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Christine Gundry, Sergi Marco, Elena Rainero, Bryan Miller, Emmanuel Dornier, Louise Mitchell, Patrick T Caswell, Andrew D Campbell, Anna Hogeweg, Owen J Sansom, Jennifer P Morton, Jim C Norman
The Rab GTPase effector, Rab-coupling protein (RCP) is known to promote invasive behaviour in vitro by controlling integrin and receptor tyrosine kinase (RTK) trafficking, but how RCP influences metastasis in vivo is unclear. Here we identify an RTK of the Eph family, EphA2, to be a cargo of an RCP-regulated endocytic pathway which controls cell:cell repulsion and metastasis in vivo. Phosphorylation of RCP at Ser(435) by Lemur tyrosine kinase-3 (LMTK3) and of EphA2 at Ser(897) by Akt are both necessary to promote Rab14-dependent (and Rab11-independent) trafficking of EphA2 which generates cell:cell repulsion events that drive tumour cells apart...
March 15, 2017: Nature Communications
Bo Guo, Wenjing Wang, Zhenghao Zhao, Qian Li, Kaiyue Zhou, Lingyu Zhao, Lumin Wang, Juan Yang, Chen Huang
Rab14 is a member of RAS oncogene family, and its dysfunction has been reported to be involved in various types of human cancer. However, its expression and function were still unclear in gastric cancer. The aim of this study was to investigate the function and mechanism of Rab14 in gastric cancer cell lines. Quantitative real-time PCR (qRT-PCR) was performed in 17 gastric adenocarcinoma tissues and 4 cell lines to detect the expression of Rab14. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT), colony formation and flow cytometry assays were employed to determine the proliferative ability, cell cycle transition and apoptosis in vitro in BGC-823 or SGC-7901 cells...
2017: PloS One
Eun-Ae Kim, Tae Ghab Kim, Eon-Gi Sung, In-Hwan Song, Joo-Young Kim, Kyung-Oh Doh, Tae-Jin Lee
MicroRNA (miR) can exert various biological functions by targeting oncogenes or tumor suppressor genes in numerous human malignancies. Recent evidence has shown that miR-148a increases the drug sensitivity of various cancer cells. Herein, we show that ectopic expression of miR-148a induces apoptosis, reduces clonogenicity, and increases the sensitivity to TRAIL and cisplatin in renal cancer cells. The luciferase reporter assay showed that miR-148a negatively regulated ras-related protein 14 (Rab14) expression by binding to the miR-148a binding site in the 3' untranslated region (3'UTR) of Rab14...
March 2017: International Journal of Oncology
Juan Yu, Lei Wang, Haiping Yang, Di Ding, Lei Zhang, Jigang Wang, Qi Chen, Qiang Zou, Yiting Jin, Xiuping Liu
We found that microRNA-320a (miR-320a) was an attractive prognostic biomarker in breast cancer (BC) previously, whereas its regulatory mechanism in BC was not well understood. Our aim was to identify miR-320a target gene, examine the clinical relationship between miR-320a and its target, and further explore the functions of its target in BC. In this study, miR-320a downstream target gene was determined in HEK-293T cells by dual luciferase reporter assay. Then western blotting and immunohistochemistry were used to assess miR-320a target gene expression in fresh frozen (n=19, breast cancer and matched non-malignant adjacent tissue samples) and formalin-fixed paraffin-embedded (FFPE) (n=130, invasive BC tissues, the same panel detected for miR-320a expression previously) breast tissues, respectively...
2016: Journal of Cancer
Ruifeng Lu, Jean M Wilson
The generation of cell polarity is essential for the development of multi-cellular organisms as well as for the function of epithelial organs in the mature animal. Small GTPases regulate the establishment and maintenance of polarity through effects on cytoskeleton, membrane trafficking, and signaling. Using short-term 3-dimensional culture of MDCK cells, we find that the small GTPase Rab14 is required for apical membrane specification. Rab14 knockdown results in disruption of polarized lipid domains and failure of the Par/aPKC/Cdc42 polarity complex to localize to the apical membrane...
November 30, 2016: Scientific Reports
Rui Hou, Luo Jiang, Zhuo Yang, Shizhuo Wang, Qifang Liu
The Rab GTPase family protein Rab14 has been implicated in cancer development. However, its clinical significance in ovarian cancers and its biological effects have not been examined. The present study aims to examine the clinical significance, biological roles, and molecular mechanism of Rab14 in ovarian cancer progression. We examined expression pattern of Rab14 in 122 cases of ovarian cancer specimens using immunohistochemistry and found Rab14 overexpression correlated with FIGO stage (p = 0.0041). We depleted Rab14 in SKOV3 cells using siRNA and overexpressed Rab14 in SW626 cells...
