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Allison Alwan TerBush, Florianne Hafkamp, Hee Jun Lee, Laurent Coscoy
Host receptor usage by KSHV has been best studied using primary microvascular endothelial and fibroblast cells, although the virus infects a wide variety of cell types in culture and in natural infections. In these two infection models, KSHV adheres to the cell though heparan sulfate (HS) binding, then interacts with a complex of EphA2, xct, and integrins α3β1, αVβ3, αVβ5 to catalyze viral entry. We dissected this receptor complex at the genetic level with CRISPR-Cas9 to precisely determine receptor usage in two epithelial cell lines...
June 13, 2018: Journal of Virology
Yixin Liu, Heidi Kaljunen, Ana Pavić, Tuulia Saarenpää, Juha P Himanen, Dimitar B Nikolov, Adrian Goldman
Eph/Ephrin signaling pathways are crucial in regulating a large variety of physiological processes during development, such as cell morphology, proliferation, migration and axonal guidance. EphrinA (efn-A) ligands, in particular, can be activated by EphA receptors at cell-cell interfaces and have been proposed to cause reverse signaling via RET receptor tyrosine kinase. Such association has been reported to mediate spinal motor axon navigation, but conservation of the interactive signaling pathway and the molecular mechanism of the interaction are unclear...
2018: PloS One
Yuya Tazaki, Kayo Sugitani, Kazuhiro Ogai, Isao Kobayashi, Haruki Kawasaki, Takafumi Aoyama, Nobuo Suzuki, Yoshiaki Tabuchi, Atsuhiko Hattori, Kei-Ichiro Kitamura
This study aimed to investigate the precise data of gene expression, functions, and chronological relationships amongst communication molecules involved in the bone remodeling process with an in vivo model using autologous transplanted scales of goldfish. Autotransplantation of methanol-fixed cell-free scales triggers scale resorption and regeneration, as well as helps elucidate the process of bone remodeling. We investigated osteoclastic markers, osteoblastic markers, and gene expressions of communicating molecules (RANKL, ephrinB2, EphB4, EphA4, Wnt10b) by qPCR, in situ hybridization for Wnt10b, and immunohistochemistry for EphrinB2 and EphA4 proteins to elucidate the bone remodeling process...
June 7, 2018: Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology
Kin-Hing William Lau, Matilda H-C Sheng
Information about the molecular mechanisms leading to the activation of the osteoclast is relatively limited. While there is compelling evidence that the signaling mechanisms of Src and integrin β3 are essential for osteoclast activation, the regulation of these two signaling mechanisms is not fully understood. In this review, evidence supporting a novel regulatory axis of osteoclast activation that plays an upstream regulatory role in both the Src and integrin β3 signaling during osteoclast activation is discussed...
May 16, 2018: Archives of Biochemistry and Biophysics
Shuo Gu, Wing-Yu Fu, Amy K Y Fu, Estella Pui Sze Tong, Fanny C F Ip, Xuhui Huang, Nancy Y Ip
The receptor tyrosine kinase, erythropoietin-producing hepatocellular A4 (EphA4), was recently identified as a molecular target for Alzheimer's disease (AD). We found that blockade of the interaction of the receptor and its ligands, ephrins, alleviates the disease phenotype in an AD transgenic mouse model, suggesting that targeting EphA4 is a potential approach for developing AD interventions. In this study, we identified five FDA-approved drugs-ergoloid, cyproheptadine, nilotinib, abiraterone, and retapamulin-as potential inhibitors of EphA4 by using an integrated approach combining virtual screening with biochemical and cellular assays...
May 9, 2018: Scientific Reports
Simona Bianco, Darío G Lupiáñez, Andrea M Chiariello, Carlo Annunziatella, Katerina Kraft, Robert Schöpflin, Lars Wittler, Guillaume Andrey, Martin Vingron, Ana Pombo, Stefan Mundlos, Mario Nicodemi
Structural variants (SVs) can result in changes in gene expression due to abnormal chromatin folding and cause disease. However, the prediction of such effects remains a challenge. Here we present a polymer-physics-based approach (PRISMR) to model 3D chromatin folding and to predict enhancer-promoter contacts. PRISMR predicts higher-order chromatin structure from genome-wide chromosome conformation capture (Hi-C) data. Using the EPHA4 locus as a model, the effects of pathogenic SVs are predicted in silico and compared to Hi-C data generated from mouse limb buds and patient-derived fibroblasts...
May 2018: Nature Genetics
Karen K Ling, Michaela Jackson, Duah Alkam, Dawei Liu, Norm Allaire, Chao Sun, Mahmoud Kiaei, Alexander McCampbell, Frank Rigo
Amyotrophic lateral sclerosis (ALS) is a fatal adult onset motor neuron disease characterized by progressive denervation and subsequent motor impairment. EphA4, a negative regulator of axonal growth, was recently identified as a genetic modifier in fish and rodent models of ALS. To evaluate the therapeutic potential of EphA4 for ALS, we examined the effect of CNS-directed EphA4 reduction in preclinical mouse models of ALS, and assessed if the levels of EPHA4 mRNA in blood correlate with disease onset and progression in human ALS patients...
