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Rho GTPases

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https://www.readbyqxmd.com/read/29155102/targeting-of-rac1-prevents-bronchoconstriction-and-airway-hyperresponsiveness
#1
Gwennan André-Grégoire, Florian Dilasser, Julie Chesné, Faouzi Braza, Antoine Magnan, Gervaise Loirand, Vincent Sauzeau
BACKGROUND: The molecular mechanisms responsible for airway smooth muscle cells (aSMC) contraction and proliferation in airway hyperresponsiveness (AHR) associated with asthma are still largely unknown. The small GTPases of the Rho family (RhoA, Rac1 and Cdc42) play a central role in SMC functions including migration, proliferation and contraction. OBJECTIVE: The objective of this study is to identify the role of Rac1 in aSMC contraction and to investigate its involvement in AHR associated with allergic asthma...
November 15, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29152096/the-non-canonical-ubiquitin-activating-enzyme-uba6-suppresses-epithelial-mesenchymal-transition-of-mammary-epithelial-cells
#2
Xianpeng Liu, Limin Sun, Demirkan B Gursel, Chonghui Cheng, Sui Huang, Alfred W Rademaker, Seema A Khan, Jun Yin, Hiroaki Kiyokawa
Ubiquitination plays critical roles in the regulation of oncoproteins and tumor suppressors during carcinogenesis. The two ubiquitin activating enzymes (E1) in human genome, UBA1 and UBA6, initiate ubiquitination by ATP-dependent activation of ubiquitin. Recent evidence suggests that UBA1 and UBA6 play partially overlapped yet distinct roles in controlling the proteome. Here we demonstrate that ubiquitination pathways initiated specifically by UBA6 set a suppressive barrier against critical steps of mammary carcinogenesis such as loss of polarity, anoikis resistance and epithelial-mesenchymal transition (EMT)...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29152087/specific-role-of-rhoc-in-tumor-invasion-and-metastasis
#3
Sarah Lang, Hauke Busch, Melanie Boerries, Tilman Brummer, Sylvia Timme, Silke Lassmann, Klaus Aktories, Gudula Schmidt
Rho GTPases are regulators of many cellular functions and are often dysregulated in cancer. However, the precise role of Rho proteins for tumor development is not well understood. In breast cancer, overexpression of RhoC is linked with poor prognosis. Here, we aim to compare the function of RhoC and its homolog family member RhoA in breast cancer progression. We established stable breast epithelial cell lines with inducible expression of RhoA and RhoC, respectively. Moreover, we made use of Rho-activating bacterial toxins (Cytotoxic Necrotizing Factors) to stimulate the endogenous pool of Rho GTPases in benign breast epithelial cells and simultaneously knocked down specific Rho proteins...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29146177/clostridium-difficile-and-clostridium-sordellii-toxins-proinflammatory-versus-anti-inflammatory-response
#4
Michel R Popoff
Clostridium difficile and Clostridium sordellii produce related potent toxins (C. difficile toxin A (TcdA) and toxin B (TcdB), C. sordellii lethal toxin (TcsL) and hemorrhagic toxin (TcsH)) which belong to the large clostridial glucosylating toxin (LCGT) family. TcsL is the main C. sordellii toxin as most of toxigenic C. sordellii strains only synthesize this toxin. Intestinal colonization by C. difficile subsequently to unbalanced microbiota is accompanied by release of toxins which induce local tissue destruction and severe inflammatory response...
November 13, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/29136506/a-paradoxical-tumor-suppressor-role-for-the-rac1-exchange-factor-vav1-in-t-cell-acute-lymphoblastic-leukemia
#5
Javier Robles-Valero, L Francisco Lorenzo-Martín, Mauricio Menacho-Márquez, Isabel Fernández-Pisonero, Antonio Abad, Mireia Camós, María L Toribio, Lluis Espinosa, Anna Bigas, Xosé R Bustelo
Rho guanine exchange factors (GEFs), the enzymes that stimulate Rho GTPases, are deemed as potential therapeutic targets owing to their protumorigenic functions. However, the understanding of the spectrum of their pathobiological roles in tumors is still very limited. We report here that the GEF Vav1 unexpectedly possesses tumor-suppressor functions in immature T cells. This function entails the noncatalytic nucleation of complexes between the ubiquitin ligase Cbl-b and the intracellular domain of Notch1 (ICN1) that favors ICN1 ubiquitinylation and degradation...
