Expression and Function of the Eph Receptor
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Targeting Synthetic Lethality Between the SRC Kinase and the EPHB6 Receptor May Benefit Cancer Treatment
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 31 Research Paper Targeting synthetic lethality between the SRC kinase and the EPHB6 receptor may benefit cancer treatment James M. Paul1,*, Behzad Toosi2,*, Frederick S. Vizeacoumar2,*, Kalpana Kalyanasundaram Bhanumathy2, Yue Li3,4,5, Courtney Gerger2, Amr El Zawily2,6, Tanya Freywald7, Deborah H. Anderson7, Darrell Mousseau8, Rani Kanthan2, Zhaolei Zhang3,4, Franco J. Vizeacoumar2,7, Andrew Freywald2 1Department of Biochemistry, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada 2Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Royal University Hospital, Saskatoon, SK, S7N 0W8, Canada 3Department of Computer Science, University of Toronto, Toronto, ON, M5S 3G4, Canada 4The Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada 5Present address: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA 6Faculty of Science, Damanhour University, Damanhour, 22516, Egypt 7Cancer Research, Saskatchewan Cancer Agency, Saskatoon, SK, S7N 5E5, Canada 8Cell Signaling Laboratory, Neuroscience Cluster, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada *These authors contributed equally to this work Correspondence to: Franco J. Vizeacoumar, email: [email protected] Andrew Freywald, email: [email protected] Keywords: breast cancer, genetic interaction, synthetic lethality, EPHB6, SRC kinase Received: April 22, 2016 Accepted: June 17, 2016 Published: July 13, 2016 ABSTRACT Application of tumor genome sequencing has identified numerous loss-of-function alterations in cancer cells. While these alterations are difficult to target using direct interventions, they may be attacked with the help of the synthetic lethality (SL) approach. In this approach, inhibition of one gene causes lethality only when another gene is also completely or partially inactivated. -
Ephrin-A4/Fc Chimera Human
EPHRIN-A4 EXTRACELLULAR DOMAIN/FC CHIMERA Human, Recombinant Expressed in NSO mouse myeloma cells Product Number E 0403 Storage Temperature –20 °C Synonyms: LERK-4; EFL-4 Reagents Recombinant human Ephrin-A4 extracellular domain/Fc Product Description chimera is supplied as approximately 200 mg of protein Recombinant human Ephrin-A4 extracellular domain/Fc lyophilized from a sterile-filtered phosphate-buffered chimera consists of amino acid residues 1-171 saline (PBS) solution. 1 (extracellular domain of human Ephrin-A4) that was fused by means of a polypeptide linker to the Fc portion Preparation Instructions of human IgG1 that is 6X histidine-tagged at the Reconstitute the vial contents with sterile PBS. carboxyl terminus. The chimeric protein is expressed in Stock solution concentration should be no less than a mouse myeloma cell line, NSO. Recombinant Ephrin 100 µg/ml. A4 is a disulfide-linked homodimer. The amino terminus is Leu 26 determined by N-terminal Storage/Stability sequencing. The calculated molecular mass of the Lyophilized samples are stable for greater than six reduced protein is approximately 43.7 kDa, but as a months at –20 °C. Upon reconstitution, store at 2-4 °C result of glycosylation, the recombinant Ephrin-A4/Fc for up to one month. For extended storage, store in migrates as an approximately 50 kDa protein on working aliquots at –20 °C. Repeated freeze-thaw reducing SDS -PAGE. cycles should be avoided. Do not store in frost-free freezer. The Ephrin ligand family, of which Ephrin-A4 is a member, binds members of the Eph receptor family. All Product Profile ligands share a conserved extracellular sequence, Identity of Ephrin-A4/Fc was determined by western thought to correspond to the receptor binding domain. -