June 2018: Neurobiology of Disease
Lin Luo, Ze-Ping Yu, Han Qin, Ze-Xin Zhu, Ming-Heng Liao, Hao-Tian Liao, Ke-Fei Yuan, Yong Zeng
Background: MicroRNAs (miRNAs) have been reported to play vital roles in liver regeneration. Previous studies mainly focused on the functions of intracellular miRNAs, while the functions of circulating exosomal miRNAs in liver regeneration remain largely unknown. The aim of this study was to identify the key exosomal miRNA that played vital roles in liver regeneration. Methods: The Sprague-Dawley male rats were assigned to 70% partially hepatectomized group (n = 6) and sham surgery group (n = 6)...
February 20, 2018: Chinese Medical Journal
L M Vargas, W Cerpa, F J Muñoz, S Zanlungo, A R Alvarez
Alzheimer's disease (AD) is characterized by progressive memory loss and dementia. The strong correlation between cognitive decline and the loss of synapses supports the idea that synaptic damage is a relevant pathogenic mechanism underlying AD progression. It has been shown that amyloid beta oligomers (AβOs) induce synaptotoxicity ultimately leading to the reduction of dendritic spine density, which underlies cognitive damage. However, the signaling pathways connecting AβOs to synaptic dysfunction have not been completely elucidated...
April 2018: Biochimica et Biophysica Acta
Mette Harboe, Julie Torvund-Jensen, Kasper Kjaer-Sorensen, Lisbeth S Laursen
During development of the central nervous system not all axons are myelinated, and axons may have distinct myelination patterns. Furthermore, the number of myelin sheaths formed by each oligodendrocyte is highly variable. However, our current knowledge about the axo-glia communication that regulates the formation of myelin sheaths spatially and temporally is limited. By using axon-mimicking microfibers and a zebrafish model system, we show that axonal ephrin-A1 inhibits myelination. Ephrin-A1 interacts with EphA4 to activate the ephexin1-RhoA-Rock-myosin 2 signaling cascade and causes inhibition of oligodendrocyte process extension...
May 2018: Glia
Zhiwei Qiao, Kumiko Shiozawa, Tadashi Kondo
Pazopanib, a multitarget tyrosine kinase (TK) inhibitor, has been approved for treatment of soft tissue sarcoma. Elucidation of the molecular background of pazopanib resistance should lead to improved clinical outcomes in sarcomas; accordingly, we investigated this in synovial sarcoma using a proteomic approach. Pazopanib sensitivity was examined in four synovial sarcoma cell lines: SYO-1, HS-SYII, 1273/99, and YaFuSS. The 1273/99 cell line showed significantly higher IC50 values than the others for pazopanib...
December 12, 2017: Oncotarget
Timothy Y Huang, Yingjun Zhao, Lu-Lin Jiang, Xiaoguang Li, Yan Liu, Yu Sun, Juan C Piña-Crespo, Bing Zhu, Eliezer Masliah, Thomas E Willnow, Elena B Pasquale, Huaxi Xu
Sortilin-related receptor with LDLR class A repeats (SORLA, SORL1, or LR11) is a genetic risk factor associated with Alzheimer's disease (AD). Although SORLA is known to regulate trafficking of the amyloid β (Aβ) precursor protein to decrease levels of proteotoxic Aβ oligomers, whether SORLA can counteract synaptic dysfunction induced by Aβ oligomers remains unclear. Here, we show that SORLA interacts with the EphA4 receptor tyrosine kinase and attenuates ephrinA1 ligand-induced EphA4 clustering and activation to limit downstream effects of EphA4 signaling in neurons...
December 4, 2017: Journal of Experimental Medicine
Ibrahim Y Hachim, Manuel Villatoro, Lucie Canaff, Mahmood Y Hachim, Julien Boudreault, Halema Haiub, Suhad Ali, Jean-Jacques Lebrun
Breast cancer consists of a range of tumor subtypes with different clinical characteristics, disease prognosis, and treatment-response. Luminal breast cancer has the best prognosis while basal-like breast cancer (BLBC) represents the worst subtype. Transforming growth factor-beta (TGFβ) plays a prominent role in stimulating the migration and invasion of malignant breast cancer cells contributing to tumor progression. In this study, we identified the Ephrin type-A receptor 4 (EPHA4) as a novel target of TGFβ in breast cancer...
