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Ali Ben Djoudi Ouadda, Yi He, Viviane Calabrese, Hidetaka Ishii, Rony Chidiac, Jean-Philippe Gratton, Philippe P Roux, Nathalie Lamarche-Vane
Cdc42 GTPase-activating protein (CdGAP, also named ARHGAP31) is a negative regulator of the GTPases Rac1 and Cdc42. Associated with the rare developmental disorder Adams-Oliver Syndrome (AOS), CdGAP is critical for embryonic vascular development and VEGF-mediated angiogenesis. Moreover, CdGAP is an essential component in the synergistic interaction between TGFβ and ErbB-2 signaling pathways during breast cancer cell migration and invasion, and is a novel E-cadherin transcriptional co-repressor with Zeb2 in breast cancer...
February 20, 2018: Oncotarget
Teklab Gebregiworgis, Christopher Boyd Marshall, Tadateru Nishikawa, Nikolina Radulovich, María-José Sandi, Zhenhao Fang, Robert Rottapel, Ming-Sound Tsao, Mitsuhiko Ikura
Small GTPases (sGTPases) are critical switch-like regulators that mediate several important cellular functions and are often mutated in human cancers. They are activated by guanine nucleotide exchange factors (GEFs), which specifically catalyze the exchange of GTP for GDP. GEFs coordinate signaling networks in normal cells, and are frequently deregulated in cancers. sGTPase signaling pathways are complex and interconnected; however, most GEF assays do not reveal such complexity. In this communication, we describe the development of a unique real-time NMR-based multiplexed GEF assay that employs distinct isotopic labeling schemes for each sGTPase protein to enable simultaneous observation of six proteins of interest...
March 15, 2018: Journal of the American Chemical Society
Alexis Bonfim-Melo, Éden R Ferreira, Renato A Mortara
This study evaluated the participation of host cell Rho-family GTPases and their effector proteins in the actin-dependent invasion by Trypanosoma cruzi extracellular amastigotes (EAs). We observed that all proteins were recruited and colocalized with actin at EA invasion sites in live or fixed cells. EA internalization was inhibited in cells depleted in Rac1, N-WASP, and WAVE2. Time-lapse experiments with Rac1, N-WASP and WAVE2 depleted cells revealed that EA internalization kinetics is delayed even though no differences were observed in the proportion of EA-induced actin recruitment in these groups...
2018: Frontiers in Microbiology
Elizabeth Delve, Justin Parreno, Vivian Co, Po-Han Wu, Jasmine Chong, Matteo Di Scipio, Rita A Kandel
Osteoarthritis (OA) is a degenerative disease that initially manifests as loss of the superficial zone (SZ) of articular cartilage. SZ chondrocytes (SZC) differ in morphology from other chondrocytes as they are elongated and oriented parallel to the tissue surface. Proteoglycan 4 (PRG4) and tenascin C (TNC) are molecules expressed by SZC, which have been shown to be chondroprotective. Identification of the signalling pathway(s) regulating expression of SZ molecules may lead to a therapeutic target that can be used to delay or prevent the onset of OA...
March 14, 2018: Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society
Liya Pi, Chunhua Fu, Yuanquing Lu, Junmei Zhou, Marda Jorgensen, Vinayak Shenoy, Kenneth E Lipson, Edward W Scott, Andrew J Bryant
Chronic hypoxia frequently complicates the care of patients with interstitial lung disease, contributing to the development of pulmonary hypertension (PH), and premature death. Connective tissue growth factor (CTGF), a matricellular protein of the Cyr61/CTGF/Nov (CCN) family, is known to exacerbate vascular remodeling within the lung. We have previously demonstrated that vascular endothelial-cell specific down-regulation of CTGF is associated with protection against the development of PH associated with hypoxia, though the mechanism for this effect is unknown...
2018: Frontiers in Physiology
Michael Pablo, Samuel A Ramirez, Timothy C Elston
Polarity establishment, the spontaneous generation of asymmetric molecular distributions, is a crucial component of many cellular functions. Saccharomyces cerevisiae (yeast) undergoes directed growth during budding and mating, and is an ideal model organism for studying polarization. In yeast and many other cell types, the Rho GTPase Cdc42 is the key molecular player in polarity establishment. During yeast polarization, multiple patches of Cdc42 initially form, then resolve into a single front. Because polarization relies on strong positive feedback, it is likely that the amplification of molecular-level fluctuations underlies the generation of multiple nascent patches...
March 12, 2018: PLoS Computational Biology
Aijaz A John, Ravi Prakash, Jyoti Kureel, Divya Singh
We report the role of miR-1187 in regulation of osteoblast functions. Over-expression of miR-1187 inhibited osteoblast differentiation. Target prediction analysis tools and experimental validation by luciferase 3' UTR reporter assay identified BMPR-II and ArhGEF-9 as direct targets of miR-1187. ArhGEF-9 activates Cdc42 which has a major role in actin reorganization. BMP-2 also induces actin polymerization. Role of miR-1187 in actin reorganization was determined by western blotting, immunofluorescence, and in vivo gene silencing studies...
