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Richard Wong, Larry Feig
RalGDS is a guanine nucleotide exchange factor that promotes the active GTP-bound form of Ral GTPases, RalA and RalB. GTP-bound Ras has the capacity to activate Ral GTPases at least in part by binding to the C-terminal Ras-binding domain (RBD) of RalGDS and directing the protein to Ral GTPases in the plasma membrane. In many cases, activation of Ral proteins complements other Ras effector pathways to carry out a cell function, but in others it opposes them. Moreover, in many cases activation of Ral proteins contributes to the oncogenic potential of Ras...
October 20, 2016: Biochemical and Biophysical Research Communications
Hongyan Zhang, Wanbin Li
The objective of the present study was to identify the association between mir-143-3p and RalA-binding protein 1 (RALBP1), and their roles in regulating the development of ovarian cancer. Overexpression of RALBP1 induced apoptosis of the ovarian cancer cells, and developed ovarian cancer. In silico analysis and luciferase assay were used to identify whether RALBP1 was the target of mir-143-3p. Subsequently, real‑time PCR and western blotting were used to determine the expression level of mir-143-3p, RALBP1 mRNA and protein in different groups, furthermore, MTT assay and flow cytometry were used to detect the viability and apoptosis of cells in different treatment groups...
October 4, 2016: Oncology Reports
Shunsuke Kimura, Masami Yamashita, Megumi Yamakami-Kimura, Yusuke Sato, Atsushi Yamagata, Yoshihiro Kobashigawa, Fuyuhiko Inagaki, Takako Amada, Koji Hase, Toshihiko Iwanaga, Hiroshi Ohno, Shuya Fukai
The tunneling nanotube (TNT) is a structure used for intercellular communication, and is a thin membrane protrusion mediating transport of various signaling molecules and cellular components. M-Sec has potent membrane deformation ability and induces TNT formation in cooperation with the Ral/exocyst complex. Here, we show that the N-terminal polybasic region of M-Sec directly binds phosphatidylinositol (4,5)-bisphosphate for its localization to the plasma membrane during the initial stage of TNT formation. We further report a crystal structure of M-Sec, which consists of helix bundles arranged in a straight rod-like shape, similar to the membrane tethering complex subunits...
2016: Scientific Reports
Karen M Mann, Haoqiang Ying, Joseph Juan, Nancy A Jenkins, Neal G Copeland
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease with a high mortality rate. Genetic and biochemical studies have shown that RAS signaling mediated by KRAS plays a pivotal role in disease initiation, progression and drug resistance. RAS signaling affects several cellular processes in PDAC, including cellular proliferation, migration, cellular metabolism and autophagy. 90% of pancreatic cancer patients harbor somatic oncogenic point mutations in KRAS, which lead to constitutive activation of the molecule...
September 3, 2016: Pharmacology & Therapeutics
Kevin F Ginn, Ben Fangman, Kaoru Terai, Amanda Wise, Daniel Ziazadeh, Kushal Shah, Robyn Gartrell, Brandon Ricke, Kyle Kimura, Sharad Mathur, Emma Borrego-Diaz, Faris Farassati
Medulloblastoma (MDB) represents a major form of malignant brain tumors in the pediatric population. A vast spectrum of research on MDB has advanced our understanding of the underlying mechanism, however, a significant need still exists to develop novel therapeutics on the basis of gaining new knowledge about the characteristics of cell signaling networks involved. The Ras signaling pathway, one of the most important proto-oncogenic pathways involved in human cancers, has been shown to be involved in the development of neurological malignancies...
August 26, 2016: Journal of Neuro-oncology
Ying Jiang, Maria S Sverdlov, Peter T Toth, Long Shuang Huang, Guangwei Du, Yiyao Liu, Viswanathan Natarajan, Richard D Minshall
Caveolae are the primary route for internalization and transendothelial transport of macromolecules, such as insulin and albumin. Caveolae-mediated endocytosis is activated by Src-dependent caveolin-1 (Cav-1) phosphorylation and subsequent recruitment of dynamin-2 and filamin A (FilA), which facilitate vesicle fission and trafficking, respectively. Here, we tested the role of RalA and phospholipase D (PLD) signaling in the regulation of caveolae-mediated endocytosis and trafficking. The addition of albumin to human lung microvascular endothelial cells induced the activation of RalA within minutes, and siRNA-mediated down-regulation of RalA abolished fluorescent BSA uptake...
September 23, 2016: Journal of Biological Chemistry
Chenran Zhang, Zheng Cai, Qiang Liang, Qi Wang, Yicheng Lu, Liuhua Hu, Guohan Hu
Our previous study showed that RalA-binding protein 1 (RLIP76) is overexpressed in gliomas and is associated with higher tumour grade and decreased patient survival. Furthermore, RLIP76 downregulation increases chemosensitivity of glioma cells to temozolomide by inducing apoptosis. However, other mechanisms underlying RLIP76-associated chemoresistance are unknown. In this study, we investigated the effect of RLIP76 depletion on autophagy. RLIP76 was knocked down in U251 glioma cells using shRNA and autophagy-related proteins, and PI3K/Akt signalling components were evaluated...