Epha Receptors and Ephrin-A Ligands Are Upregulated by Monocytic
Mukai et al. BMC Cell Biology (2017) 18:28 DOI 10.1186/s12860-017-0144-x RESEARCHARTICLE Open Access EphA receptors and ephrin-A ligands are upregulated by monocytic differentiation/ maturation and promote cell adhesion and protrusion formation in HL60 monocytes Midori Mukai, Norihiko Suruga, Noritaka Saeki and Kazushige Ogawa* Abstract 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. Results: Using RT-PCR, we have shown that EphA2, ephrin-A1, and ephrin-A2 expression was upregulated in murine bone marrow mononuclear cells during monocyte maturation. Moreover, EphA2 and EphA4 expression was induced, and ephrin-A4 expression was upregulated, in a human promyelocytic leukemia cell line, HL60, along with monocyte differentiation toward the classical CD14++CD16− monocyte subset. Using RT-PCR and flow cytometry, we have also shown that expression levels of αL, αM, αX, and β2 integrin subunits were upregulated in HL60 cells along with monocyte differentiation while those of α4, α5, α6, and β1 subunits were unchanged. Using a cell attachment stripe assay, we have shown that stimulation by EphA as well as ephrin-A, likely promoted adhesion to an integrin ligand- coated surface in HL60 monocytes. Moreover, EphA and ephrin-A stimulation likely promoted the formation of protrusions in HL60 monocytes. -
Patents Related to EPH Receptors and Ligands
NEWS & ANALYSIS discuss EPH receptor–ephrin signalling Patents related to EPH receptors and its role in disorders such as tumour and ligands growth and progression, nerve injury and inflammation, and highlight therapeutic EPH receptors are a family of receptor approaches that are currently under tyrosine kinases that, together with their investigation. Here in TABLE 1 we highlight ligands, are involved in cell positioning, patent applications published in the past tissue and organ patterning as well as the 3 years related to EPH receptors and ligands. control of cell survival. In their Review Data were researched using the Espacenet on page 39, Lackman and colleagues database. Table 1 | Recent patent applications related to EPH receptors and ligands Nature Reviews | Drug Discovery Publication Applicants Subject numbers NZ 581397 AstraZeneca Pyrimidine compounds that inhibit EPH receptors and are useful for treating cancer HK 1108702 Sanford-Burnham Peptides that selectively bind to EPH type-B receptors (EPHBs); useful for tumour imaging and the Institute treatment of neoplastic disease, neurological disease and vascular disease US 2013091591 California Institute of During angiogenesis, arterial cells express ephrin B2, and its receptor EPHB4 is expressed on venous Technology cells; this distinction can be used in methods to alter angiogenesis and to assess the effect of drugs WO 2013052710 Expression Pathology Selected reaction monitoring mass spectrometry-based and multiple reaction monitoring mass spectrometry-based assays for quantifying -
The Kinase Defective EPHB6 Receptor Tyrosine Kinase Activates MAP Kinase Signaling in Lung Adenocarcinoma