November 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29133936/the-rho-gtpase-signalling-pathway-in-urothelial-carcinoma
#6
REVIEW
Solomon L Woldu, Ryan C Hutchinson, Laura-Maria Krabbe, Oner Sanli, Vitaly Margulis
Urothelial carcinoma remains a clinical challenge: non-muscle-invasive disease has a high rate of recurrence and risk of progression, and outcomes for patients with advanced disease are poor, owing to a lack of effective systemic therapies. The Rho GTPase family of enzymes was first identified >30 years ago and contains >20 members, which are divided into eight subfamilies: Cdc42, Rac, Rho, RhoUV, RhoBTB, RhoDF, RhoH, and Rnd. Rho GTPases are molecular on-off switches, which are increasingly being understood to have a critical role in a number of cellular processes, including cell migration, cell polarity, cell adhesion, cell cycle progression, and regulation of the cytoskeleton...
November 14, 2017: Nature Reviews. Urology
https://www.readbyqxmd.com/read/29133526/involvement-of-g%C3%AE-%C3%AE-subunits-of-gi-protein-coupled-with-s1p-receptor-on-multivesicular-endosomes-in-f-actin-formation-and-cargo-sorting-into-exosomes
#7
Taketoshi Kajimoto, Nesma Nabil Ibrahim Mohamed, Shaymaa Mohamed Mohamed Badawy, Shubi Ambwene Matovelo, Mitsuhiro Hirase, Shunsuke Nakamura, Daisuke Yoshida, Taro Okada, Takeshi Ijuin, Shun-Ichi Nakamura
Exosomes play a critical role in cell-to-cell communication by delivering cargo molecules to recipient cells. However, the mechanism underlying the generation of the exosomal multivesicular endosome (MVE) is one of the mysteries in the field of endosome research. Although sphingolipid metabolites such as ceramide and sphingosine 1-phosphate (S1P) are known to play important roles in MVE formation and maturation, the detailed molecular mechanisms are still unclear. Here, we show that Rho family GTPases, including Cdc42 and Rac1, are constitutively activated on exosomal MVEs and are regulated by S1P signaling as measured by fluorescence resonance energy transfer (FRET)-based conformational changes...
November 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29133163/non-visual-arrestins-regulate-the-focal-adhesion-formation-via-small-gtpases-rhoa-and-rac1-independently-of-gpcrs
#8
Whitney M Cleghorn, Nada Bulus, Seunghyi Kook, Vsevolod V Gurevich, Roy Zent, Eugenia V Gurevich
Arrestins recruit a variety of signaling proteins to active phosphorylated G protein-coupled receptors in the plasma membrane and to the cytoskeleton. Loss of arrestins leads to decreased cell migration, altered cell shape, and an increase in focal adhesions. Small GTPases of the Rho family are molecular switches that regulate actin cytoskeleton and affect a variety of dynamic cellular functions including cell migration and cell morphology. Here we show that non-visual arrestins differentially regulate RhoA and Rac1 activity to promote cell spreading via actin reorganization, and focal adhesion formation via two distinct mechanisms...
November 11, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/29130632/dock3-related-neurodevelopmental-syndrome-biallelic-intragenic-deletion-of-dock3-in-a-boy-with-developmental-delay-and-hypotonia
#9
Aiko Iwata-Otsubo, Alyssa L Ritter, Brooke Weckselbatt, Nicole R Ryan, David Burgess, Laura K Conlin, Kosuke Izumi
Dedicator of cytokinesis (DOCK) family are evolutionary conserved guanine nucleotide exchange factors (GEFs) for the Rho GTPases, Rac, and Cdc42. DOCK3 functions as a GEF for Rac1, and plays an important role in promoting neurite and axonal growth by stimulating actin dynamics and microtubule assembly pathways in the central nervous system. Here we report a boy with developmental delay, hypotonia, and ataxia due to biallelic DOCK3 deletion. Chromosomal single nucleotide polymorphism (SNP) microarray analysis detected a 170 kb homozygous deletion including exons 6-12 of the DOCK3 gene at 3p21...
November 12, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29129728/paks-in-the-brain-function-and-dysfunction
#10
REVIEW
Laura Civiero, Elisa Greggio
p21-Activated kinases (PAKs) comprise a family of proteins covering a central role in signal transduction. They are downstream effectors of Rho GTPases and can affect a variety of processes in different cell types and tissues by remodeling the cytoskeleton and by promoting gene transcription and cell survival. Given the relevance of cytoskeletal organization in neuronal development as well as synaptic function and the importance of pro-survival signals in controlling neuronal cell fate, accumulating studies investigated the role of PAKs in the nervous system...
