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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
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
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
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
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
Kazadi Mutoji, Anukriti Singh, Thu Nguyen, Heidi Gildersleeve, Amy V Kaucher, Melissa J Oatley, Jon M Oatley, Ellen K Velte, Chris 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 the Postnatal Day 6 (P6) mouse testis, 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...
October 12, 2016: Biology of Reproduction
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
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
Santosh Lakshmi 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 cancer entities (breast, head and neck, non-small cell lung cancer). Small molecule-based inhibition of the activity of the EPHA2 kinase domain (KD) has been seen as an important strategy for achieving therapeutic intervention. However, obtaining structural information by protein crystallography or by NMR spectroscopy aiding drug discovery, has been severely hampered due to the lack of pure and 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
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
S U Din, H Ashamalla, K S T Gilbert, L M Graves, P R Graves
No abstract text is available yet for this article.
October 1, 2016: International Journal of Radiation Oncology, Biology, Physics
Naoko Konda, Noritaka Saeki, Shingo Nishino, Kazushige Ogawa
We previously established a J774.1 monocyte/macrophage subline expressing a truncated EphA2 construct lacking the kinase domain. We demonstrated that following ephrin-A1 stimulation, endogenous EphA2 promotes cell adhesion through interaction with integrins and integrin ligands such as ICAM1 and that truncated EphA2 potentiates the adhesion and becomes associated with the integrin/integrin ligand complex. Based on these findings, we hypothesized that the EphA/ephrin-A system, particularly EphA2/ephrin-A1, regulates transendothelial migration/tissue infiltration of monocytes/macrophages, because ephrin-A1 is widely recognized to be upregulated in inflammatory vasculatures...
September 24, 2016: Histochemistry and Cell Biology
Jianwen Zhao, Fengfeng Zhao, Xiyong Wang, Xiaobo Fan, Guoqiu Wu
A novel multifunctional nano-drug delivery system based on reversal of peptide charge was successfully developed for anticancer drug delivery and imaging. Mesoporous silica nano-particles (MSN) ~50 nm in diameter were chosen as the drug reservoirs, and their surfaces were modified with HIV-1 transactivator peptide-fluorescein isothiocyanate (TAT-FITC) and YSA-BHQ1. The short TAT peptide labeled with FITC was used to facilitate intranuclear delivery, while the YSA peptide tagged with the BHQ1 quencher group was used to specifically bind to the tumor EphA2 membrane receptor...
September 20, 2016: Oncotarget
Ian F Pollack, Regina I Jakacki, Lisa H Butterfield, Ronald L Hamilton, Ashok Panigrahy, Daniel P Normolle, Angela K Connelly, Sharon Dibridge, Gary Mason, Theresa L Whiteside, Hideho Okada
Recurrent high-grade gliomas (HGGs) of childhood have an exceedingly poor prognosis with current therapies. Accordingly, new treatment approaches are needed. We initiated a pilot trial of vaccinations with peptide epitopes derived from glioma-associated antigens (GAAs) overexpressed in these tumors in HLA-A2+ children with recurrent HGG that had progressed after prior treatments. Peptide epitopes for three GAAs (EphA2, IL13Rα2, survivin), emulsified in Montanide-ISA-51, were administered subcutaneously adjacent to intramuscular injections of poly-ICLC every 3 weeks for 8 courses, followed by booster vaccines every 6 weeks...
September 13, 2016: Journal of Neuro-oncology
Erik Ladomersky, Matthew Genet, Lijie Zhai, Galina Gritsina, Kristen L Lauing, Rishi R Lulla, Jason Fangusaro, Alicia Lenzen, Priya Kumthekar, Jeffrey J Raizer, David C Binder, C David James, Derek A Wainwright
The effective treatment of adult and pediatric malignant glioma is a significant clinical challenge. In adults, glioblastoma (GBM) accounts for the majority of malignant glioma diagnoses with a median survival of 14.6 mo. In children, malignant glioma accounts for 20% of primary CNS tumors with a median survival of less than 1 y. Here, we discuss vaccine treatment for children diagnosed with malignant glioma, through targeting EphA2, IL-13Rα2 and/or histone H3 K27M, while in adults, treatments with RINTEGA, Prophage Series G-100 and dendritic cells are explored...