175-179.qxd 29/5/2009 01:21 ÌÌ ™ÂÏ›‰·175 INTERNATIONAL JOURNAL OF ONCOLOGY 35: 175-179, 2009 175 The kinase defective EPHB6 receptor tyrosine kinase activates MAP kinase signaling in lung adenocarcinoma JUN YU1,2, ETMAR BULK1, PING JI1, ANTJE HASCHER1, STEFFEN KOSCHMIEDER1, WOLFGANG E. BERDEL1 and CARSTEN MÜLLER-TIDOW1 1Department of Medicine, Hematology and Oncology, University of Münster, Münster, Germany; 2Department of Preclinical Experiment Center, Fourth Military Medical University, Xi'an, P.R. China Received January 28, 2009; Accepted March 13, 2009 DOI: 10.3892/ijo_00000326 Abstract. Decreased expression levels of EPHB6, a member Elk-1 (8,9). ERK1/2 are negatively regulated by a family of of the receptor tyrosine kinases (RTKs), are associated with dual-specificity (Thr/Tyr) MAPK phosphatases, known as an increased risk of metastasis development in early stage DUSPs or MKPs, and pharmacologically by MEK inhibitors non-small cell lung cancer (NSCLC). However, the signaling such as U0126 and PD98059 (10). properties of the kinase-defective EPHB6 receptor are not EPH receptors form the largest known subfamily of well-understood. Here, we show that expression of EPHB6 receptor tyrosine kinases, and to date, the EPH subfamily in A549 lung adenocarinoma cells led to phosphorylation of contains 16 members in vertebrates (11,12). The EPH receptors the MAP kinase ERK. Conversely, siRNA based knockdown interact with a family of ligands located on the surfaces of of EPHB6 reversed ERK phosphorylation. Intriguingly, adjacent cells, named Ephrins including Ephrin-As and EPHB6-induced phosphorylation of ERK was uncoupled Ephrin-Bs subgroups. The EPH receptors are also grouped by activation of the Elk-1 transcriptional factor. -
A Review of VEGF/VEGFR-Targeted Therapeutics for Recurrent Glioblastoma
414 Original Article A Review of VEGF/VEGFR-Targeted Therapeutics for Recurrent Glioblastoma David A. Reardon, MDa,b; Scott Turner, MDc; Katherine B. Peters, MD, PhDc; Annick Desjardins, MDc; Sridharan Gururangan, MDa,b; John H. Sampson, MD, PhDa; Roger E. McLendon, MDd; James E. Herndon II, PhDe; Lee W. Jones, PhDf; John P. Kirkpatrick, MD, PhDf; Allan H. Friedman, MDa; James J. Vredenburgh, MDc; Darell D. Bigner, MD, PhDd; and Henry S. Friedman, MDa,b; Durham, North Carolina Key Words ability effect of VEGF inhibitors, the Radiologic Assessment in Neu- Glioblastoma, angiogenesis, vascular endothelial growth factor, ro-Oncology (RANO) criteria were recently implemented to bet- malignant glioma ter assess response among patients with glioblastoma. Although bevacizumab improves survival and quality of life, eventual tumor progression is the norm. Better understanding of resistance mech- Abstract anisms to VEGF inhibitors and identification of effective therapy Glioblastoma, the most common primary malignant brain tumor after bevacizumab progression are currently a critical need for pa- among adults, is a highly angiogenic and deadly tumor. Angiogen- tients with glioblastoma. (JNCCN 2011;9:414–427) esis in glioblastoma, driven by hypoxia-dependent and indepen- dent mechanisms, is primarily mediated by vascular endothelial growth factor (VEGF), and generates blood vessels with distinctive features. The outcome for patients with recurrent glioblastoma is poor because of ineffective therapies. However, recent encourag- ing rates of radiographic response and progression-free survival, Malignant gliomas, including the most common sub- and adequate safety, led the FDA to grant accelerated approval of type of glioblastoma, are rapidly growing destructive tu- bevacizumab, a humanized monoclonal antibody against VEGF, for mors that extensively invade locally but rarely metasta- the treatment of recurrent glioblastoma in May 2009. -