November 9, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29129684/rhoa-gtpase-controls-yap-mediated-ereg-signaling-in-small-intestinal-stem-cell-maintenance
#11
Ming Liu, Zheng Zhang, Leesa Sampson, Xuan Zhou, Kodandaramireddy Nalapareddy, Yuxin Feng, Shailaja Akunuru, Jaime Melendez, Ashley Kuenzi Davis, Feng Bi, Hartmut Geiger, Mei Xin, Yi Zheng
RHOA, a founding member of the Rho GTPase family, is critical for actomyosin dynamics, polarity, and morphogenesis in response to developmental cues, mechanical stress, and inflammation. In murine small intestinal epithelium, inducible RHOA deletion causes a loss of epithelial polarity, with disrupted villi and crypt organization. In the intestinal crypts, RHOA deficiency results in reduced cell proliferation, increased apoptosis, and a loss of intestinal stem cells (ISCs) that mimic effects of radiation damage...
November 6, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/29128904/pharmacological-rescue-of-hippocampal-fear-learning-deficits-in-fragile-x-syndrome
#12
Luis A Martinez, Maria Victoria Tejada-Simon
Fragile X Syndrome (FXS) is the leading cause of autism spectrum disorder and intellectual disability and results from loss of Fragile X mental retardation protein (FMRP). In neurons, FMRP controls the translation of synaptic plasticity proteins that are implicated in learning and memory. FMRP also regulates development- and experience-dependent actin cytoskeleton remodeling within dendritic spines through the small Rho GTPase Rac1. Modulation of Rac1 activity is critical during synaptic plasticity as well as learning and memory...
November 11, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/29121646/the-phosphomimetic-mutation-of-syndecan-4-binds-and-inhibits-tiam1-modulating-rac1-activity-in-pdz-interaction-dependent-manner
#13
Aniko Keller-Pinter, Bettina Ughy, Monika Domoki, Aladar Pettko-Szandtner, Tamas Letoha, Jozsef Tovari, Jozsef Timar, Laszlo Szilak
The small GTPases of the Rho family comprising RhoA, Rac1 and Cdc42 function as molecular switches controlling several essential biochemical pathways in eukaryotic cells. Their activity is cycling between an active GTP-bound and an inactive GDP-bound conformation. The exchange of GDP to GTP is catalyzed by guanine nucleotide exchange factors (GEFs). Here we report a novel regulatory mechanism of Rac1 activity, which is controlled by a phosphomimetic (Ser179Glu) mutant of syndecan-4 (SDC4). SDC4 is a ubiquitously expressed transmembrane, heparan sulfate proteoglycan...
2017: PloS One
https://www.readbyqxmd.com/read/29114068/receptor-tyrosine-kinase-activation-of-rhoa-is-mediated-by-akt-phosphorylation-of-dlc1
#14
Brajendra K Tripathi, Tiera Grant, Xiaolan Qian, Ming Zhou, Philipp Mertins, Dunrui Wang, Alex G Papageorge, Sergey G Tarasov, Kent W Hunter, Steven A Carr, Douglas R Lowy
We report several receptor tyrosine kinase (RTK) ligands increase RhoA-guanosine triphosphate (GTP) in untransformed and transformed cell lines and determine this phenomenon depends on the RTKs activating the AKT serine/threonine kinase. The increased RhoA-GTP results from AKT phosphorylating three serines (S298, S329, and S567) in the DLC1 tumor suppressor, a Rho GTPase-activating protein (RhoGAP) associated with focal adhesions. Phosphorylation of the serines, located N-terminal to the DLC1 RhoGAP domain, induces strong binding of that N-terminal region to the RhoGAP domain, converting DLC1 from an open, active dimer to a closed, inactive monomer...
November 7, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29114038/aberrant-rac1-cofilin-signaling-mediates-defects-in-dendritic-spines-synaptic-function-and-sensory-perception-in-fragile-x-syndrome
#15
Alexander Pyronneau, Qionger He, Jee-Yeon Hwang, Morgan Porch, Anis Contractor, R Suzanne Zukin
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disabilities and a leading cause of autism. FXS is caused by a trinucleotide expansion in the gene FMR1 on the X chromosome. The neuroanatomical hallmark of FXS is an overabundance of immature dendritic spines, a factor thought to underlie synaptic dysfunction and impaired cognition. We showed that aberrantly increased activity of the Rho GTPase Rac1 inhibited the actin-depolymerizing factor cofilin, a major determinant of dendritic spine structure, and caused disease-associated spine abnormalities in the somatosensory cortex of FXS model mice...