October 7, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Julie Jurczyluk, Marcia A Munoz, Oliver P Skinner, Ryan C Chai, Naveid Ali, Umaimainthan Palendira, Julian Mw Quinn, Alexandra Preston, Stuart G Tangye, Andrew J Brown, Elizabeth Argent, John B Ziegler, Sam Mehr, Michael J Rogers
Mevalonate kinase deficiency (MKD) is caused by mutations in a key enzyme of the mevalonate-cholesterol biosynthesis pathway, leading to recurrent autoinflammatory disease characterised by enhanced release of interleukin-1β (IL-1β). It is currently believed that the inflammatory phenotype of MKD is triggered by temperature-sensitive loss of mevalonate kinase activity and reduced biosynthesis of isoprenoid lipids required for the prenylation of small GTPase proteins. However, previous studies have not clearly shown any change in protein prenylation in patient cells under normal conditions...
November 2016: Immunology and Cell Biology
Caroline Mauvezin, Thomas P Neufeld
The intracellular movement of membrane-bound vesicles is closely tied to their formation, maturation and ultimate function within the cell. Motor proteins and their associated cytoskeletal networks are critical for vesicle transport, but whether these factors play a more direct role in vesicle biogenesis is unclear. In recent work, we found that the Drosophila kinesin proteins Khc and Klp98A are both required for the normal anterograde movement of autophagosomes and autolysosomes during starvation-induced autophagy...
January 2, 2017: Small GTPases
Paul Duffield Brewer, Estifanos N Habtemichael, Irina Romenskaia, Adelle C F Coster, Cynthia Corley Mastick
Insulin increases glucose uptake by increasing the rate of exocytosis of the facilitative glucose transporter isoform 4 (Glut4) relative to its endocytosis. Insulin also releases Glut4 from highly insulin-regulated secretory compartments (GSVs or Glut4 storage vesicles) into constitutively cycling endosomes. Previously it was shown that both overexpression and knockdown of the small GTP-binding protein Rab14 decreased Glut4 translocation to the plasma membrane (PM). To determine the mechanism of this perturbation, we measured the effects of Rab14 knockdown on the trafficking kinetics of Glut4 relative to two proteins that partially co-localize with Glut4, the transferrin (Tf) receptor and low-density-lipoprotein-receptor-related protein 1 (LRP1)...
May 15, 2016: Biochemical Journal
Wilhelm W Just, Johan Peränen
In this review article, we summarize current knowledge on peroxisome biogenesis/functions and the role that small GTPases may play in these processes. Precise intracellular distribution of cell organelles requires their regulated association to microtubules and the actin cytoskeleton. In this respect, RhoGDP/RhoGTP favor binding of peroxisomes to microtubules and actin filaments. In its GTP-bound form, RhoA activates a regulatory cascade involving Rho kinaseII and non-muscle myosinIIA. Such interactions frequently depend on phosphoinositides (PIs) of which PI4P, PI(4,5)P2, and PI(3,5)P2 were found to be present in the peroxisomal membrane...
May 2016: Biochimica et Biophysica Acta
Caroline Mauvezin, Amanda L Neisch, Carlos I Ayala, Jung Kim, Abigail Beltrame, Christopher R Braden, Melissa K Gardner, Thomas S Hays, Thomas P Neufeld
Degradation of cellular material by autophagy is essential for cell survival and homeostasis, and requires intracellular transport of autophagosomes to encounter acidic lysosomes through unknown mechanisms. Here, we identify the PX-domain-containing kinesin Klp98A as a new regulator of autophagosome formation, transport and maturation in Drosophila. Depletion of Klp98A caused abnormal clustering of autophagosomes and lysosomes at the cell center and reduced the formation of starvation-induced autophagic vesicles...
March 1, 2016: Journal of Cell Science
Ernest C So, Gunnar N Schroeder, Danielle Carson, Corinna Mattheis, Aurélie Mousnier, Malgorzata Broncel, Edward W Tate, Gad Frankel
Legionella pneumophila, the causative agent of Legionnaire's disease, uses its type IV secretion system to translocate over 300 effector proteins into host cells. These effectors subvert host cell signaling pathways to ensure bacterial proliferation. Despite their importance for pathogenesis, the roles of most of the effectors are yet to be characterized. Key to understanding the function of effectors is the identification of host proteins they bind during infection. We previously developed a novel tandem-affinity purification (TAP) approach using hexahistidine and BirA-specific biotinylation tags for isolating translocated effector complexes from infected cells whose composition were subsequently deciphered by mass spectrometry...
March 11, 2016: Journal of Biological Chemistry
Hiroki Takeuchi, Akihiko Takada, Masae Kuboniwa, Atsuo Amano
Although human gingival epithelium prevents intrusions by periodontal bacteria, Porphyromonas gingivalis, the most well-known periodontal pathogen, is able to invade gingival epithelial cells and pass through the epithelial barrier into deeper tissues. We previously reported that intracellular P. gingivalis exits from gingival epithelial cells via a recycling pathway. However, the underlying molecular process remains unknown. In the present study, we found that the pathogen localized in early endosomes recruits VAMP2 and Rab4A...
