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Christian Ostalecki, Jung-Hyun Lee, Jochen Dindorf, Lena Collenburg, Stephan Schierer, Beate Simon, Stefan Schliep, Elisabeth Kremmer, Gerold Schuler, Andreas S Baur
The evolution of cancer is characterized by the appearance of specific mutations, but these mutations are translated into proteins that must cooperate to induce malignant transformation. Using a systemic approach with the multiepitope ligand cartography (MELC) technology, we analyzed protein expression profiles (PEPs) in nevi and BRAF(V600E)-positive superficial spreading melanomas (SSMs) from patient tissues to identify key transformation events. The PEPs in nevi and SSMs differed predominantly in the abundance of specific antigens, but the PEPs of nevi- and melanoma-associated keratinocytes gradually changed during the transformation process...
March 14, 2017: Science Signaling
Jinxie Zhang, Danfeng Chang, Yao Yang, Xudong Zhang, Wei Tao, Lijuan Jiang, Xin Liang, Hsiangi Tsai, Laiqiang Huang, Lin Mei
Polymeric nanoparticles such as PLGA-based nanoparticles are emerging as promising carriers for controlled drug delivery. However, little is known about the intracellular trafficking network of polymeric nanoparticles. Here, more than 30 Rab proteins were used as markers of multiple trafficking vesicles in endocytosis, exocytosis and autophagy to investigate in detail the intracellular trafficking pathways of PLGA nanoparticles. We observed that coumarin-6-loaded PLGA nanoparticles were internalized by the cells mainly through caveolin and clathrin-dependent endocytosis and Rab34-mediated macropinocytosis...
February 22, 2017: Nanoscale
Javier Chinen, Luigi D Notarangelo, William T Shearer
Advances in clinical immunology in the past year included the report of practice parameters for the diagnosis and management of primary immunodeficiencies to guide the clinician in the approach to these relatively uncommon disorders. We have learned of new gene defects causing immunodeficiency and of new phenotypes expanding the spectrum of conditions caused by genetic mutations such as a specific regulator of telomere elongation (RTEL1) mutation causing isolated natural killer cell deficiency and mutations in ras-associated RAB (RAB27) resulting in immunodeficiency without albinism...
December 2016: Journal of Allergy and Clinical Immunology
Joana G Silva, Nuno P Martins, Ricardo Henriques, Helena Soares
The ability of HIV-1 to replicate and to establish long-term reservoirs is strongly influenced by T cell activation. Through the use of membrane-tethered, genetically encoded calcium (Ca(2+)) indicators, we were able to detect for the first time, to our knowledge, the formation of Ca(2+) territories and determine their role in coordinating the functional signaling nanostructure of the synaptic membrane. Consequently, we report a previously unknown immune subversion mechanism involving HIV-1 exploitation, through its Nef accessory protein, of the interconnectivity among three evolutionarily conserved cellular processes: vesicle traffic, signaling compartmentalization, and the second messenger Ca(2+) We found that HIV-1 Nef specifically associates with the traffic regulators MAL and Rab11b compelling the vesicular accumulation of Lck...
November 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Christian Ostalecki, Sebastian Wittki, Jung-Hyun Lee, Miriam M Geist, Nadine Tibroni, Thomas Harrer, Gerold Schuler, Oliver T Fackler, Andreas S Baur
Tumor necrosis factor (TNF) is a key cytokine in HIV replication and pathogenesis. For reasons that are not entirely clear, the cytokine remains upregulated despite anti-retroviral therapy (ART). Here we demonstrate that HIV Nef induces an alternative TNF secretion mechanism that remains active in chronic infection. Ingestion of Nef-containing plasma extracellular vesicles (pEV) from ART patients by primary immune cells, but also Nef expression, induced intracellular proTNF cleavage and secretion of vesicular TNF endosomes...
November 2016: EBioMedicine
Angela R M Kurz, Monika Pruenster, Ina Rohwedder, Mahalakshmi Ramadass, Kerstin Schäfer, Ute Harrison, Gabriel Gouveia, Claudia Nussbaum, Roland Immler, Johannes R Wiessner, Andreas Margraf, Dae-Sik Lim, Barbara Walzog, Steffen Dietzel, Markus Moser, Christoph Klein, Dietmar Vestweber, Rainer Haas, Sergio D Catz, Markus Sperandio
Neutrophils need to penetrate the perivascular basement membrane for successful extravasation into inflamed tissue, but this process is incompletely understood. Recent findings have associated mammalian sterile 20-like kinase 1 (MST1) loss of function with a human primary immunodeficiency disorder, suggesting that MST1 may be involved in immune cell migration. Here, we have shown that MST1 is a critical regulator of neutrophil extravasation during inflammation. Mst1-deficient (Mst1-/-) neutrophils were unable to migrate into inflamed murine cremaster muscle venules, instead persisting between the endothelium and the basement membrane...
