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https://www.readbyqxmd.com/read/27903608/progranulin-and-the-receptor-tyrosine-kinase-epha2-partners-in-crime
#1
Babykumari Chitramuthu, Andrew Bateman
Progranulin is a secreted protein with roles in tumorigenesis, inflammation, and neurobiology, but its signaling receptors have remained unclear. In this issue, Neill et al. (2016. J. Cell Biol https://doi.org/10.1083/jcb.201603079) identify the tyrosine kinase EphA2 as a strong candidate for such a receptor, providing insight into progranulin and EphA2 signaling.
December 5, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27903606/epha2-is-a-functional-receptor-for-the-growth-factor-progranulin
#2
Thomas Neill, Simone Buraschi, Atul Goyal, Catherine Sharpe, Elizabeth Natkanski, Liliana Schaefer, Andrea Morrione, Renato V Iozzo
Although the growth factor progranulin was discovered more than two decades ago, the functional receptor remains elusive. Here, we discovered that EphA2, a member of the large family of Ephrin receptor tyrosine kinases, is a functional signaling receptor for progranulin. Recombinant progranulin bound with high affinity to EphA2 in both solid phase and solution. Interaction of progranulin with EphA2 caused prolonged activation of the receptor, downstream stimulation of mitogen-activated protein kinase and Akt, and promotion of capillary morphogenesis...
December 5, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27882199/straightforward-glycoengineering-approach-to-site-specific-antibody-pyrrolobenzodiazepine-conjugates
#3
Pamela Thompson, Ebele Ezeadi, Ian Hutchinson, Ryan Fleming, Binyam Bezabeh, Jia Lin, Shenlan Mao, Cui Chen, Luke Masterson, Haihong Zhong, Dorin Toader, Philip Howard, Herren Wu, Changshou Gao, Nazzareno Dimasi
Antibody-drug conjugates (ADCs) have become a powerful platform to deliver cytotoxic agents selectively to cancer cells. ADCs have traditionally been prepared by stochastic conjugation of a cytotoxic drug using an antibody's native cysteine or lysine residues. Through strategic selection of the mammalian expression host, we were able to introduce azide-functionalized glycans onto a homogeneously glycosylated anti-EphA2 monoclonal antibody in one step. Conjugation with an alkyne-bearing pyrrolobenzodiazepine dimer payload (SG3364) using copper-catalyzed click chemistry yielded a site-specific ADC with a drug-to-antibody ratio (DAR) of four...
November 10, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27854239/kshv-entry-and-trafficking-in-target-cells-hijacking-of-cell-signal-pathways-actin-and-membrane-dynamics
#4
REVIEW
Binod Kumar, Bala Chandran
Kaposi's sarcoma associated herpesvirus (KSHV) is etiologically associated with human endothelial cell hyperplastic Kaposi's sarcoma and B-cell primary effusion lymphoma. KSHV infection of adherent endothelial and fibroblast cells are used as in vitro models for infection and KSHV enters these cells by host membrane bleb and actin mediated macropinocytosis or clathrin endocytosis pathways, respectively. Infection in endothelial and fibroblast cells is initiated by the interactions between multiple viral envelope glycoproteins and cell surface associated heparan sulfate (HS), integrins (α3β1, αVβ3 and αVβ5), and EphA2 receptor tyrosine kinase (EphA2R)...
November 14, 2016: Viruses
https://www.readbyqxmd.com/read/27854147/improving-the-developability-of-an-anti-epha2-single-chain-variable-fragment-for-nanoparticle-targeting
#5
Melissa L Geddie, Neeraj Kohli, Dmitri B Kirpotin, Maja Razlog, Yang Jiao, Tad Kornaga, Rachel Rennard, Lihui Xu, Birgit Schoerberl, James D Marks, Daryl C Drummond, Alexey A Lugovskoy
Antibody-targeted nanoparticles have great promise as anti-cancer drugs; however, substantial developmental challenges of antibody modules prevent many candidates from reaching the clinic. Here, we describe a robust strategy for developing an EphA2-targeting antibody fragment for immunoliposomal drug delivery. A highly bioactive single-chain variable fragment (scFv) was engineered to overcome developmental liabilities, including low thermostability and weak binding to affinity purification resins. Improved thermostability was achieved by modifying the framework of the scFv, and complementarity-determining region (CDR)-H2 was modified to increase binding to protein A resins...
