Cdc42 and Rac1 Activity Is Reduced in Human Pheochromocytoma and Correlates with FARP1 and ARHGEF1 Expression
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The Smooth Muscle-Selective Rhogap GRAF3 Is a Critical Regulator of Vascular Tone and Hypertension
ARTICLE Received 9 Jun 2013 | Accepted 11 Nov 2013 | Published 13 Dec 2013 DOI: 10.1038/ncomms3910 The smooth muscle-selective RhoGAP GRAF3 is a critical regulator of vascular tone and hypertension Xue Bai1, Kaitlin C. Lenhart1, Kim E. Bird1, Alisa A. Suen1, Mauricio Rojas2, Masao Kakoki1, Feng Li1, Oliver Smithies1,2, Christopher P. Mack1,2 & Joan M. Taylor1,2 Although hypertension is a worldwide health issue, an incomplete understanding of its aetiology has hindered our ability to treat this complex disease. Here we identify arhgap42 (also known as GRAF3) as a Rho-specific GAP expressed specifically in smooth muscle cells (SMCs) in mice and humans. We show that GRAF3-deficient mice exhibit significant hypertension and increased pressor responses to angiotensin II and endothelin-1; these effects are prevented by treatment with the Rho-kinase inhibitor, Y27632. RhoA activity and myosin light chain phosphorylation are elevated in GRAF3-depleted SMCs in vitro and in vivo, and isolated vessel segments from GRAF3-deficient mice show increased contractility. Taken together, our data indicate that GRAF3-mediated inhibition of RhoA activity in vascular SMCs is necessary for maintaining normal blood pressure homoeostasis. Moreover, these findings provide a potential mechanism for a hypertensive locus recently identified within arhgap42 and provide a foundation for the future development of innovative hypertension therapies. 1 Department of Pathology and Lab Medicine, University of North Carolina, 501 Brinkhous-Bullitt Building CB 7525, Chapel Hill, North Carolina 27599, USA. 2 McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina 27599, USA. Correspondence and requests for materials shouldbe addressed to J.M.T. -
Focus on Cdc42 in Breast Cancer: New Insights, Target Therapy Development and Non-Coding Rnas
Review Focus on Cdc42 in Breast Cancer: New Insights, Target Therapy Development and Non-Coding RNAs Yu Zhang †, Jun Li †, Xing-Ning Lai, Xue-Qiao Jiao, Jun-Ping Xiong and Li-Xia Xiong * Department of Pathophysiology, Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Medical College, Nanchang University, 461 Bayi Road, Nanchang 330006, China; [email protected] (Y.Z.); [email protected] (J.L.); [email protected] (X.-N.L.); [email protected] (X.-Q.J.); [email protected] (J.-P.X.) * Correspondence: [email protected]; Tel.: +86-791-8636-0556 † These authors contributed equally to this work. Received: 30 December 2018; Accepted: 8 February 2019; Published: 11 February 2019 Abstract: Breast cancer is the most common malignant tumors in females. Although the conventional treatment has demonstrated a certain effect, some limitations still exist. The Rho guanosine triphosphatase (GTPase) Cdc42 (Cell division control protein 42 homolog) is often upregulated by some cell surface receptors and oncogenes in breast cancer. Cdc42 switches from inactive guanosine diphosphate (GDP)-bound to active GTP-bound though guanine-nucleotide- exchange factors (GEFs), results in activation of signaling cascades that regulate various cellular processes such as cytoskeletal changes, proliferation and polarity establishment. Targeting Cdc42 also provides a strategy for precise breast cancer therapy. In addition, Cdc42 is a potential target for several types of non-coding RNAs including microRNAs and lncRNAs. These non-coding RNAs is extensively involved in Cdc42-induced tumor processes, while many of them are aberrantly expressed. Here, we focus on the role of Cdc42 in cell morphogenesis, proliferation, motility, angiogenesis and survival, introduce the Cdc42-targeted non-coding RNAs, as well as present current development of effective Cdc42-targeted inhibitors in breast cancer. -
Dysregulation of Rho Gtpases in the Apix/Arhgef6 Mouse Model of X
Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2011 Dysregulation of Rho GTPases in the Pix/Arhgef6 mouse model of X-linked intellectual disability is paralleled by impaired structural and synaptic plasticity and cognitive deficits Ramakers, G J A ; Wolfer, D ; Rosenberger, G ; Kuchenbecker, K ; Kreienkamp, H J ; Prange-Kiel, J ; Rune, G ; Richter, K ; Langnaese, K ; Masneuf, S ; Bösl, M R ; Fischer, K D ; Krugers, H J ; Lipp, H P ; van Galen, E ; Kutsche, K Abstract: Mutations in the ARHGEF6 gene, encoding the guanine nucleotide exchange factor PIX/Cool- 2 for the Rho GTPases Rac1 and Cdc42, cause X-linked intellectual disability (ID) in humans. We show here that Pix/Arhgef6 is primarily expressed in neuropil regions of the hippocampus. To study the role of Pix/Arhgef6 in neuronal development and plasticity and gain insight into the pathogenic mechanisms underlying ID, we generated Pix/Arhgef6-deficient mice. Gross brain structure in these mice appeared to be normal; however, analysis of Golgi-Cox-stained pyramidal neurons revealed an increase in both dendritic length and spine density in the hippocampus, accompanied by an overall loss in spine synapses. Early-phase long-term potentiation was reduced and long-term depression was increased in the CA1 hippocampal area of Pix/Arhgef6-deficient animals. Knockout animals exhibited impaired spatial and complex learning and less behavioral control in mildly stressful situations, suggesting that this model mimics the human ID phenotype. The structural and electrophysiological alterations in the hippocampus were accompanied by a significant reduction in active Rac1 and Cdc42, but not RhoA. -
Individual Protomers of a G Protein-Coupled Receptor Dimer Integrate Distinct Functional Modules
OPEN Citation: Cell Discovery (2015) 1, 15011; doi:10.1038/celldisc.2015.11 © 2015 SIBS, CAS All rights reserved 2056-5968/15 ARTICLE www.nature.com/celldisc Individual protomers of a G protein-coupled receptor dimer integrate distinct functional modules Nathan D Camp1, Kyung-Soon Lee2, Jennifer L Wacker-Mhyre2, Timothy S Kountz2, Ji-Min Park2, Dorathy-Ann Harris2, Marianne Estrada2, Aaron Stewart2, Alejandro Wolf-Yadlin1, Chris Hague2 1Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; 2Department of Pharmacology, University of Washington School of Medicine, Seattle, WA, USA Recent advances in proteomic technology reveal G-protein-coupled receptors (GPCRs) are organized as large, macromolecular protein complexes in cell membranes, adding a new layer of intricacy to GPCR signaling. We previously reported the α1D-adrenergic receptor (ADRA1D)—a key regulator of cardiovascular, urinary and CNS function—binds the syntrophin family of PDZ domain proteins (SNTA, SNTB1, and SNTB2) through a C-terminal PDZ ligand inter- action, ensuring receptor plasma membrane localization and G-protein coupling. To assess the uniqueness of this novel GPCR complex, 23 human GPCRs containing Type I PDZ ligands were subjected to TAP/MS proteomic analysis. Syntrophins did not interact with any other GPCRs. Unexpectedly, a second PDZ domain protein, scribble (SCRIB), was detected in ADRA1D complexes. Biochemical, proteomic, and dynamic mass redistribution analyses indicate syntrophins and SCRIB compete for the PDZ ligand, simultaneously exist within an ADRA1D multimer, and impart divergent pharmacological properties to the complex. Our results reveal an unprecedented modular dimeric architecture for the ADRA1D in the cell membrane, providing unexpected opportunities for fine-tuning receptor function through novel protein interactions in vivo, and for intervening in signal transduction with small molecules that can stabilize or disrupt unique GPCR:PDZ protein interfaces. -
High Throughput Strategies Aimed at Closing the GAP in Our Knowledge of Rho Gtpase Signaling