November 7, 2017: Science Signaling
https://www.readbyqxmd.com/read/29113998/rhoc-regulates-actin-remodeling-to-form-phagosomes-during-fc%C3%AE-r-mediated-phagocytosis
#16
Youhei Egami, Katsuhisa Kawai, Nobukazu Araki
Phagosome formation is a complicated process that requires spatiotemporally regulated actin reorganization. We found that RhoC GTPase is a critical regulator of FcγR-mediated phagocytosis in macrophages. Our live-cell imaging revealed that RhoC, but not RhoA, is recruited to phagocytic cups engulfing IgG-opsonized erythrocytes (IgG-Es). RhoC silencing by RNAi, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas-mediated RhoC knockout and the expression of dominant-negative or dominant-active RhoC mutants suppressed the phagocytosis of IgG-Es...
November 7, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/29111771/staphylococcus-aureus-alpha-toxin-induces-actin-filament-remodeling-in-human-airway-epithelial-model-cells
#17
Sabine Ziesemer, Ina Eiffler, Alfrun Schönberg, Christian Müller, Falko Hochgräfe, Achim G Beule, Jan-Peter Hildebrandt
Exposure of cultured human airway epithelial model cells (16HBE14o-, S9) to Staphylococcus aureus alpha-toxin (hemolysin A, Hla) induces changes in cell morphology and cell layer integrity which are due to the inability of the cells to maintain stable cell-cell or focal contacts and to properly organize their actin cytoskeleton. The aim of this study was to identify Hla-activated signaling pathways involved in regulating the phosphorylation level of the actin depolymerizing factor cofilin. We used recombinant wild-type Hla (rHla) as well as a variant of Hla (rHla-H35L) that is unable to form functional transmembrane pores to treat immortalized human airway epithelial cells (16HBE14o-, S9) as well as freshly isolated human nasal tissue...
November 7, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/29104227/inter-species-host-gene-expression-differences-in-response-to-human-and-avian-influenza-a-virus-strains
#18
Biruhalem Taye, Dawn Yeo, Raphael Tze Chuen Lee, Boon Huan Tan, Richard J Sugrue, Sebastian Maurer-Stroh
Low pathogenic avian influenza (LPAI) viruses are a source of sporadic human infections and could also contribute to future pandemic outbreaks but little is known about inter-species differences in the host responses to these viruses. Here, we studied host gene expression signatures of cell lines from three species (human, chicken, and canine) in response to six different viruses (H1N1/WSN, H5N2/F59, H5N2/F118, H5N2/F189, H5N3 and H9N2). Comprehensive microarray probe set re-annotation and ortholog mapping of the host genes was necessary to allow comparison over extended functionally annotated gene sets and orthologous pathways...
November 1, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29101495/deletion-of-cdc42-in-embryonic-cardiomyocytes-results-in-right-ventricle-hypoplasia
#19
Yang Liu, Jian Wang, Jieli Li, Rui Wang, Binu Tharakan, Shenyuan L Zhang, Carl W Tong, Xu Peng
BACKGROUND: Cdc42 is a member of the Rho GTPase family and functions as a molecular switch in regulating cytoskeleton remodeling and cell polarity establishment. Inactivating Cdc42 in cardiomyocytes resulted in embryonic lethality with heart developmental defects, including ventricular septum defects and thin ventricle wall syndrome. FINDINGS: In this study, we have generated a Cdc42 cardiomyocyte knockout mouse line by crossing Cdc42/flox mice with myosin light chain 2a (MLC2a)-Cre mice...
November 3, 2017: Clinical and Translational Medicine
https://www.readbyqxmd.com/read/29099277/the-intracellular-microbial-sensor-nlrp4-directs-rho-actin-signaling-to-facilitate-group-a-streptococcus-containing-autophagosome-like-vacuole-formation
#20
Takashi Nozawa, Chihiro Aikawa, Atsuko Minowa-Nozawa, Ichiro Nakagawa
Xenophagy, also known as antibacterial autophagy, functions as a crucial defense system that can utilize intracellular pattern recognition sensors, such as NLRP4, to recognize and selectively eliminate bacterial pathogens. However, little is known about how NLRP4 regulates xenophagy. Here, we report that NLRP4 binds ARHGDIA (Rho GDP dissociation inhibitor α) to regulate Rho GTPase signaling and facilitate actin-mediated xenophagy. Specifically, NLRP4 is recruited to Group A Streptococcus (GAS) and colocalizes with GAS-containing autophagosome-like vacuoles (GcAVs), where it regulates ARHGDIA-Rho GTPase recruitment to promote autophagosome formation...
November 3, 2017: Autophagy
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