2016: Cellular Microbiology
Naveid Ali, Julie Jurczyluk, Gemma Shay, Zakir Tnimov, Kirill Alexandrov, Marcia A Munoz, Oliver P Skinner, Nathan J Pavlos, Michael J Rogers
Bisphosphonate drugs such as zoledronic acid (ZOL), used for the treatment of common bone disorders, target the skeleton and inhibit bone resorption by preventing the prenylation of small GTPases in bone-destroying osteoclasts. Increasing evidence indicates that bisphosphonates also have pleiotropic effects outside the skeleton, most likely via cells of the monocyte/macrophage lineage exposed to nanomolar circulating drug concentrations. However, no effects of such low concentrations of ZOL have been reported using existing approaches...
October 2, 2015: Small GTPases
Gunnar N Schroeder, Philipp Aurass, Clare V Oates, Edward W Tate, Elizabeth L Hartland, Antje Flieger, Gad Frankel
Legionella pneumophila is a bacterial pathogen that thrives in alveolar macrophages, causing a severe pneumonia. The virulence of L. pneumophila depends on its Dot/Icm type IV secretion system (T4SS), which delivers more than 300 effector proteins into the host, where they rewire cellular signaling to establish a replication-permissive niche, the Legionella-containing vacuole (LCV). Biogenesis of the LCV requires substantial redirection of vesicle trafficking and remodeling of intracellular membranes. In order to achieve this, several T4SS effectors target regulators of membrane trafficking, while others resemble lipases...
October 2015: Infection and Immunity
Julian Gambarte Tudela, Anahi Capmany, Maryse Romao, Cristian Quintero, Stephanie Miserey-Lenkei, Graca Raposo, Bruno Goud, Maria Teresa Damiani
Given their obligate intracellular lifestyle, Chlamydia trachomatis ensure that they have access to multiple host sources of essential lipids by interfering with vesicular transport. These bacteria hijack Rab6-, Rab11- and Rab14-controlled trafficking pathways to acquire sphingomyelin from the Golgi complex. Another important source of sphingolipids, phospholipids and cholesterol are multivesicular bodies (MVBs). Despite their participation in chlamydial inclusion development and bacterial replication, the molecular mechanisms mediating the interaction between MVBs and chlamydial inclusions remain unknown...
August 15, 2015: Journal of Cell Science
Victoria Cano, Catalina March, Jose Luis Insua, Nacho Aguiló, Enrique Llobet, David Moranta, Verónica Regueiro, Gerard P Brennan, Maria Isabel Millán-Lou, Carlos Martín, Junkal Garmendia, José A Bengoechea
Klebsiella pneumoniae is an important cause of community-acquired and nosocomial pneumonia. Evidence indicates that Klebsiella might be able to persist intracellularly within a vacuolar compartment. This study was designed to investigate the interaction between Klebsiella and macrophages. Engulfment of K. pneumoniae was dependent on host cytoskeleton, cell plasma membrane lipid rafts and the activation of phosphoinositide 3-kinase (PI3K). Microscopy studies revealed that K. pneumoniae resides within a vacuolar compartment, the Klebsiella-containing vacuole (KCV), which traffics within vacuoles associated with the endocytic pathway...
November 2015: Cellular Microbiology
Patrick Lall, Andrew J Lindsay, Sara Hanscom, Tea Kecman, Elizabeth S Taglauer, Una M McVeigh, Edward Franklin, Mary W McCaffrey, Amir R Khan
Rab GTPases recruit effector proteins, via their GTP-dependent switch regions, to distinct subcellular compartments. Rab11 and Rab25 are closely related small GTPases that bind to common effectors termed the Rab11 family of interacting proteins (FIPs). The FIPs are organized into two subclasses (class I and class II) based on sequence and domain organization, and both subclasses contain a highly conserved Rab-binding domain at their C termini. Yeast two-hybrid and biochemical studies have revealed that the more distantly related Rab14 also interacts with class I FIPs...
July 24, 2015: Journal of Biological Chemistry
Andrew J Lindsay, Mary W McCaffrey
Rab14 functions in the endocytic recycling pathway, having been implicated in the trafficking of the ADAM10 protease, GLUT4, and components of cell-cell junctions to the plasma membrane. It localizes predominantly to endocytic membranes with a pool also found on trans-Golgi network (TGN) membranes, and is most closely related to the Rab11 subfamily of GTPases. Certain intracellular bacteria such as Legionella pneumophila, Chlamydia trachomatis, and Salmonella enterica utilize Rab14 to promote their maturation and replication...
2015: Methods in Molecular Biology
Sabrina J Nolan, Julia D Romano, Thomas Luechtefeld, Isabelle Coppens
Toxoplasma gondii and Neospora caninum, which cause the diseases toxoplasmosis and neosporosis, respectively, are two closely related apicomplexan parasites. They have similar heteroxenous life cycles and conserved genomes and share many metabolic features. Despite these similarities, T. gondii and N. caninum differ in their transmission strategies and zoonotic potential. Comparative analyses of the two parasites are important to identify the unique biological features that underlie the basis of host preference and pathogenicity...
May 2015: Eukaryotic Cell
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