Ephb3 Suppresses Non-Small-Cell Lung Cancer Metastasis Via a PP2A/RACK1/Akt Signalling Complex
ARTICLE Received 7 Nov 2011 | Accepted 11 Jan 2012 | Published 7 Feb 2012 DOI: 10.1038/ncomms1675 EphB3 suppresses non-small-cell lung cancer metastasis via a PP2A/RACK1/Akt signalling complex Guo Li1, Xiao-Dan Ji1, Hong Gao1, Jiang-Sha Zhao1, Jun-Feng Xu1, Zhi-Jian Sun1, Yue-Zhen Deng1, Shuo Shi1, Yu-Xiong Feng1, Yin-Qiu Zhu1, Tao Wang2, Jing-Jing Li1 & Dong Xie1 Eph receptors are implicated in regulating the malignant progression of cancer. Here we find that despite overexpression of EphB3 in human non-small-cell lung cancer, as reported previously, the expression of its cognate ligands, either ephrin-B1 or ephrin-B2, is significantly downregulated, leading to reduced tyrosine phosphorylation of EphB3. Forced activation of EphB3 kinase in EphB3-overexpressing non-small-cell lung cancer cells inhibits cell migratory capability in vitro as well as metastatic seeding in vivo. Furthermore, we identify a novel EphB3-binding protein, the receptor for activated C-kinase 1, which mediates the assembly of a ternary signal complex comprising protein phosphatase 2A, Akt and itself in response to EphB3 activation, leading to reduced Akt phosphorylation and subsequent inhibition of cell migration. Our study reveals a novel tumour-suppressive signalling pathway associated with kinase-activated EphB3 in non-small-cell lung cancer, and provides a potential therapeutic strategy by activating EphB3 signalling, thus inhibiting tumour metastasis. 1 Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of Chinese Academy of Sciences, Shanghai 200031, China. 2 The Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai 200433, China. -
Profiling Data
Compound Name DiscoveRx Gene Symbol Entrez Gene Percent Compound Symbol Control Concentration (nM) JNK-IN-8 AAK1 AAK1 69 1000 JNK-IN-8 ABL1(E255K)-phosphorylated ABL1 100 1000 JNK-IN-8 ABL1(F317I)-nonphosphorylated ABL1 87 1000 JNK-IN-8 ABL1(F317I)-phosphorylated ABL1 100 1000 JNK-IN-8 ABL1(F317L)-nonphosphorylated ABL1 65 1000 JNK-IN-8 ABL1(F317L)-phosphorylated ABL1 61 1000 JNK-IN-8 ABL1(H396P)-nonphosphorylated ABL1 42 1000 JNK-IN-8 ABL1(H396P)-phosphorylated ABL1 60 1000 JNK-IN-8 ABL1(M351T)-phosphorylated ABL1 81 1000 JNK-IN-8 ABL1(Q252H)-nonphosphorylated ABL1 100 1000 JNK-IN-8 ABL1(Q252H)-phosphorylated ABL1 56 1000 JNK-IN-8 ABL1(T315I)-nonphosphorylated ABL1 100 1000 JNK-IN-8 ABL1(T315I)-phosphorylated ABL1 92 1000 JNK-IN-8 ABL1(Y253F)-phosphorylated ABL1 71 1000 JNK-IN-8 ABL1-nonphosphorylated ABL1 97 1000 JNK-IN-8 ABL1-phosphorylated ABL1 100 1000 JNK-IN-8 ABL2 ABL2 97 1000 JNK-IN-8 ACVR1 ACVR1 100 1000 JNK-IN-8 ACVR1B ACVR1B 88 1000 JNK-IN-8 ACVR2A ACVR2A 100 1000 JNK-IN-8 ACVR2B ACVR2B 100 1000 JNK-IN-8 ACVRL1 ACVRL1 96 1000 JNK-IN-8 ADCK3 CABC1 100 1000 JNK-IN-8 ADCK4 ADCK4 93 1000 JNK-IN-8 AKT1 AKT1 100 1000 JNK-IN-8 AKT2 AKT2 100 1000 JNK-IN-8 AKT3 AKT3 100 1000 JNK-IN-8 ALK ALK 85 1000 JNK-IN-8 AMPK-alpha1 PRKAA1 100 1000 JNK-IN-8 AMPK-alpha2 PRKAA2 84 1000 JNK-IN-8 ANKK1 ANKK1 75 1000 JNK-IN-8 ARK5 NUAK1 100 1000 JNK-IN-8 ASK1 MAP3K5 100 1000 JNK-IN-8 ASK2 MAP3K6 93 1000 JNK-IN-8 AURKA AURKA 100 1000 JNK-IN-8 AURKA AURKA 84 1000 JNK-IN-8 AURKB AURKB 83 1000 JNK-IN-8 AURKB AURKB 96 1000 JNK-IN-8 AURKC AURKC 95 1000 JNK-IN-8 -
