Focus on Cdc42 in Breast Cancer: New Insights, Target Therapy Development and Non-Coding Rnas
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Cdc42 and Rac1 Activity Is Reduced in Human Pheochromocytoma and Correlates with FARP1 and ARHGEF1 Expression
234 P Croisé et al. Rho-GTPase activity in human 23:4 281–293 Research pheochromocytoma Cdc42 and Rac1 activity is reduced in human pheochromocytoma and correlates with FARP1 and ARHGEF1 expression Pauline Croisé1, Sébastien Houy1, Mathieu Gand1, Joël Lanoix2, Valérie Calco1, Petra Tóth1, Laurent Brunaud3, Sandra Lomazzi4, Eustache Paramithiotis2, Daniel Chelsky2, Stéphane Ory1,* and Stéphane Gasman1,* Correspondence 1Institut des Neurosciences Cellulaires et Intégratives (INCI), CNRS UPR 3212, Strasbourg, France should be addressed 2Caprion Proteome, Inc., Montréal, Québec, Canada to S Ory or S Gasman 3Service de Chirurgie Digestive, Hépato-bilaire et Endocrinienne, CHRU Nancy, Hôpitaux de Brabois, Email Vandoeuvre les Nancy, France [email protected] or 4Centre de Ressources Biologiques (CRB), CHRU Nancy, Hôpitaux de Brabois, Vandoeuvres les Nancy, France [email protected] *(S Ory and S Gasman contributed equally to this work) Abstract Among small GTPases from the Rho family, Cdc42, Rac, and Rho are well known to mediate Key Words a large variety of cellular processes linked with cancer biology through their ability to cycle f Rho-GTPases between an inactive (GDP-bound) and an active (GTP-bound) state. Guanine nucleotide f pheochromocytoma exchange factors (GEFs) stimulate the exchange of GDP for GTP to generate the activated f mass spectrometry form, whereas the GTPase-activating proteins (GAPs) catalyze GTP hydrolysis, leading to f Rho-GEF Endocrine-Related Cancer Endocrine-Related the inactivated form. Modulation of Rho GTPase activity following altered expression of Rho-GEFs and/or Rho-GAPs has already been reported in various human tumors. However, nothing is known about the Rho GTPase activity or the expression of their regulators in human pheochromocytomas, a neuroendocrine tumor (NET) arising from chromaffin cells of the adrenal medulla. -
Small Rho Gtpase Family Member Cdc42 and Its Role in Neuronal Survival and Apoptosis
University of Denver Digital Commons @ DU Electronic Theses and Dissertations Graduate Studies 1-1-2017 Small Rho GTPase Family Member Cdc42 and Its Role in Neuronal Survival and Apoptosis Noelle Christine Punessen University of Denver Follow this and additional works at: https://digitalcommons.du.edu/etd Part of the Biology Commons, and the Genetics and Genomics Commons Recommended Citation Punessen, Noelle Christine, "Small Rho GTPase Family Member Cdc42 and Its Role in Neuronal Survival and Apoptosis" (2017). Electronic Theses and Dissertations. 1337. https://digitalcommons.du.edu/etd/1337 This Thesis is brought to you for free and open access by the Graduate Studies at Digital Commons @ DU. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of Digital Commons @ DU. For more information, please contact [email protected],[email protected]. Small Rho GTPase Family Member Cdc42 and its Role in Neuronal Survival and Apoptosis A Thesis Presented to the Faculty of Natural Sciences and Mathematics University of Denver In Partial Fulfillment of the Requirements for the Degree Master of Science by Noelle C. Punessen August 2017 Advisor: Dr. Daniel A. Linseman Author: Noelle C. Punessen Title: Small Rho GTPase Family Member Cdc42 and its Role in Neuronal Survival and Apoptosis Advisor: Dr. Daniel A. Linseman Degree Date: August 2017 Abstract Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer’s and Parkinson’s disease are caused by a progressive and aberrant destruction of neurons in the brain and spinal cord. These disorders lack effective long term treatments, and existing options focus primarily on either delaying disease onset or alleviating symptomology. -
Supplementary Information Method CLEAR-CLIP. Mouse Keratinocytes