November 1, 2016: Journal of Clinical Investigation
Adam J Trexler, Kem A Sochacki, Justin W Taraska
How and when the dozens of molecules that control exocytosis assemble in living cells to regulate the fusion of a vesicle with the plasma membrane is unknown. Here we image with two-color total internal reflection fluorescence microscopy the local changes of 27 proteins at single dense-core vesicles undergoing calcium-triggered fusion. We identify two broad dynamic behaviors of exocytic molecules. First, proteins enriched at exocytic sites are associated with DCVs long before exocytosis, and near the time of membrane fusion, they diffuse away...
August 1, 2016: Molecular Biology of the Cell
Zhen Meng, Maria C Edman, Pang-Yu Hsueh, Chiao-Yu Chen, Wannita Klinngam, Tanya Tolmachova, Curtis T Okamoto, Sarah F Hamm-Alvarez
The mechanism responsible for the altered spectrum of tear proteins secreted by lacrimal gland acinar cells (LGAC) in patients with Sjögren's Syndrome (SS) remains unknown. We have previously identified increased cathepsin S (CTSS) activity as a unique characteristic of tears of patients with SS. Here, we investigated the role of Rab3D, Rab27a, and Rab27b proteins in the enhanced release of CTSS from LGAC. Similar to patients with SS and to the male nonobese diabetic (NOD) mouse model of SS, CTSS activity was elevated in tears of mice lacking Rab3D...
June 1, 2016: American Journal of Physiology. Cell Physiology
Kouichi Mizuno, Takuji Fujita, Hiroshi Gomi, Tetsuro Izumi
In regulated exocytosis, it is generally assumed that vesicles must stably "dock" at the plasma membrane before they are primed to become fusion-competent. However, recent biophysical analyses in living cells that visualize fluorescent secretory granules have revealed that exocytic behaviors are not necessarily uniform: some granules beneath the plasma membrane are resistant to Ca(2+)-triggered release, while others are accelerated to fuse without a pause for stable docking. These findings suggest that stable docking is unnecessary, and can even be inhibitory or nonfunctional, for fusion...
April 1, 2016: Scientific Reports
Tomohide Uno, Masayuki Furutani, Chihiro Watanabe, Katsuhiko Sakamoto, Yuichi Uno, Kengo Kanamaru, Hiroshi Yamagata, Akira Mizoguchi, Makio Takeda
In eukaryotic cells, Rab guanosine triphosphate-ases serve as key regulators of membrane-trafficking events, such as exocytosis and endocytosis. Rab3, Rab6, and Rab27 control the regulatory secretory pathway of neuropeptides and neurotransmitters. The cDNAs of Rab3, Rab6, and Rab27 from B. mori were inserted into a plasmid, transformed into Escherichia coli, and then subsequently purified. We then produced antibodies against Rab3, Rab6, and Rab27 of Bombyx mori in rabbits and rats for use in western immunoblotting and immunohistochemistry...
July 2016: Histochemistry and Cell Biology
Hironori Higashio, Yoh-ichi Satoh, Tomoyuki Saino
Mast cell degranulation is regulated by the small guanosine triphosphatases (GTPases) Rab27a and Rab27b, which have distinct and opposing roles: Rab27b acts as a positive regulator through its effector protein Munc13-4, a non-neuronal isoform of the vesicle-priming Munc13 family of proteins, whereas Rab27a acts as a negative regulator through its effector protein melanophilin, by maintaining integrity of cortical filamentous actin (F-actin), a barrier to degranulation. Here we investigated the role of Rab37, one of the Rab GTPases assumed to be implicated in regulated secretion during mast cell degranulation...
March 2, 2016: Scientific Reports
Weiwei Dong, Jiantao Cui, Jingwen Yang, Wenmei Li, Shuo Wang, Xiaojuan Wang, Xing Li, Youyong Lu, Wenhua Xiao
The Rab27 subfamily of secretory small GTPase plays a vital role in vesicle trafficking and regulates tumor growth and metastasis in several cancer types. Thus, this research was designed to explore the clinical and prognostic significance of Rab27A and Rab27B in colorectal cancer (CRC) patients. Reverse transcription-polymerase chain reaction (RT-PCR), western blot, and immunohistochemistry (IHC) analysis were used to examine Rab27A and Rab27B expression in human CRC cell lines and primary tumors. The correlation of gene expression with clinicopathological features and prognosis was also evaluated...
December 2015: Discovery Medicine
Rajshekhar A Kore, Edathara C Abraham
Exosomes mediate secretion of crystallin alphaB (cryAB), a well characterized molecular chaperone with anti-apoptotic activity. However, the mechanisms governing its packaging and secretion remained unexplored. In glioma cells, notwithstanding extensive phosphorylation of cryAB at Ser59 followed by Ser45 (Ser19 is largely unphosphorylated), we discovered that the majority of secreted exosomal cryAB is nonphosphorylated. Transient ectopic expression of a yellow fluorescent protein (YFP) tagged triple phosphomimic (3-SD) cryAB construct in cryAB absent glioma cells led to the formation of large cytosolic inclusions...