November 3, 2017: Scientific Reports
Kuo-Tai Hua, Jin-Bong Hong, Yi-Shuan Sheen, Hsin-Yi Huang, Yi-Ling Huang, Jau-Shiuh Chen, Yi-Hua Liao
Increasing evidence suggests that there is a unique cell subpopulation in melanoma that can form nonadherent melanospheres in serum-free stem cell medium, mimicking aggressive malignancy. Using melanospheres as a model to investigate progression mechanisms, we found that miR-519d overexpression was sufficient to promote cell proliferation, migration, invasion, and adhesion in vitro and lung metastatic capability in vivo The cell adhesion receptor EphA4 was determined to be a direct target of miR-519d. Forced expression of EphA4 reversed the effects of miR-519d overexpression, whereas silencing of EphA4 phenocopied the effect of miR-519d...
January 1, 2018: Cancer Research
Jing Wang, Xiaoqian Leng, Guiping Wang, Xiaoyang Wan, Hong Cao
Intrahepatic cholangiocarcinoma (ICC) is a highly malignant tumor, difficult to diagnose even at an early stage. In this study, we successfully constructed an nras61K -induced ICC model in zebrafish. Transcriptome analysis and gene set enrichment analysis (GSEA) of liver samples of the ICC and WT (wild-type) zebrafish revealed that the genes differentially expressed between the two groups were mainly involved in focal adhesion, chemokine signaling and metabolic pathways. Analysis of DNA methylomes revealed that compared with WT samples, methylated genes in ICC samples were enriched in functions associated with cellular, single-organism and metabolic processes...
October 17, 2017: Scientific Reports
Tomonori Higuchi, Yumiko Hashida, Ayuko Taniguchi, Mikio Kamioka, Masanori Daibata
The genetic events that lead to aggressive transformation of cases of splenic marginal zone lymphoma (SMZL) after the chronic clinical stage have not been well understood. We aimed to find candidate genes associated with aggressive features of SMZL. We have successfully established two SMZL cell lines, designated SL-15 and SL-22, derived from the same patient's tumor clone in chronic and aggressive phases, respectively. Microarray analysis identified cell cycle-associated genes-specifically PLK1-as the most significantly upregulated in primary aggressive SMZL cells compared with cells from chronic phase...
September 8, 2017: Scientific Reports
Søren S L Andersen
How axons are wired in the vertebrate spinal cord has been studied mostly using fixed samples or looking at individually growing axons. Using light-sheet microscopy, early neural development is here followed in vivo in real time at high resolution along several hundred micrometers of the zebrafish spinal cord. The dynamics and time course of cellular development and axonal wiring of interneurons expressing GFP under control of the dmrt3 promotor are analyzed. Following neurulation, commissural axons are observed crossing the ventral floor plate midline perpendicularly at about 20 microns/h and in a manner dependent on the Robo3 but not the EphA4 receptors...
August 30, 2017: Journal of Comparative Neurology
Midori Mukai, Norihiko Suruga, Noritaka Saeki, Kazushige Ogawa
BACKGROUND: Eph signaling is known to induce contrasting cell behaviors such as promoting and inhibiting cell adhesion/spreading by altering F-actin organization and influencing integrin activities. We have previously demonstrated that EphA2 stimulation by ephrin-A1 promotes cell adhesion through interaction with integrins and integrin ligands in two monocyte/macrophage cell lines. Although mature mononuclear leukocytes express several members of the EphA/ephrin-A subclass, their expression has not been examined in monocytes undergoing during differentiation and maturation...
August 29, 2017: BMC Cell Biology
Hitendra S Solanki, Jayshree Advani, Aafaque Ahmad Khan, Aneesha Radhakrishnan, Nandini A Sahasrabuddhe, Sneha M Pinto, Xiaofei Chang, Thottethodi Subrahmanya Keshava Prasad, Premendu Prakash Mathur, David Sidransky, Harsha Gowda, Aditi Chatterjee
Proteomics analysis of chronic cigarette smoke exposure is a rapidly emerging postgenomics research field. While smoking is a major cause of lung cancer, functional studies using proteomics approaches could enrich our mechanistic understanding of the elusive lung cancer global molecular signaling and cigarette smoke relationship. We report in this study on a stable isotope labeling by amino acids in cell culture-based quantitative phosphoproteomic analysis of a human lung mucoepidermoid carcinoma cell line, H292 cells, chronically exposed to cigarette smoke...
August 2017: Omics: a Journal of Integrative Biology
Yilong Dong, Yang Liu, Aimei Jiang, Ruiqian Li, Min Yin, Yanmei Wang
MicroRNAs (miRNAs) are small noncoding RNAs that exert their functions by targeting specific mRNA sequences. Many studies have demonstrated that miRNAs are crucial for cancer progression, during which they can act as either oncogenes or tumor suppressors. Previous research has shown that miR-335 is downregulated in breast cancer, and it has been shown to be a breast cancer suppressor. In addition, emerging evidence indicates that erythropoietin-producing hepatocellular A4 (EphA4) is implicated in cancer cell proliferation, migration, and invasion...
February 2018: Molecular and Cellular Biochemistry
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