March 9, 2018: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Jianxin Wei, Su Dong, Kangning Yao, Maria Francesca Ysabelle M Martinez, Paine R Fleisher, Yutong Zhao, Haichun Ma, Jing Zhao
Ubiquitin E3 ligases mediate ubiquitination and degradation of intracellular proteins. We have shown that a relatively new Skp, Cullin, F-box (SCF) protein E3 ligase, SCF FBXL19, has an anti-inflammatory effect and controls actin cytoskeleton dynamics via targeting cell membrane receptor and small GTPases for their ubiquitination and degradation, but the molecular regulation of its subunit FBXL19 stability remains unclear. Here we show that FBXL19 degradation is controlled by the balance between its ubiquitination and acetylation...
March 9, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Rhian F Walther, Mubarik Burki, Noelia Pinal, Clare Rogerson, Franck Pichaud
In Drosophila epithelial cells, apical exclusion of Bazooka/Par3 defines the position of the Zonula Adherens (ZA), which demarcates the apical and lateral membrane and allows cells to assemble into sheets. Here, we show that the small GTPase Rap1, its effector AF6/Canoe (Cno) and the Cdc42-effector Pak4/Mushroom bodies tiny (Mbt), converge in regulating epithelial morphogenesis by coupling stabilization of the Adherens Junction (AJ) protein E-Cadherin, and Bazooka retention at the ZA Furthermore, our results show that the localization of Rap1, Cno and Mbt at the ZA is interdependent, indicating their functions during ZA morphogenesis are interlinked...
March 5, 2018: Journal of Cell Science
Jenny N Fung, Grant W Montgomery
Developments in high-throughput genotyping technology have driven discovery of genomic regions associated with an increased risk of endometriosis. In all, 16 genomic regions have been associated with risk of endometriosis in one or more populations. The latest meta-analysis including 17,045 endometriosis cases identified 14 genomic regions supported by results from multiple studies. No independent associations were identified from direct genotyping of common and low-frequency protein-coding variants. This suggests that the most common genetic factors that contribute to endometriosis risk are located in regulatory DNA sequences and alter the regulation of gene transcription...
February 8, 2018: Best Practice & Research. Clinical Obstetrics & Gynaecology
Ruth Nussinov, Chung-Jung Tsai, Hyunbum Jang
Ras signaling initiates at the plasma membrane. Thus, Ras behavior at the membrane and how it relates to its interactions with Raf and PI3Kα, are of immense interest. Here we review factors influencing Ras lateral diffusion. We then ask whether oncogenic Ras diffusion speed in the membrane is important for signaling response times and whether it affects ubiquitously all pathways. We suggest that if Ras expression is sufficiently high to dimerize (or form nanoclusters), signaling response of those pathways where dimers (or nanoclusters) are involved corresponds to the speed with which Ras molecules travel in the membrane...
February 27, 2018: Seminars in Cancer Biology
Md Mohibbullah, Jae-Suk Choi, Mohammad Maqueshudul Haque Bhuiyan, Md Nazmul Haque, Md Khalilur Rahman, Il Soo Moon, Yong-Ki Hong
Exogenous neurotrophins can induce neuronal differentiation, outgrowth, survival, and synaptic function in the central nervous system. In primary cultures of rat hippocampal neurons, an ethanol extract of the red alga Gracilariopsis chorda (GCE) and its active compound arachidonic acid (AA) significantly increased the densities of dendritic filopodia and spines, promoted the expression of presynaptic vesicle protein 2 (SV2) and postsynaptic density protein 95 (PSD-95), induced robust synaptogenesis, and increased the expression of cell division control protein 42 (CDC42) and actin-related protein 2 (ARP2), which are important for actin organization in dendritic protrusions, and facilitated presynaptic plasticity by increasing the size of the synaptic vesicle pool at presynaptic nerve terminals...
March 2, 2018: Journal of Medicinal Food
Xin Tan, Aizhang Xu, Tuo Zhao, Qin Zhao, Jun Zhang, Cuihong Fan, Yulin Deng, Andrew Freywald, Harald Genth, Jim Xiang
Simulated microgravity (SMG) was reported to affect tumor cell proliferation and metastasis. However, the underlying mechanism is elusive. In this study, we demonstrate that clinostat-modelled SMG reduces BL6-10 melanoma cell proliferation, adhesion and invasiveness in vitro and decreases tumor lung metastasis in vivo. It down-regulates metastasis-related integrin α6β4, MMP9 and Met72 molecules. SMG significantly reduces formation of focal adhesions and activation of focal adhesion kinase (FAK) and Rho family proteins (RhoA, Rac1 and Cdc42) and of mTORC1 kinase, but activates AMPK and ULK1 kinases...