Supplemental Material 1
Supplemental Fig. 1 12 1mg/ml A1AT p<0.001 10 8 p=0.004 6 p=0.029 (fold change) 4 mRNA ofmRNA angptl4 at h 1 2 0 Control Prolastin Aralast A1AT Sigma Supplemental Figure 1. Adherent PBMCs were incubated with 1 mg/ml A1AT from different sources (Prolastin, Grifols; Aralast, Baxter; or Sigma Aldrich) for 1h and mRNA levels of angplt4 were determined by RT-PCR. Bars represent the mean ± SD of four experiments. Supplemental Fig. 2 12 8 h p=0.005 10 8 6 mRNA angplt4 mRNA change Fold 4 2 0 Control A1AT 0.5 mg/ml Supplemental Figure 2. HMVEC-L were incubated with 0.5 mg/ml A1AT (Calbiochem) for 8 h and mRNA levels of angptl4 were determined by RT-PCR. Bars represent the mean ± SEM of three experiments. Supplemental Table I. Influence of A1AT (1 mg/ml, 8 h) on expression of angiogenesis genesa in HMVEC-L Unigene Symbol Description Gname fold changeb Hs.525622 AKT1 V-akt murine thymoma viral AKT/MGC99656/PKB/PKB- 0,94 0,14 oncogene homolog 1 ALPHA/PRKBA/RAC/RAC- ALPHA Hs.369675 ANGPT1 Angiopoietin 1 AGP1/AGPT/ANG1 3,61 5,11 Hs.583870 ANGPT2 Angiopoietin 2 AGPT2/ANG2 0,98 0,01 Hs.209153 ANGPTL3 Angiopoietin-like 3 ANGPT5/FHBL2 1,10 0,59 Hs.9613 ANGPTL4 Angiopoietin-like 4 ANGPTL2/ARP4/FIAF/HFAR 5,79 1,66 P/NL2/PGAR/pp1158 Hs.1239 ANPEP Alanyl (membrane) APN/CD13/GP150/LAP1/P150 1,03 0,01 aminopeptidase /PEPN Hs.194654 BAI1 Brain-specific angiogenesis FLJ41988/GDAIF 0,89 0,26 inhibitor 1 Hs.54460 CCL11 Chemokine (C-C motif) ligand 11 MGC22554/SCYA11 1,04 0,15 Hs.303649 CCL2 Chemokine (C-C motif) ligand 2 GDCF- 1,09 0,14 2/HC11/HSMCR30/MCAF/M CP- -
Detection of Pro Angiogenic and Inflammatory Biomarkers in Patients With
www.nature.com/scientificreports OPEN Detection of pro angiogenic and infammatory biomarkers in patients with CKD Diana Jalal1,2,3*, Bridget Sanford4, Brandon Renner5, Patrick Ten Eyck6, Jennifer Laskowski5, James Cooper5, Mingyao Sun1, Yousef Zakharia7, Douglas Spitz7,9, Ayotunde Dokun8, Massimo Attanasio1, Kenneth Jones10 & Joshua M. Thurman5 Cardiovascular disease (CVD) is the most common cause of death in patients with native and post-transplant chronic kidney disease (CKD). To identify new biomarkers of vascular injury and infammation, we analyzed the proteome of plasma and circulating extracellular vesicles (EVs) in native and post-transplant CKD patients utilizing an aptamer-based assay. Proteins of angiogenesis were signifcantly higher in native and post-transplant CKD patients versus healthy controls. Ingenuity pathway analysis (IPA) indicated Ephrin receptor signaling, serine biosynthesis, and transforming growth factor-β as the top pathways activated in both CKD groups. Pro-infammatory proteins were signifcantly higher only in the EVs of native CKD patients. IPA indicated acute phase response signaling, insulin-like growth factor-1, tumor necrosis factor-α, and interleukin-6 pathway activation. These data indicate that pathways of angiogenesis and infammation are activated in CKD patients’ plasma and EVs, respectively. The pathways common in both native and post-transplant CKD may signal similar mechanisms of CVD. Approximately one in 10 individuals has chronic kidney disease (CKD) rendering CKD one of the most common diseases worldwide1. CKD is associated with a high burden of morbidity in the form of end stage kidney disease (ESKD) requiring dialysis or transplantation 2. Furthermore, patients with CKD are at signifcantly increased risk of death from cardiovascular disease (CVD)3,4. -