cells Review High Throughput strategies Aimed at Closing the GAP in Our Knowledge of Rho GTPase Signaling Manel Dahmene 1, Laura Quirion 2 and Mélanie Laurin 1,3,* 1 Oncology Division, CHU de Québec–Université Laval Research Center, Québec, QC G1V 4G2, Canada; [email protected] 2 Montréal Clinical Research Institute (IRCM), Montréal, QC H2W 1R7, Canada; [email protected] 3 Université Laval Cancer Research Center, Québec, QC G1R 3S3, Canada * Correspondence: [email protected] Received: 21 May 2020; Accepted: 7 June 2020; Published: 9 June 2020 Abstract: Since their discovery, Rho GTPases have emerged as key regulators of cytoskeletal dynamics. In humans, there are 20 Rho GTPases and more than 150 regulators that belong to the RhoGEF, RhoGAP, and RhoGDI families. Throughout development, Rho GTPases choregraph a plethora of cellular processes essential for cellular migration, cell–cell junctions, and cell polarity assembly. Rho GTPases are also significant mediators of cancer cell invasion. Nevertheless, to date only a few molecules from these intricate signaling networks have been studied in depth, which has prevented appreciation for the full scope of Rho GTPases’ biological functions. Given the large complexity involved, system level studies are required to fully grasp the extent of their biological roles and regulation. Recently, several groups have tackled this challenge by using proteomic approaches to map the full repertoire of Rho GTPases and Rho regulators protein interactions. These studies have provided in-depth understanding of Rho regulators specificity and have contributed to expand Rho GTPases’ effector portfolio. Additionally, new roles for understudied family members were unraveled using high throughput screening strategies using cell culture models and mouse embryos. -
4 Understanding the Role of GNA13 Deregulation in Lymphomagenesis
Integrative Genomics Reveals a Role for GNA13 in Lymphomagenesis by Adrienne Greenough University Program in Genetics and Genomics Duke University Approved: ___________________________ Sandeep Dave, Supervisor ___________________________ Fred Dietrich ___________________________ Jack Keene ___________________________ Yuan Zhuang Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the University Program in Genetics and Genomics in the Graduate School of Duke University 2014 i v ABSTRACT Integrative Genomics Reveals a Role for GNA13 in Lymphomagenesis by Adrienne Greenough University Program in Genetics and Genomics Duke University Approved: ___________________________ Sandeep Dave, Supervisor ___________________________ Fred Dietrich ___________________________ Jack Keene ___________________________ Yuan Zhuang An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the University Program in Genetics and Genomics in the Graduate School of Duke University 2014 Copyright by Adrienne Greenough 2014 Abstract Lymphomas comprise a diverse group of malignancies derived from immune cells. High throughput sequencing has recently emerged as a powerful and versatile method for analysis of the cancer genome and transcriptome. As these data continue to emerge, the crucial work lies in sorting through the wealth of information to hone in on the critical aspects that will give us a better understanding of biology and new insight for how to treat disease. Finding the important signals within these large data sets is one of the major challenges of next generation sequencing. In this dissertation, I have developed several complementary strategies to describe the genetic underpinnings of lymphomas. I begin with developing a better method for RNA sequencing that enables strand-specific total RNA sequencing and alternative splicing profiling in the same analysis. -
Leukocyte Rhoa Exchange Factor Arhgef1 Mediates Vascular
Leukocyte RhoA exchange factor Arhgef1 mediates vascular inflammation and atherosclerosis Maria Luigia Carbone, Gilliane Chadeuf, Sandrine Heurtebise-Chrétien, Xavier Prieur, Thibault Quillard, Yann Goueffic, Nathalie Vaillant, Marc Rio, Laure Castan, Maxim Durand, et al. To cite this version: Maria Luigia Carbone, Gilliane Chadeuf, Sandrine Heurtebise-Chrétien, Xavier Prieur, Thibault Quil- lard, et al.. Leukocyte RhoA exchange factor Arhgef1 mediates vascular inflammation and atheroscle- rosis. Journal of Clinical Investigation, American Society for Clinical Investigation, 2017, Equipe III Equipe IV, 127 (12), pp.4516–4526. 10.1172/JCI92702. hal-01832942 HAL Id: hal-01832942 https://hal.archives-ouvertes.fr/hal-01832942 Submitted on 11 Jul 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. RESEARCH ARTICLE The Journal of Clinical Investigation Leukocyte RhoA exchange factor Arhgef1 mediates vascular inflammation and atherosclerosis Maria Luigia Carbone,1 Gilliane Chadeuf,1 Sandrine Heurtebise-Chrétien,1 Xavier Prieur,1 Thibault Quillard,2 Yann Goueffic,2,3 Nathalie Vaillant,1 Marc Rio,1 Laure Castan,1 Maxim Durand,4 Céline Baron-Menguy,1 Julien Aureille,1 Juliette Desfrançois,5 Angela Tesse,1 Raul M. Torres,6 and Gervaise Loirand1,3 1INSERM, CNRS, UNIV Nantes, l’institut du thorax, Nantes, France. -