Supplementary Information Method CLEAR-CLIP. Mouse keratinocytes of the designated genotype were maintained in E-low calcium medium. Inducible cells were treated with 3 ug/ml final concentration doxycycline for 24 hours before performing CLEAR-CLIP. One 15cm dish of confluent cells was used per sample. Cells were washed once with cold PBS. 10mls of cold PBS was then added and cells were irradiated with 300mJ/cm2 UVC (254nM wavelength). Cells were then scraped from the plates in cold PBS and pelleted by centrifugation at 1,000g for 2 minutes. Pellets were frozen at -80oC until needed. Cells were then lysed on ice with occasional vortexing in 1ml of lysis buffer (50mM Tris-HCl pH 7.4, 100mM NaCl, 1mM MgCl2, 0.1 mM CaCl2, 1% NP-40, 0.5% Sodium Deoxycholate, 0.1% SDS) containing 1X protease inhibitors (Roche #88665) and RNaseOUT (Invitrogen #10777019) at 4ul/ml final concentration. Next, TurboDNase (Invitrogen #AM2238, 10U), RNase A (0.13ug) and RNase T1 (0.13U) were added and samples were incubated at 37oC for 5 minutes with occasional mixing. Samples were immediately placed on ice and then centrifuged at 16,160g at 4oC for 20 minutes to clear lysate. 25ul of Protein-G Dynabeads (Invitrogen #10004D) were used per IP. Dynabeads were pre-washed with lysis buffer and pre- incubated with 3ul of Wako Anti-Mouse-Ago2 (2D4) antibody. The dynabead/antibody mixture was added to the lysate and rocked for 2 hours at 4oC. All steps after the IP were done on bead until samples were loaded into the polyacrylamide gel. -
G Protein Regulation of MAPK Networks
Oncogene (2007) 26, 3122–3142 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW G Protein regulation of MAPK networks ZG Goldsmith and DN Dhanasekaran Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA, USA G proteins provide signal-coupling mechanisms to hepta- the a-subunits has been used as a basis for the helical cell surface receptors and are criticallyinvolved classification of G proteins into Gs,Gi,Gq and G12 in the regulation of different mitogen-activated protein families in which the a-subunits that show more than kinase (MAPK) networks. The four classes of G proteins, 50% homology are grouped together (Simon et al., defined bythe G s,Gi,Gq and G12 families, regulate 1991). In G-protein-coupled receptor (GPCR)-mediated ERK1/2, JNK, p38MAPK, ERK5 and ERK6 modules by signaling pathways, ligand-activated receptors catalyse different mechanisms. The a- as well as bc-subunits are the exchange of the bound GDP to GTP in the a-subunit involved in the regulation of these MAPK modules in a following which the GTP-bound a-subunit disassociate context-specific manner. While the a- and bc-subunits from the receptor as well as the bg-subunit. The GTP- primarilyregulate the MAPK pathwaysvia their respec- bound a-subunit and the bg-subunit stimulate distinct tive effector-mediated signaling pathways, recent studies downstream effectors including enzymes, ion channels have unraveled several novel signaling intermediates and small GTPase, thus regulating multiple signaling including receptor tyrosine kinases and small GTPases pathways including those involved in the activation of through which these G-protein subunits positivelyas well mitogen-activated protein kinase (MAPK) modules as negativelyregulate specific MAPK modules. -
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. -
CDC42 and Three Newly Identified Genes Including the Ras-Related
Proc. Natl. Acad. Sci. USA Vol. 86, pp. 9976-9980, December 1989 Genetics Multicopy suppression of the cdc24 budding defect in yeast by CDC42 and three newly identified genes including the ras-related gene RSRI (cell polarity/cell cycle/morphogenesis/Saccharomyces cerevisiae/guanine nucleotide-binding protein) ALAN BENDER AND JOHN R. PRINGLE Department of Biology, The University of Michigan, Ann Arbor, MI 48109 Communicated by Leland Hartwell, July 31, 1989 ABSTRACT Genes CDC24, CDC42, and CDC43 are re- Johnson, and J.R.P., unpublished data), and overproduction quired for the establishment ofcell polarity and the localization of the CDC42 product can produce a mislocalization of of secretion in Saccharomyces cerevisiae; mutants defective in budding sites like that seen in some cdc24 mutants (D. these genes fail to form buds and display isotropic expansion of Johnson and J.R.P., unpublished data). Sequencing of the cell surface. To identify other genes that may be involved CDC42 (D. Johnson and J.R.P., unpublished data) revealed in these processes, we screened yeast genomic DNA libraries for that it is a member of the rho family (11) of ras oncogene- heterologous genes that, when overexpressed from a plasmid, related genes and encodes typical domains for GTP binding can suppress a temperature-sensitive cdc24 mutation. We and hydrolysis. Moreover, its C-terminal sequence suggests identified four such genes. One of these proved to be CDC42, that the CDC42 product, like the ras products, may be which has previously been shown to be a member of the rho modified and thence membrane-associated. The available (ras-homologous) family of genes, and a second is a newly observations suggest a tentative model in which the products identified ras-related gene that we named RSR1. -