Recombinant Human Epha8 Fc Chimera Catalog Number: 6828-A8
Recombinant Human EphA8 Fc Chimera Catalog Number: 6828-A8 DESCRIPTION Source Mouse myeloma cell line, NS0derived Human EphA8 Human IgG (Glu31Thr542) IEGRMD 1 (Pro100Lys330) Accession # NP_065387 Nterminus Cterminus Nterminal Sequence Glu31 Analysis Structure / Form Disulfidelinked homodimer Predicted Molecular 83.2 kDa (monomer) Mass SPECIFICATIONS SDSPAGE 94 kDa, reducing conditions Activity Measured by its binding ability in a functional ELISA. When Recombinant Human EphA8 Fc Chimera is coated at 2 μg/mL (100 μL/well), the concentration of Biotinylayed Recombinant Human EphrinA5 Fc Chimera (Catalog # BT374) that produces 50% of the optimal binding response is 212 ng/mL. Endotoxin Level <0.01 EU per 1 μg of the protein by the LAL method. Purity >90%, by SDSPAGE under reducing conditions and visualized by silver stain. Formulation Supplied as a 0.2 μm filtered solution in MES, NaCl, PEG, CHAPS and Imidazole. See Certificate of Analysis for details. PREPARATION AND STORAGE Shipping The product is shipped with dry ice or equivalent. Upon receipt, store it immediately at the temperature recommended below. Stability & Storage Use a manual defrost freezer and avoid repeated freezethaw cycles. l 12 months from date of receipt, 70 °C as supplied. l 1 month, 2 to 8 °C under sterile conditions after opening. l 3 months, 20 to 70 °C under sterile conditions after opening. BACKGROUND EphA8, also known as Hek3 and Eek, is a 120 kDa glycosylated member of the Eph family of transmembrane receptor tyrosine kinases (1, 2). The A and B classes of Eph proteins are distinguished by Ephrin ligand binding preference but have a common structural organization. -
A Tyrosine Kinase Expression Signature Predicts the Post-Operative Clinical Outcome in Triple Negative Breast Cancers
cancers Article A Tyrosine Kinase Expression Signature Predicts the Post-Operative Clinical Outcome in Triple Negative Breast Cancers Alexandre de Nonneville 1, Pascal Finetti 2 , José Adelaide 2, Éric Lambaudie 3, Patrice Viens 1, Anthony Gonçalves 1 , Daniel Birnbaum 2, Emilie Mamessier 2 and François Bertucci 1,2,* 1 Department of Medical Oncology, Institut Paoli-Calmettes, Aix-Marseille Univ, CRCM, CNRS, INSERM, 13000 Marseille, France 2 Laboratory of Predictive Oncology, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Inserm UMR1068, CNRS UMR725, Aix-Marseille Université, 13000 Marseille, France 3 Department of Surgical Oncology, Institut Paoli-Calmettes, Aix-Marseille Univ, CNRS, INSERM, CRCM, 13000 Marseille, France * Correspondence: [email protected]; Tel.: +33-4-91-22-35-37; Fax: +33-4-91-22-36-70 Received: 15 July 2019; Accepted: 9 August 2019; Published: 13 August 2019 Abstract: Triple negative breast cancer (TNBC) represent 15% of breast cancers. Histoclinical features and marketed prognostic gene expression signatures (GES) failed to identify good- and poor-prognosis patients. Tyrosine kinases (TK) represent potential prognostic and/or therapeutic targets for TNBC. We sought to define a prognostic TK GES in a large series of TNBC. mRNA expression and histoclinical data of 6379 early BCs were collected from 16 datasets. We searched for a TK-based GES associated with disease-free survival (DFS) and tested its robustness in an independent validation set. A total of 1226 samples were TNBC. In the learning set of samples (N = 825), we identified a 13-TK GES associated with DFS. This GES was associated with cell proliferation and immune response.