The Human Gene Connectome As a Map of Short Cuts for Morbid Allele Discovery
The human gene connectome as a map of short cuts for morbid allele discovery Yuval Itana,1, Shen-Ying Zhanga,b, Guillaume Vogta,b, Avinash Abhyankara, Melina Hermana, Patrick Nitschkec, Dror Friedd, Lluis Quintana-Murcie, Laurent Abela,b, and Jean-Laurent Casanovaa,b,f aSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; bLaboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris Descartes University, Institut National de la Santé et de la Recherche Médicale U980, Necker Medical School, 75015 Paris, France; cPlateforme Bioinformatique, Université Paris Descartes, 75116 Paris, France; dDepartment of Computer Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; eUnit of Human Evolutionary Genetics, Centre National de la Recherche Scientifique, Unité de Recherche Associée 3012, Institut Pasteur, F-75015 Paris, France; and fPediatric Immunology-Hematology Unit, Necker Hospital for Sick Children, 75015 Paris, France Edited* by Bruce Beutler, University of Texas Southwestern Medical Center, Dallas, TX, and approved February 15, 2013 (received for review October 19, 2012) High-throughput genomic data reveal thousands of gene variants to detect a single mutated gene, with the other polymorphic genes per patient, and it is often difficult to determine which of these being of less interest. This goes some way to explaining why, variants underlies disease in a given individual. However, at the despite the abundance of NGS data, the discovery of disease- population level, there may be some degree of phenotypic homo- causing alleles from such data remains somewhat limited. geneity, with alterations of specific physiological pathways under- We developed the human gene connectome (HGC) to over- come this problem. -
SOS1, ARHGEF1, and DOCK2 Rho-Gefs Mediate JAK-Dependent LFA-1 Activation by Chemokines
SOS1, ARHGEF1, and DOCK2 rho-GEFs Mediate JAK-Dependent LFA-1 Activation by Chemokines This information is current as Lara Toffali, Alessio Montresor, Michela Mirenda, Giorgio of September 23, 2021. Scita and Carlo Laudanna J Immunol published online 16 December 2016 http://www.jimmunol.org/content/early/2016/12/15/jimmun ol.1600933 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2016/12/15/jimmunol.160093 Material 3.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 23, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published December 16, 2016, doi:10.4049/jimmunol.1600933 The Journal of Immunology SOS1, ARHGEF1, and DOCK2 rho-GEFs Mediate JAK-Dependent LFA-1 Activation by Chemokines Lara Toffali,*,† Alessio Montresor,*,† Michela Mirenda,* Giorgio Scita,‡,x and Carlo Laudanna*,† JAK-dependent activation of the rho module of integrin affinity triggering mediates chemokine-induced leukocyte adhesion. -
Endothelial Rhogefs: a Systematic Analysis of Their Expression Profiles in VEGF- Stimulated and Tumor Endothelial Cells
UC Office of the President Recent Work Title Endothelial RhoGEFs: A systematic analysis of their expression profiles in VEGF- stimulated and tumor endothelial cells. Permalink https://escholarship.org/uc/item/3zm3j5bn Authors Hernández-García, Ricardo Iruela-Arispe, M Luisa Reyes-Cruz, Guadalupe et al. Publication Date 2015-11-01 DOI 10.1016/j.vph.2015.10.003 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Vascular Pharmacology 74 (2015) 60–72 Contents lists available at ScienceDirect Vascular Pharmacology journal homepage: www.elsevier.com/locate/vph Endothelial RhoGEFs: A systematic analysis of their expression profiles in VEGF-stimulated and tumor endothelial cells Ricardo Hernández-García a, M. Luisa Iruela-Arispe c, Guadalupe Reyes-Cruz b, José Vázquez-Prado a,⁎ a Department of Pharmacology,CINVESTAV-IPN,México D.F.,Mexico