Ingenuity Canonical Pathways
Supplementary Table 4: Canonical pathways of differentially expressed genes between cases and controls in combined microarray and RT- qPCR experiments Ingenuity Canonical Pathways -log(p-value) Ratio Molecules Complement System 6.35 0.111 CD55,CD59,ITGAM,C3AR1 Granulocyte Adhesion and Diapedesis 5.02 0.0303 IL1R2,GNAI3,ITGAM,IL1RN,MMP9 LXR/RXR Activation 4.24 0.0331 IL1R2,IL1RN,SERPINA1,MMP9 IL-10 Signaling 3.64 0.0441 IL1R2,MAPK14,IL1RN Leukocyte Extravasation Signaling 3.36 0.0195 GNAI3,MAPK14,ITGAM,MMP9 p38 MAPK Signaling 2.95 0.0256 IL1R2,MAPK14,IL1RN Atherosclerosis Signaling 2.88 0.0242 IL1RN,SERPINA1,MMP9 IL-6 Signaling 2.85 0.0236 IL1R2,MAPK14,IL1RN Inhibition of Angiogenesis by TSP1 2.84 0.0625 MAPK14,MMP9 Glucocorticoid Receptor Signaling 2.83 0.0141 IL1R2,MAPK14,BAG1,IL1RN IL-17A Signaling in Fibroblasts 2.77 0.0571 MAPK14,LCN2 Notch Signaling 2.72 0.0541 NUMB,PSEN1 Acute Phase Response Signaling 2.5 0.0179 MAPK14,IL1RN,SERPINA1 Amyloid Processing 2.46 0.04 MAPK14,PSEN1 Agranulocyte Adhesion and Diapedesis 2.45 0.0171 GNAI3,IL1RN,MMP9 NF-κB Signaling 2.44 0.0169 IL1R2,LCK,IL1RN Molecular Mechanisms of Cancer 2.42 0.0109 GNAI3,MAPK14,CFLAR,PSEN1 IL-8 Signaling 2.31 0.0153 GNAI3,ITGAM,MMP9 LPS/IL-1 Mediated Inhibition of RXR Function 2.24 0.0144 IL1R2,IL1RN,ACSL1 CCR5 Signaling in Macrophages 2.21 0.0299 GNAI3,MAPK14 Chemokine Signaling 2.2 0.0294 GNAI3,MAPK14 Caveolar-mediated Endocytosis Signaling 2.16 0.0282 CD55,ITGAM Arginine Degradation I (Arginase Pathway) 2.15 0.25 ARG1 Acetate Conversion to Acetyl-CoA 2.15 0.25 ACSL1 -
The Small GTP-Binding Proteins Racl, and Cdc42 Regulate the Activity of the JNK/SAPK Signaling Pathway
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Cell, Vol. 81, 1137-1146, June 30, 1995, Copyright © 1995 by Cell Press The Small GTP-Binding Proteins Racl, and Cdc42 Regulate the Activity of the JNK/SAPK Signaling Pathway Omar A. Coso,* Mario Chiariello,* Jin-Chen Yu,t closely related to MAPKs have been identified. One class Hidemi Teramoto,* Piero Crespo,* Ningzhi Xu,* presents extended similarity to the Saccharomyces cere- Toru Miki,t and J. Silvio Gutkind* visiae HOG1 kinase (Han et al., 1994), which is involved *Molecular Signaling Unit in protecting S. cerevisiae from hyperosmotic solutions Laboratory of Cellular Development and Oncology (reviewed by Herskowitz, 1995). The role of this mamma- National Institute of Dental Research lian HOG1 homolog is largely unknown. Although it can tLaboratory of Cellular and Molecular Biology also be activated by changes in osmolarity, it appears to National Cancer Institute participate in the inflammatory response to lipopolysac- National Institutes of Health charides or to inflammatory mediators such as interleu- Bethesda, Maryland 20892 kin-1 (IL-1) (Han et al., 1994; Freshney et al., 1994). The other class of MAPKs represents a family of closely related enzymes activated by cellular stress, which have been Summary named stress-activated protein kinases (SAPKs) (Kyriakis et al., 1994). SAPKs were independently identified by vir- c-Jun amino-terminal kinases (JNKs) and mitogen- tue of their ability to phosphorylate the amino terminus of activated protein kinases (MAPKs) are closely related; the c-Jun transcription factor; hence, they have been also however, they are independently regulated by a variety termed c-Jun amino-terminal kinases (JNKs) (D~rijard et of environmental stimuli. -
Identification of Key Genes and Pathways for Alzheimer's Disease
Biophys Rep 2019, 5(2):98–109 https://doi.org/10.1007/s41048-019-0086-2 Biophysics Reports RESEARCH ARTICLE Identification of key genes and pathways for Alzheimer’s disease via combined analysis of genome-wide expression profiling in the hippocampus Mengsi Wu1,2, Kechi Fang1, Weixiao Wang1,2, Wei Lin1,2, Liyuan Guo1,2&, Jing Wang1,2& 1 CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China 2 Department of Psychology, University of Chinese Academy of Sciences, Beijing 10049, China Received: 8 August 2018 / Accepted: 17 January 2019 / Published online: 20 April 2019 Abstract In this study, combined analysis of expression profiling in the hippocampus of 76 patients with Alz- heimer’s disease (AD) and 40 healthy controls was performed. The effects of covariates (including age, gender, postmortem interval, and batch