February 28, 2018: Scientific Reports
Tianshi Ma, Hongwei Ma, Zigui Zou, Xuezhi He, Yanhua Liu, You Shuai, Min Xie, Zhihong Zhang
BACKGROUND/AIMS: Lung cancer (LC) is a serious disease with high morbidity and mortality. Long noncoding RNAs (lncRNAs) have garnered attention because they participate in diverse human disorders, including cancer. Our study examined the long intergenic noncoding RNA 00707 (LINC00707). The effects of LINC00707 on lung adenocarcinoma (LAD) and molecular mechanisms are unclear. This study is aimed to investigate the role of LINC00707 in the malignant processes of LAD. METHODS: Quantitative reverse transcription PCR (qRT-PCR) was used to examine the expression level of LINC00707 in tissues and cell lines...
February 21, 2018: Cellular Physiology and Biochemistry
Sandra Pelleieux, Cynthia Picard, Louise Lamarre-Théroux, Doris Dea, Valérie Leduc, Youla S Tsantrizos, Judes Poirier
The mevalonate pathway has been described to play a key role in Alzheimer's disease (AD) physiopathology. Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are nonsterol isoprenoids derived from mevalonate, which serve as precursors to numerous human metabolites. They facilitate protein prenylation; hFPP and hGGPP synthases act as gateway enzymes to the prenylation of the small guanosine triphosphate (GTP) ase proteins such as RhoA and cdc42 that have been shown to facilitate phospho-tau (p-Tau, i...
February 2, 2018: Neurobiology of Aging
Grégory Ghézali, Charles-Félix Calvo, Laure-Elise Pillet, Flora Llense, Pascal Ezan, Ulrike Pannasch, Alexis-Pierre Bemelmans, Sandrine Etienne Manneville, Nathalie Rouach
Astrocytes undergo intense morphological maturation during development, changing from individual sparsely branched cells to polarized and tremendously ramified cells. Connexin 30, an astroglial gap-junction channel-forming protein expressed postnatally, regulates in situ the extension and ramification of astroglial processes. However, the involvement of connexin 30 in astroglial polarization, which is known to control cell morphology, remains unexplored. We found that connexin 30, independently of gap-junction-mediated intercellular biochemical coupling, alters the orientation of astrocyte protrusion, centrosome and Golgi apparatus during polarized migration in an in vitro wound-healing assay...
February 23, 2018: Development
Simi Muraleedharan, Aksah Sam, Helen Skaer, Maneesha S Inamdar
Insect nephrocytes provide a valuable model for kidney disease, as they are structurally and functionally homologous to mammalian kidney podocytes. They possess an exceptional macromolecular assembly, the nephrocyte diaphragm (ND), which serves as a filtration barrier and helps maintain tissue homeostasis by filtering out wastes and toxic products. However, the elements that maintain nephrocyte architecture and the ND are not understood. We show that Drosophila nephrocytes have a unique cytoplasmic cluster of F-actin, which is maintained by the microtubule cytoskeleton and Rho-GTPases...
February 16, 2018: Experimental Cell Research
Qing Deng, Yan-Xiao Tian, JianJun Liang
Breast tumour progression results from the advancement of the disease to a metastatic phenotype. Rac1 and Cdc42 belong to the Rho family of genes that, together with their downstream effectors, Wiskott-Aldrich Syndrome protein-family verprolin-homologous protein 2 (WAVE2) and Arp2/3, assume a vital part in cytoskeletal rearrangement and the arrangement of film projections that advance malignant cell relocation and invasion. Mangiferin is a characteristic polyphenolic compound from Mangifera indica L. (Anacardiaceae), ordinarily referred to as mango, that is consumed worldwide as a natural product, including culinary and seasoning applications...
February 17, 2018: Cytotechnology
Lisa E Kursel, Harmit S Malik
During female meiosis, only one of four meiotic products is retained in the egg. It was previously proposed that chromosomes might compete for inclusion in the egg via their centromere 'strength'. Recent findings have revealed the primary requirements for such 'centromere drive'. First, CDC42 signaling from the oocyte cortex renders the meiotic I spindle asymmetric. Second, 'stronger' centromeres preferentially detach from microtubules in cortical proximity, making them more likely to orient away from the cortex, and be included in the egg...
February 14, 2018: Current Opinion in Cell Biology
Mario Aguilar-Aragon, Ahmed Elbediwy, Valentina Foglizzo, Georgina C Fletcher, Vivian S W Li, Barry J Thompson
Epithelial cells are polarized along their apical-basal axis by the action of the small GTPase Cdc42, which is known to activate the aPKC kinase at the apical domain. However, loss of aPKC kinase activity was reported to have only mild effects on epithelial cell polarity. Here, we show that Cdc42 also activates a second kinase, Pak1, to specify apical domain identity in Drosophila and mammalian epithelia. aPKC and Pak1 phosphorylate an overlapping set of polarity substrates in kinase assays. Inactivating both aPKC kinase activity and the Pak1 kinase leads to a complete loss of epithelial polarity and morphology, with cells losing markers of apical polarization such as Crumbs, Par3/Bazooka, or ZO-1...
February 13, 2018: Cell Reports
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