b Department of Cell Biology,CINVESTAV-IPN,México D.F.,Mexico c Department of Molecular, Cell, and Developmental Biology and Molecular Biology Institute,University of California,Los Angeles, CA,USA article info abstract Article history: Rho guanine nucleotide exchange factors (RhoGEFs) integrate cell signaling inputs into morphological and func- Received 3 December 2014 tional responses. However, little is known about the endothelial repertoire of RhoGEFs and their regulation. Thus, Received in revised form 8 October 2015 we assessed the expression of 81 RhoGEFs (70 homologous to Dbl and 11 of the DOCK family) in endothelial cells. Accepted 9 October 2015 Further, in the case of DH-RhoGEFs, we also determined their responses to VEGF exposure in vitro and in the con- Available online 17 October 2015 text of tumors. -
Whole-Genome DNA Methylation and Hydroxymethylation Profiling for HBV-Related Hepatocellular Carcinoma
INTERNATIONAL JOURNAL OF ONCOLOGY 49: 589-602, 2016 Whole-genome DNA methylation and hydroxymethylation profiling for HBV-related hepatocellular carcinoma CHAO YE*, RAN TAO*, QINGYI CAO, DANHUA ZHU, YINI WANG, JIE WANG, JUAN LU, ERMEI CHEN and LANJUAN LI State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China Received March 18, 2016; Accepted May 13, 2016 DOI: 10.3892/ijo.2016.3535 Abstract. Hepatocellular carcinoma (HCC) is a common tions between them. Taken together, in the present study we solid tumor worldwide with a poor prognosis. Accumulating conducted the first genome-wide mapping of DNA methyla- evidence has implicated important regulatory roles of epigen- tion combined with hydroxymethylation in HBV-related HCC etic modifications in the occurrence and progression of HCC. and provided a series of potential novel epigenetic biomarkers In the present study, we analyzed 5-methylcytosine (5-mC) for HCC. and 5-hydroxymethylcytosine (5-hmC) levels in the tumor tissues and paired adjacent peritumor tissues (APTs) from Introduction four individual HCC patients using a (hydroxy)methylated DNA immunoprecipitation approach combined with deep Hepatocellular carcinoma (HCC), a common solid tumor, is sequencing [(h)MeDIP-Seq]. Bioinformatics analysis revealed the third most frequent cause of cancer-related death in the that the 5-mC levels in the promoter regions of 2796 genes and world. Hepatitis B virus (HBV) infection is the main cause of the 5-hmC levels in 507 genes differed significantly between HCC in China (1). -
Membrane and Protein Interactions of the Pleckstrin Homology Domain Superfamily
Membranes 2015, 5, 646-663; doi:10.3390/membranes5040646 OPEN ACCESS membranes ISSN 2077-0375 www.mdpi.com/journal/membranes Article Membrane and Protein Interactions of the Pleckstrin Homology Domain Superfamily Marc Lenoir 1, Irina Kufareva 2, Ruben Abagyan 2, and Michael Overduin 3,* 1 School of Cancer Sciences, Faculty of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK; E-Mail: [email protected] 2 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; E-Mails: [email protected] (I.K.); [email protected] (R.A.) 3 Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada * Author to whom correspondence should be addressed: E-Mail: [email protected]; Tel.: +1-780-492-3357; Fax: +1-780-492-0886. Academic Editor: Shiro Suetsugu Received: 15 September 2015 / Accepted: 16 October 2015 / Published: 23 October 2015 Abstract: The human genome encodes about 285 proteins that contain at least one annotated pleckstrin homology (PH) domain. As the first phosphoinositide binding module domain to be discovered, the PH domain recruits diverse protein architectures to cellular membranes. PH domains constitute one of the largest protein superfamilies, and have diverged to regulate many different signaling proteins and modules such as Dbl homology (DH) and Tec homology (TH) domains. The ligands of approximately 70 PH domains have been validated by binding assays and complexed structures, allowing meaningful extrapolation across the entire superfamily. Here the Membrane Optimal Docking Area (MODA) program is used at a genome-wide level to identify all membrane docking PH structures and map their lipid-binding determinants.