effect) were controlled, and differentially expressed genes (DEGs) were identified using a linear mixed-effects model. To explore the biological processes, func- tional pathway enrichment and protein–protein interaction (PPI) network analyses were performed on the DEGs. The extended genes with PPI to the DEGs were obtained. Finally, the DEGs and the extended genes were ranked using the convergent functional genomics method. Eighty DEGs with q \ 0.1, including 67 downregulated and 13 upregulated genes, were identified. In the pathway enrichment analysis, the 80 DEGs were significantly enriched in one Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, GABAergic synapses, and 22 Gene Ontology terms. These genes were mainly involved in neuron, synaptic signaling and transmission, and vesicle metabolism. These processes are all linked to the pathological features of AD, demonstrating that the GABAergic system, neurons, and synaptic function might be affected in AD. -
New Structural Perspectives in G Protein-Coupled Receptor-Mediated Src Family Kinase Activation
International Journal of Molecular Sciences Review New Structural Perspectives in G Protein-Coupled Receptor-Mediated Src Family Kinase Activation Sandra Berndt * and Ines Liebscher Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-341-9722175 Abstract: Src family kinases (SFKs) are key regulators of cell proliferation, differentiation, and survival. The expression of these non-receptor tyrosine kinases is strongly correlated with cancer development and tumor progression. Thus, this family of proteins serves as an attractive drug target. The activation of SFKs can occur via multiple signaling pathways, yet many of them are poorly understood. Here, we summarize the current knowledge on G protein-coupled receptor (GPCR)- mediated regulation of SFKs, which is of considerable interest because GPCRs are among the most widely used pharmaceutical targets. This type of activation can occur through a direct interaction between the two proteins or be allosterically regulated by arrestins and G proteins. We postulate that a rearrangement of binding motifs within the active conformation of arrestin-3 mediates Src regulation by comparison of available crystal structures. Therefore, we hypothesize a potentially different activation mechanism compared to arrestin-2. Furthermore, we discuss the probable direct regulation of SFK by GPCRs and investigate the intracellular domains of exemplary GPCRs with conserved polyproline binding motifs that might serve as scaffolding domains to allow such a direct interaction. Large intracellular domains in GPCRs are often understudied and, in general, not much Citation: Berndt, S.; Liebscher, I. is known of their contribution to different signaling pathways. -
Small Gtpases of the Ras and Rho Families Switch On/Off Signaling
International Journal of Molecular Sciences Review Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases Alazne Arrazola Sastre 1,2, Miriam Luque Montoro 1, Patricia Gálvez-Martín 3,4 , Hadriano M Lacerda 5, Alejandro Lucia 6,7, Francisco Llavero 1,6,* and José Luis Zugaza 1,2,8,* 1 Achucarro Basque Center for Neuroscience, Science Park of the Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), 48940 Leioa, Spain; [email protected] (A.A.S.); [email protected] (M.L.M.) 2 Department of Genetics, Physical Anthropology, and Animal Physiology, Faculty of Science and Technology, UPV/EHU, 48940 Leioa, Spain 3 Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Granada, 180041 Granada, Spain; [email protected] 4 R&D Human Health, Bioibérica S.A.U., 08950 Barcelona, Spain 5 Three R Labs, Science Park of the UPV/EHU, 48940 Leioa, Spain; [email protected] 6 Faculty of Sport Science, European University of Madrid, 28670 Madrid, Spain; [email protected] 7 Research Institute of the Hospital 12 de Octubre (i+12), 28041 Madrid, Spain 8 IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain * Correspondence: [email protected] (F.L.); [email protected] (J.L.Z.) Received: 25 July 2020; Accepted: 29 August 2020; Published: 31 August 2020 Abstract: Small guanosine triphosphatases (GTPases) of the Ras superfamily are key regulators of many key cellular events such as proliferation, differentiation, cell cycle regulation, migration, or apoptosis. To control these biological responses, GTPases activity is regulated by guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and in some small GTPases also guanine nucleotide dissociation inhibitors (GDIs).