August 2016: Oncoimmunology
Haeryung Lee, Hyuna Noh, Jiyoung Mun, Changkyu Gu, Sanja Sever, Soochul Park
ErbB2 signalling, which is amplified by EphA2 binding, is an important therapeutic target for breast cancer. Despite the importance of the EphA2/ErbB2 complex in promoting breast tumorigenesis, the mechanism by which these receptor tyrosine kinases (RTKs) are exported from the endoplasmic reticulum (ER) remains poorly understood. Here we report that the PTB adaptor Anks1a is specifically localized to the ER on its own serine phosphorylation. Once there, Anks1a acts as an important regulator of COPII-mediated EphA2 ER export...
2016: Nature Communications
Jingxin Zhang, Lili Qiao, Ning Liang, Jian Xie, Hui Luo, Guodong Deng, Jiandong Zhang
Vasculogenic mimicry (VM), a microvascular channel made up of nonendothelial cells, has been accepted as a new model of neovascularization in aggressive tumors, owning to the specific capacity of malignant cells to form vessel-like networks which provide sufficient blood supply for tumor growth. Multiple molecular mechanisms, especially vascular endothelial (VE)-cadherin, erythropoietin-producing hepatocellular receptor A2 (EphA2), phosphatidyl inositol 3-kinase (PI3K), matrix metalloproteinases (MMPs), vascular endothelial growth factor receptor (VEGFR1), and hypoxia inducible factor (HIF)-1a, have been reported to participate in VM formation which is associated with tumor migration and invasion...
May 2016: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
Laura Dominguez, Leigh Foster, John E Straub, D Thirumalai
Cleavage of the amyloid precursor protein (APP) by γ-secretase is a crucial first step in the evolution of Alzheimer's disease. To discover the cleavage mechanism, it is urgent to predict the structures of APP monomers and dimers in varying membrane environments. We determined the structures of the C9923-55 monomer and homodimer as a function of membrane lipid composition using a multiscale simulation approach that blends atomistic and coarse-grained models. We demonstrate that the C9923-55 homodimer structures form a heterogeneous ensemble with multiple conformational states, each stabilized by characteristic interpeptide interactions...
September 6, 2016: Proceedings of the National Academy of Sciences of the United States of America
Ji Young Hong, Mi Hwa Shin, Ivor S Douglas, Kyung Soo Chung, Eun Young Kim, Ji Ye Jung, Young Ae Kang, Se Kyu Kim, Joon Chang, Young Sam Kim, Moo Suk Park
Eph-Ephrin signalling mediates various cellular processes, including vasculogenesis, angiogenesis, cell migration, axon guidance, fluid homoeostasis and repair after injury. Although previous studies have demonstrated that stimulation of the EphA receptor induces increased vascular permeability and inflammatory response in lung injury, the detailed mechanisms of EphA2 signalling are unknown. In the present study, we evaluated the role of EphA2 signalling in mice with lipopolysaccharide (LPS)-induced lung injury...
November 1, 2016: Clinical Science (1979-)
Ghazal Efazat, Metka Novak, Vitaliy O Kaminskyy, Luigi De Petris, Lena Kanter, Therese Juntti, Per Bergman, Boris Zhivotovsky, Rolf Lewensohn, Petra Hååg, Kristina Viktorsson
Ephrin receptors (Ephs) are reported to control metastatic signaling of non-small cell lung cancer (NSCLC) and other tumors. Here we show for the first time that blocking expression of the Eph ligand Ephrin B3 inhibits NSCLC cell migration and invasion. We demonstrate that Ephrin B3 directly binds the EphAs EphA2, EphA3, EphA4, and EphA5. EphA2 Ser897 was previously shown to drive migration propensity of tumor cells and our study reveals that EphA2 stays phosphorylated on Ser897 in the Ephrin B3/EphA2 complex in NSCLC cells of different histology...
August 11, 2016: Oncotarget
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