and protein overexpression experiments here we show that the Src kinase Blk is involved in Gα13-activated tyrosine phosphorylation of p190RhoGAP, which causes RhoA inactivation and ultimately leads to deficient cell invasion...
November 2014: Cellular Signalling
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