July 29, 2016: Cellular and Molecular Neurobiology
Shivangi M Inamdar, Shu-Chan Hsu, Charles Yeaman
Spatial regulation of exocytosis relies on the exocyst, a hetero-octameric protein complex that tethers vesicles to fusion sites at the plasma membrane. Nevertheless, our understanding of mechanisms regulating exocyst assembly/disassembly, localization, and function are incomplete. Here, we have exploited a panel of anti-Sec6 monoclonal antibodies (mAbs) to probe possible configurational changes accompanying transitions in exocyst function in epithelial MDCK cells. Sec6 is quantitatively associated with Sec8 in high molecular weight complexes, as shown by gel filtration and co-immunoprecipitation studies...
2016: Frontiers in Cell and Developmental Biology
Jitian Li, Liping Dai, Ningjing Lei, Mengtao Xing, Pei Li, Chenglin Luo, Carlos A Casiano, Jian-Ying Zhang
Autoantibodies against intracellular tumor-associated antigens (TAAs) are commonly found in human cancers. In this study, we characterized the serum autoantibody response to the RalA, Ras-like GTPase, in patients with prostate cancer (PCa). The autoantibodies were detected by immunofluorescence assay in PCa cell lines, ELISA, and immunoblotting in 339 serum samples from patients with PCa and benign prostatic hyperplasia (BPH), and in normal human sera (NHS). The expression of RalA in prostate tumor tissues was evaluated by immunohistochemistry (IHC) in tumor microarrays...
June 7, 2016: Oncotarget
Archana Pawar, Jeremy A Meier, Anwesha Dasgupta, Neha Diwanji, Neha Deshpande, Kritika Saxena, Natasha Buwa, Siddhi Inchanalkar, Martin Alexander Schwartz, Nagaraj Balasubramanian
Integrin dependent regulation of growth factor signalling confers anchorage dependence that is deregulated in cancers. Downstream of integrins and oncogenic Ras the small GTPase Ral is a vital mediator of adhesion dependent trafficking and signalling. This study identifies a novel regulatory crosstalk between Ral and Arf6 that controls Ral function in cells. In re-adherent mouse fibroblasts (MEFs) integrin dependent activation of RalA drives Arf6 activation. Independent of adhesion constitutively active RalA and RalB could both however activate Arf6...
September 2016: Cellular Signalling
Mei Zheng, Xiaohan Zhang, NingNing Sun, Chengchun Min, Xiaowei Zhang, Kyeong-Man Kim
Filamin A (FLNA) is known to act as platform for the signaling and intracellular trafficking of various GPCRs including dopamine D2 and D3 receptors (D2R, D3R). To understand molecular mechanisms involved in the FLNA-mediated regulation of D2R and D3R, comparative studies were conducted on the signaling and intracellular trafficking of the D2R and D3R in FLNA-knockdown cells, with a specific focus on the roles of the proteins that interact with FLNA and the D2R and D3R. Lowering the level of cellular FLNA caused an elevation in RalA activity and resulted in selective interference with the normal intracellular trafficking and signaling of the D2R and D3R, through GRK2 and β-arrestins, respectively...
August 2016: Biochimica et Biophysica Acta
Takahiro Kodama, Emilie A Bard-Chapeau, Justin Y Newberg, Michiko Kodama, Roberto Rangel, Kosuke Yoshihara, Jerrold M Ward, Nancy A Jenkins, Neal G Copeland
BACKGROUND & AIMS: High-throughput sequencing technologies have identified thousands of infrequently mutated genes in hepatocellular carcinomas (HCCs). However, high intratumor and intertumor heterogeneity, combined with large numbers of passenger mutations, have made it difficult to identify driver mutations that contribute to the development of HCC. We combined transposon mutagenesis with a high-throughput screen of a small-hairpin RNA (shRNA) library to identify genes and pathways that contribute to HCC development...
August 2016: Gastroenterology
Zhi Yi Wan, Johann Shane Tian, Hayden Weng Siong Tan, Ai Lee Chow, Arthur Yi Loong Sim, Kenneth Hon Kim Ban, Yun Chau Long
UNLABELLED: Fibroblast growth factor 19 (FGF19) is an important postprandial enterokine which regulates liver metabolism and hepatocyte proliferation. However, the precise mechanism by which FGF19 regulates these cellular effects is poorly understood. Given that mechanistic target of rapamycin complex 1 (mTORC1) regulates numerous postprandial adaptations, we investigated the potential role of mTORC1 in FGF19 action. We found that FGF19 activated mTORC1 in HepG2 and HuH7 human hepatoma cells, differentiated 3T3-L1 adipocytes and mouse liver...