February 2016: Biochimica et Biophysica Acta
Yuan Lu, Mikki Bowswell, William Bowswell, Kuan Yang, Manfred Schartl, Ronald B Walter
The phenotypic and genetic similarities between Xiphophorus and human melanoma render Xiphophorus a useful animal model for studying the genetic basis of melanoma etiology. In the Xiphophorus model, melanoma has been shown to be inducible by ultraviolet light (UVB) exposure among interspecies hybrids, but not in parental line fish similarly treated. This leads to questions of what genes are responsive to UVB exposure in the skin of the interspecies hybrids, as well as how parental alleles in hybrids may be differentially regulated and the potential roles they may play in induced melanomagenesis...
December 2015: Comparative Biochemistry and Physiology. Toxicology & Pharmacology: CBP
Mami Yamaoka, Toshimasa Ishizaki, Toshihide Kimura
Small guanosine triphosphatases (GTPases) participate in a wide variety of cellular functions including proliferation, differentiation, adhesion, and intracellular transport. Conventionally, only the guanosine 5'-triphosphate (GTP)-bound small GTPase interacts with effector proteins, and the resulting downstream signals control specific cellular functions. Therefore, the GTP-bound form is regarded as active, and the focus has been on searching for proteins that bind the GTP form to look for their effectors...
2015: Biological & Pharmaceutical Bulletin
Akane Imai, Maiko Tsujimura, Sumio Yoshie, Mitsunori Fukuda
Amylase is released from exocrine parotid acinar cells via typical exocytosis. Exocytosis of amylase-containing granules occurs through several steps, including formation, maturation, and transport of granules. These steps are thought to be regulated by members of the small GTPase Rab family. We previously demonstrated that Rab27 and its effectors mediate amylase release from parotid acinar cells, but the functional involvement of other Rab proteins in exocrine granule exocytosis remains largely unknown. Here, we studied isoproterenol (IPR)-induced amylase release from parotid acinar cells to investigate the possible involvement of Rab33A, which was recently suggested to regulate exocytosis in hippocampal neurons and PC12 cells...
June 5, 2015: Biochemical and Biophysical Research Communications
Takao Yasuda, Yuta Homma, Mitsunori Fukuda
Synaptotagmin-like protein 2-a (Slp2-a) was originally described as a membrane trafficking protein that consists of a Slp homology domain (SHD), a linker domain, and tandem C2 domains (named the C2A domain and C2B domain). Slp2-a mediates docking of Rab27-bearing vesicles to the plasma membrane through simultaneous interaction with Rab27 and phospholipids in the plasma membrane. We have recently reported that Slp2-a regulates renal epithelial cell size through interaction with Rap1GAP2 via the C2B domain independently of Rab27 and demonstrated the presence of excess activation of ezrin, a membrane-cytoskeleton linker and signal transducer, in Slp2-a-knockdown Madin-Darby canine kidney II (MDCK II) cells...
May 15, 2015: Biochemical and Biophysical Research Communications
Matias A Bustos, Ornella Lucchesi, Maria C Ruete, Luis S Mayorga, Claudia N Tomes
Regulated exocytosis employs a conserved molecular machinery in all secretory cells. Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) and Rab superfamilies are members of this machinery. Rab proteins are small GTPases that organize membrane microdomains on organelles by recruiting specific effectors that strongly influence the movement, fusion and fission dynamics of intracellular compartments. Rab3 and Rab27 are the prevalent exocytotic isoforms. Many events occur in mammalian spermatozoa before they can fertilize the egg, one of them is the acrosome reaction (AR), a type of regulated exocytosis...
2015: Methods in Molecular Biology
Takao Yasuda, Paulina S Mrozowska, Mitsunori Fukuda
Polarized epithelial cells have two distinct plasma membrane domains, i.e., an apical membrane domain and a basolateral membrane domain, that are the result of polarized trafficking of proteins and lipids. Several members of the Rab-type small GTPases, which are general regulators of membrane trafficking, have been reported to be involved in the regulation of polarized trafficking in epithelial cells, but their precise role in polarized trafficking is poorly understood. In a recent study we used Madin-Darby canine kidney (MDCK) II cells as a model of polarized cells and concluded from the results that Rab27A and its effector synaptotagmin-like protein 2-a (Slp2-a) regulate apical transport of Rab27-bearing vesicles in polarized epithelial cells...
2015: Methods in Molecular Biology
Tatjana Döring, Reinhild Prange
Hepatitis B virus morphogenesis is accompanied by the production and release of non-enveloped capsids/nucleocapsids. Capsid particles are formed inside the cell cytosol by multimerization of core protein subunits and ultimately exported in an uncommon coatless state. Here, we investigated potential roles of Rab GTPases in capsid formation and trafficking by using RNA interference and overexpression studies. Naked capsid release does not require functions of the endosome-associated Rab5, Rab7 and Rab27 proteins, but depends on functional Rab33B, a GTPase participating in autophagosome formation via interaction with the Atg5-Atg12/Atg16L1 complex...
May 2015: Cellular Microbiology
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