November 17, 2016: MAbs
https://www.readbyqxmd.com/read/27851002/1366-clinical-implications-of-the-plasma-epha2-receptor-level-in-patients-with-sepsis
#6
Kyung Soo Chung, Chi Young Kim, Su Hwan Lee, Se Kyu Kim, Joon Chang, Youngsam Kim
No abstract text is available yet for this article.
December 2016: Critical Care Medicine
https://www.readbyqxmd.com/read/27850642/1004-the-effect-of-blocking-epha2-ephrina1-pathway-in-hyperoxia-induced-lung-injury
#7
Kyung Soo Chung, Chi Young Kim, Ju Hye Shin, Moo Suk Park, Se Kyu Kim, Joon Chang, Youngsam Kim
No abstract text is available yet for this article.
December 2016: Critical Care Medicine
https://www.readbyqxmd.com/read/27815408/epha2-proteomics-in-human-keratinocytes-reveals-a-novel-association-with-afadin-and-epidermal-tight-junctions
#8
Bethany E Perez White, Rosa Ventrella, Nihal Kaplan, Calvin J Cable, Paul M Thomas, Spiro Getsios
EphA2 is a receptor tyrosine kinase that helps maintain epidermal tissue homeostasis. A BioID approach was used to identify proteins in close proximity to EphA2 in primary human keratinocytes and 3-D reconstituted human epidermis cultures to map a putative protein interaction network for this membrane receptor that exhibits a polarized distribution in stratified epithelia. While a subset of known EphA2 interactors were identified in the BioID screen, >97% were uniquely detected in keratinocytes with over 50% of these vicinal proteins only present in 3-D human epidermal culture...
November 4, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27804871/the-sam-domain-of-epha2-receptor-and-its-relevance-to-cancer-a-novel-challenge-for-drug-discovery
#9
Flavia Mercurio, Marilisa Leone
BACKGROUND: Eph receptors play important functions in developmental processes and diseases and among them EphA2 is well known for its controversial role in cancer. Drug discovery strategies are mainly centered on EphA2 extracellular ligand-binding domain however, the receptor also contains a largely unexplored cytosolic Sam (Sterile alpha motif) domain at the C-terminus. EphA2-Sam binds the Sam domain from the lipid phosphatase Ship2 and the first Sam domain of Odin. Sam-Sam interactions may be important to regulate ligand-induced receptor endocytosis and degradation i...
November 1, 2016: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/27802842/defective-anks1a-disrupts-the-export-of-receptor-tyrosine-kinases-from-the-endoplasmic-reticulum
#10
Soochul Park
EphA2 has been implicated in amplifying ErbB2 tumorigenic signaling. One protein that interacts with EphA2 is Anks1a PTB adaptor. However, the precise role of Anks1a in EphA2-mediated tumorigenesis is unclear. We demonstrated that Anks1a localizes to the ER upon phosphorylation and that the ankyrin repeats and PTB of Anks1a bind to EphA2 and Sec23, respectively. Thus, Anks1a facilitates the selective packaging of EphA2 into COPII vesicles. Additionally, Anks1a knock-out mice, a phenocopy of EphA2 knock-out mice, exhibited markedly reduced ErbB2-induced breast tumorigenesis...
November 2, 2016: BMB Reports
https://www.readbyqxmd.com/read/27776928/the-sam-domain-inhibits-epha2-interactions-in-the-plasma-membrane
#11
Deo R Singh, Fozia Ahmed, Michael D Paul, Manasee Gedam, Elena B Pasquale, Kalina Hristova
All members of the Eph receptor family of tyrosine kinases contain a SAM domain near the C terminus, which has been proposed to play a role in receptor homotypic interactions and/or interactions with binding partners. The SAM domain of EphA2 is known to be important for receptor function, but its contribution to EphA2 lateral interactions in the plasma membrane has not been determined. Here we use a FRET-based approach to directly measure the effect of the SAM domain on the stability of EphA2 dimers on the cell surface in the absence of ligand binding...