October 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
K A Probst, C-H Ohlmann, M Saar, S Siemer, M Stoeckle, M Janssen
OBJECTIVES: To compare Robotic assisted laparoscopic adrenalectomy (RALA) and open adrenalectomy (OA) with regard to intraoperative complications, perioperative outcome and cost effectiveness. SUBJECTS/PATIENTS AND METHODS: Functional and statistical data from OA and RALA patients between 2001 and 2015 was prospectively recorded including intra- and post-operative outcomes. We also utilized per-day costs from current census reports (€540/d and €1145/d for normal and intermediate care) to evaluate treatment costs...
May 12, 2016: BJU International
Markus Klose, Laura B Duvall, Weihua Li, Xitong Liang, Chi Ren, Joe Henry Steinbach, Paul H Taghert
The neuropeptide PDF promotes the normal sequencing of circadian behavioral rhythms in Drosophila, but its signaling mechanisms are not well understood. We report daily rhythmicity in responsiveness to PDF in critical pacemakers called small LNvs. There is a daily change in potency, as great as 10-fold higher, around dawn. The rhythm persists in constant darkness and does not require endogenous ligand (PDF) signaling or rhythmic receptor gene transcription. Furthermore, rhythmic responsiveness reflects the properties of the pacemaker cell type, not the receptor...
May 18, 2016: Neuron
Adriana O Santos, Maria Carla Parrini, Jacques Camonis
The human genome contains six genes coding for proteins validated in vitro as specific activators of the small GTPases "Ras-related protein Ral-A" and "Ras-related protein Ral-B", generically named Ral-guanine nucleotide exchange factors (RalGEF). Ral proteins are important contributors to Ras oncogenic signaling, and RAS oncogenes are important in human Non-Small Cell Lung Carcinoma (NSCLC). Therefore in this work, RalGEF contribution to oncogenic and non-oncogenic features of human NSCLC cell lines, as anchorage-dependent and independent growth, cell survival, and proliferation, was investigated...
2016: PloS One
Chunming Gu, Maoxiao Feng, Zhao Yin, Xiaochuang Luo, Juhua Yang, Yumin Li, Tianfu Li, Ruirui Wang, Jia Fei
BCR/ABL is a well-known activator of multiple signaling pathways. RalA, a Ras downstream signaling molecule and a small GTPase, plays an important role in Bcr-Abl-induced leukemogenesis but the exact mechanism remains elusive. Here, we show that RalA GTPase activity is commonly high in chronic myelogenous leukemia (CML) cell lines and patient samples. Overexpression of RalA results in malignant transformation and progression, and induces resistance to imatinib (IM) in BaF3 and K562 cell lines. RalA reduced survival and led to IM resistance in a xenografted mouse model...
April 12, 2016: Oncotarget
Ashley S Massey, Sreekanth Pentlavalli, Richard Cunningham, Cian M McCrudden, Emma M McErlean, Philip Redpath, Ahlam A Ali, Stephanie Annett, John W McBride, Joanne McCaffrey, Tracy Robson, Marie E Migaud, Helen O McCarthy
Bisphosphonates (BPs) are a class of bone resorptive drug with a high affinity for the hydroxyapatite structure of bone matrices that are used for the treatment of osteoporosis. However, clinical application is limited by a common toxicity, BP-related osteonecrosis of the jaw. There is emerging evidence that BPs possess anticancer potential, but exploitation of these antiproliferative properties is limited by their toxicities. We previously reported the utility of a cationic amphipathic fusogenic peptide, RALA, to traffic anionic nucleic acids into various cell types in the form of cationic nanoparticles...
April 4, 2016: Molecular Pharmaceutics
Joanne McCaffrey, Cian M McCrudden, Ahlam A Ali, Ashley S Massey, John W McBride, Maelíosa T C McCrudden, Eva M Vicente-Perez, Jonathan A Coulter, Tracy Robson, Ryan F Donnelly, Helen O McCarthy
Microneedle technology provides the opportunity for the delivery of DNA therapeutics by a non-invasive, patient acceptable route. To deliver DNA successfully requires consideration of both extra and intracellular biological barriers. In this study we present a novel two tier platform; i) a peptide delivery system, termed RALA, that is able to wrap the DNA into nanoparticles, protect the DNA from degradation, enter cells, disrupt endosomes and deliver the DNA to the nucleus of cells ii) a microneedle (MN) patch that will house the nanoparticles within the polymer matrix, breach the skin's stratum corneum barrier and dissolve upon contact with skin interstitial fluid thus releasing the nanoparticles into the skin...
March 28, 2016: Journal of Controlled Release: Official Journal of the Controlled Release Society
Maaike C W van den Berg, Inkie J A van Gogh, Alida M M Smits, Miranda van Triest, Tobias B Dansen, Marieke Visscher, Paulien E Polderman, Marjolein J Vliem, Holger Rehmann, Boudewijn M T Burgering
No abstract text is available yet for this article.
January 15, 2016: Journal of Biological Chemistry
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