October 21, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27768280/chemical-proteomics-and-structural-biology-define-epha2-inhibition-by-clinical-kinase-drugs
#12
Stephanie Heinzlmeir, Denis Kudlinzki, Sridhar Sreeramulu, Susan Klaeger, Santosh Lakshmi Gande, Verena Linhard, Mathias Wilhelm, Huichao Qiao, Dominic Helm, Benjamin Ruprecht, Krishna Saxena, Guillaume Médard, Harald Schwalbe, Bernhard Kuster
The receptor tyrosine kinase EPHA2 (Ephrin type-A receptor 2) plays important roles in oncogenesis, metastasis and treatment resistance yet therapeutic targeting, drug discovery or investigation of EPHA2 biology is hampered by the lack of appropriate inhibitors and structural information. Here, we used chemical proteomics to survey 235 clinical kinase inhibitors for their kinase selectivity and identified 24 drugs with sub-micromolar affinities for EPHA2. NMR-based conformational dynamics together with nine new co-crystal structures delineated drug-EPHA2 interactions in full detail...
October 21, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27763725/targeting-epha2-sam-and-its-interactome-design-and-evaluation-of-helical-peptides-enriched-in-charged-residues
#13
Flavia A Mercurio, Daniela Marasco, Concetta Di Natale, Luciano Pirone, Susan Costantini, Emilia M Pedone, Marilisa Leone
The EphA2 receptor controls diverse physiological and pathological conditions and its levels are often upregulated in cancer. Targeting receptor overexpression, through modulation of endocytosis and consequent degradation, appears to be an appealing strategy for attacking tumor malignancy. In this scenario, the Sam domain of EphA2 plays a pivotal role because it is the site where protein regulators of endocytosis and stability are recruited by means of heterotypic Sam-Sam interactions. Because EphA2-Sam heterotypic complexes are largely based on electrostatic contacts, we have investigated the possibility of attacking these interactions with helical peptides enriched in charged residues...
October 20, 2016: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/27746866/mir-26b-enhances-radiosensitivity-of-hepatocellular-carcinoma-cells-by-targeting-epha2
#14
Qiao Jin, Xiang Jun Li, Pei Guo Cao
OBJECTIVES: Although low-dose radiotherapy (RT) that involves low collateral damage is more suitable for hepatocellular carcinoma (HCC) than traditional high-dose RT, but to achieve satisfactory therapeutic effect with low-dose RT, it is necessary to sensitize HCC cells to irradiation. This study was aimed to determine whether radiosensitivity of HCC cells can be enhanced using miR-26b by targeting erythropoietin producing human hepatocelluar A2 (EphA2). MATERIALS AND METHODS: The levels of miR-26b and EphA2 expression in multiple HCC cell lines were assessed by qPCR and western blotting, respectively, and compared with those in a hepatic cell line...
August 2016: Iranian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/27742560/regulation-of-endothelial-migration-and-proliferation-by-ephrin-a1
#15
Elisa Wiedemann, Stefanie Jellinghaus, Georg Ende, Antje Augstein, Ronny Sczech, Ben Wielockx, Sönke Weinert, Ruth H Strasser, David M Poitz
Endothelial migration and proliferation are fundamental processes in angiogenesis and wound healing of injured or inflamed vessels. The present study aimed to investigate the regulation of the Eph/ephrin-system during endothelial proliferation and the impact of the ligand ephrin-A1 on proliferation and migration of human umbilical venous (HUVEC) and arterial endothelial cells (HUAEC). Endothelial cells that underwent contact inhibition showed a massive induction of ephrin-A1. In contrast, an injury to a confluent endothelial layer, associated with induction of migration and proliferation, showed reduced ephrin-A1 levels...
October 11, 2016: Cellular Signalling
https://www.readbyqxmd.com/read/27733379/tspan8-expression-distinguishes-spermatogonial-stem-cells-in-the-prepubertal-mouse-testis
#16
Kazadi Mutoji, Anukriti Singh, Thu Nguyen, Heidi Gildersleeve, Amy V Kaucher, Melissa J Oatley, Jon M Oatley, Ellen K Velte, Christopher B Geyer, Keren Cheng, John R McCarrey, Brian P Hermann
Precise separation of spermatogonial stem cells (SSCs) from progenitor spermatogonia that lack stem cell activity and are committed to differentiation remains a challenge. To distinguish between these spermatogonial subtypes, we identified genes that exhibited bimodal mRNA levels at the single-cell level among undifferentiated spermatogonia from Postnatal Day 6 mouse testes, including Tspan8, Epha2, and Pvr, each of which encode cell surface proteins useful for cell selection. Transplantation studies provided definitive evidence that a TSPAN8-high subpopulation is enriched for SSCs...
December 2016: Biology of Reproduction
https://www.readbyqxmd.com/read/27725905/microrna-302b-targets-mcl-1-and-inhibits-cell-proliferation-and-induces-apoptosis-in-malignant-pleural-mesothelioma-cells
#17
Nazli Khodayari, Kamal A Mohammed, Hungyen Lee, Frederick Kaye, Najmunnisa Nasreen
MicroRNAs belonging to the miR-302 family are emerging as key players in the control of cell growth, and maintaining pluripotency during cell fate determination and differentiation in embryonic stem cells. However, the mechanisms whereby ephA2/ephirnA1 signaling regulates miR-302b expression and attenuates malignant pleural mesothelioma (MPM) cell growth are not known. Our study identified a novel mechanism of ephrin-A1 mediated anti-oncogenic signaling in MPM. Ephrin-A1 treatment up regulates miR-302b expression in MPM cells and attenuates cell proliferation and tumorsphere formation via repression of myeloid cell leukemia-1 (Mcl-1)...
2016: American Journal of Cancer Research
https://www.readbyqxmd.com/read/27715394/orphan-g-protein-coupled-receptor-gprc5a-modulates-integrin-%C3%AE-1-mediated-epithelial-cell-adhesion
#18
Daria R Bulanova, Yevhen A Akimov, Anne Rokka, Teemu D Laajala, Tero Aittokallio, Petri Kouvonen, Teijo Pellinen, Sergey G Kuznetsov
G-Protein Coupled Receptor (GPCR), Class C, Group 5, Member A (GPRC5A) has been implicated in several malignancies. The underlying mechanisms, however, remain poorly understood. Using a panel of human cell lines, we demonstrate that CRISPR/Cas9-mediated knockout and RNAi-mediated depletion of GPRC5A impairs cell adhesion to integrin substrates: collagens I and IV, fibronectin, as well as to extracellular matrix proteins derived from the Engelbreth-Holm-Swarm (EHS) mouse sarcoma (Matrigel). Consistent with the phenotype, knock-out of GPRC5A correlated with a reduced integrin β1 (ITGB1) protein expression, impaired phosphorylation of the focal adhesion kinase (FAK), and lower activity of small GTPases RhoA and Rac1...
October 7, 2016: Cell Adhesion & Migration
https://www.readbyqxmd.com/read/27685543/expression-and-purification-of-epha2-tyrosine-kinase-domain-for-crystallographic-and-nmr-studies
#19
Santosh L Gande, Krishna Saxena, Sridhar Sreeramulu, Verena Linhard, Denis Kudlinzki, Stephanie Heinzlmeir, Andreas J Reichert, Arne Skerra, Bernhard Kuster, Harald Schwalbe
The receptor tyrosine kinase EPHA2 is overexpressed in several cancers (breast, head and neck, non-small-cell lung cancer). Small-molecule-based inhibition of the EPHA2 kinase domain (KD) is seen as an important strategy for therapeutic intervention. However, obtaining structural information by crystallography or NMR spectroscopy for drug discovery is severely hampered by the lack of pure, homogeneous protein. Here, different fragments of the EPHA2 KD were expressed and purified from both bacterial (Escherichia coli, BL21(DE3) cells) and insect cells (Spodoptera frugiperda, Sf9 cells)...
September 29, 2016: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/27681698/association-between-polymorphisms-of-ogg1-epha2-and-age-related-cataract-risk-a-meta-analysis
#20
Hongxu Zhang, Jianguang Zhong, Zhenyu Bian, Xiang Fang, You Peng, Yongping Hu
BACKGROUND: Evidences have identified the correlation of 8-oxoguanine DNA glycosylase-1 (OGG1) and eph-receptor tyrosine kinase-type A2 (EPHA2) polymorphisms in age-related cataract (ARC) risk. However, the results were not consistent. The objective of this study was to examine the role of these two gene polymorphisms in ARC susceptibility. METHODS: Eligible case-control studies published between January 2000 and 2015 were searched and retrieved in the electronic databases...
September 29, 2016: BMC Ophthalmology
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