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Lee M Ellis - One of the best experts on this subject based on the ideXlab platform.
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Tyrosine Kinase Receptor ron in human pancreatic cancer expression function and validation as a target
Cancer, 2007Co-Authors: Ramsay E Camp, Anthony D Yang, Michael J Gray, Stanley R Hamilton, Douglas B Evans, Andrea T Hooper, Daniel S Pereira, Daniel J Hicklin, Lee M EllisAbstract:BACKGROUND Specific Tyrosine Kinase Receptors such as c-MET mediate epithelial-mesenchymal (EMT) transition, leading to phenotypic alterations associated with increased cell motility. It was hypothesized that RON, a Tyrosine Kinase Receptor related to c-MET, would be expressed in human pancreatic cancer cells, induce EMT, and would thus serve as a target for therapy in a preclinical model. METHODS RON expression in human pancreatic cancer specimens was assessed by immunohistochemistry. In pancreatic cancer cell lines, RON expression was assessed by reverse-transcriptase polymerase chain reaction (PCR) and Western blot analysis. The human pancreatic cancer cell line L3.6pl, with high RON expression, was exposed to macrophage stimulating protein (MSP), the RON ligand, and assessed for cell migration, invasion, and changes associated with EMT. Western blot analysis and immunofluorescent staining were used to assess alterations in protein expression and cellular location, respectively. A RON monoclonal antibody (MoAb) was used to block ligand-induced activation of RON. RESULTS Immunohistochemical staining revealed RON overexpression in 93% of human pancreatic cancer specimens relative to nonmalignant ductal tissue. RON mRNA and protein was expressed in 9 of 9 human pancreatic cancer cell lines. Treatment of L3.6pl cells with MSP increased Erk phosphorylation, cell migration, and invasion (P < .001). RON activation led to a decrease in membrane-bound E-cadherin in association with nuclear translocation of β-catenin. RON MoAb inhibited downstream signaling as well as cell migration and invasion. In nude mice, RON MoAb inhibited subcutaneous and orthotopic tumor growth by about 60%. CONCLUSIONS RON activation induced molecular and cellular alterations consistent with EMT. Inhibition of RON activation inhibited tumor growth in vivo. Novel antineoplastic therapies designed to inhibit RON activity may hinder mechanisms critical for pancreatic tumor progression. Cancer 2007 © 2007 American Cancer Society.
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RON, a Tyrosine Kinase Receptor Involved in Tumor Progression and Metastasis
Annals of Surgical Oncology, 2005Co-Authors: E. Ramsay Camp, Anthony Yang, Ray Somcio, Lee M EllisAbstract:Tyrosine Kinase Receptors mediate many critical cellular functions that contribute to tumor progression and metastasis and thus are potential targets for molecular-based cancer therapy. As has been found for many Receptor Tyrosine Kinases, RON (recepteur d’origine nantais) and its ligand, macrophage-stimulating protein, have recently been implicated in the progression and metastasis of tumors. In in vitro experiments using colon and breast cancer cell lines, overexpression of RON led to increased invasion and migration of cancer cells and prevented apoptosis and anoikis. In addition, transgenic mice engineered to overexpress RON in the lung epithelium developed multiple pulmonary tumors, suggesting a role for RON in tumorigenesis. In human cancer specimens, increased RON expression has been demonstrated in colon, breast, ovarian, and lung tumors. Therefore, therapies designed to inhibit RON activation may hinder critical tumor survival mechanisms and play a role in the treatment of advanced disease.
Luis F. Parada - One of the best experts on this subject based on the ideXlab platform.
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c-ros: the vertebrate homolog of the sevenless Tyrosine Kinase Receptor is tightly regulated during organogenesis in mouse embryonic development.
Development, 1992Co-Authors: Lino Tessarollo, Lalitha Nagarajan, Luis F. ParadaAbstract:The c-ros proto-oncogene is the vertebrate homologue of the Drosophila sevenless Tyrosine Kinase Receptor. Examination of c-ros mRNA transcripts in the mouse embryo reveals a stringent pattern of expression. Only kidney, intestine and lung exhibit ros-specific RNA using sensitive techniques such as RNAase protection and in situ hybridization. The temporal and spatial arrangement of c-ros transcripts is coincident with the phenotypic induction and proliferation of epithelium during organogenesis of the kidney and intestine. The data provide evidence for a role of c-ros in the obligate cell-cell interactions that characterize the morphogenic induction and proliferation of epithelial cells in the kidney, intestine and lung. The c-ros Tyrosine Kinase Receptor may provide a signal transduction pathway for epithelial-mesenchymal interactions.
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Tyrosine phosphorylation and Tyrosine Kinase activity of the trk proto oncogene product induced by ngf
Nature, 1991Co-Authors: David L Kaplan, Dionisio Martinzanca, Luis F. ParadaAbstract:NERVE growth factor (NGF) is a neurotrophic factor responsible for the differentiation and survival of sympathetic and sensory neurons as well as selective populations of cholinergic neurons1,2. NGF binds to specific cell-surface Receptors but the mechanism for transduction of the neurotrophic signal is unknown. Several experiments using the NGF-responsive pheochromocytoma cell line, PC12, have implicated Tyrosine phosphorylation in NGF-mediated responses, although no NGF-specific Tyrosine Kinases have been identified3. Here we show that NGF induces Tyrosine phosphorylation and Tyrosine Kinase activity of the trk protooncogene product, a Tyrosine Kinase Receptor whose expression is restricted in vivo to neurons of the sensory spinal and cranial ganglia of neural crest origin4. Tyrosine phosphorylation of trk by NGF is rapid, specific and occurs with picomolar quantities of factor, indicating that the response is mediated by physiological amounts of NGF. Activation of the trk Tyrosine Kinase Receptor provides a possible mechanism for signal transduction by NGF.
Wendy Maury - One of the best experts on this subject based on the ideXlab platform.
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Tyrosine Kinase Receptor axl enhances entry of zaire ebolavirus without direct interactions with the viral glycoprotein
Virology, 2011Co-Authors: Melinda A Brindley, Catherine L Hunt, Andrew S Kondratowicz, Jill Bowman, Patrick L Sinn, Paul B Mccray, Kathrina Quinn, Melodie L Weller, John A Chiorini, Wendy MauryAbstract:Abstract In a bioinformatics-based screen for cellular genes that enhance Zaire ebolavirus (ZEBOV) transduction, AXL mRNA expression strongly correlated with ZEBOV infection. A series of cell lines and primary cells were identified that require Axl for optimal ZEBOV entry. Using one of these cell lines, we identified ZEBOV entry events that are Axl-dependent. Interactions between ZEBOV-GP and the Axl ectodomain were not detected in immunoprecipitations and reduction of surface-expressed Axl by RNAi did not alter ZEBOV-GP binding, providing evidence that Axl does not serve as a Receptor for the virus. However, RNAi knock down of Axl reduced ZEBOV pseudovirion internalization and α-Axl antisera inhibited pseudovirion fusion with cellular membranes. Consistent with the importance of Axl for ZEBOV transduction, Axl transiently co-localized on the surface of cells with ZEBOV virus particles and was internalized during virion transduction. In total, these findings indicate that endosomal uptake of filoviruses is facilitated by Axl.
Yuping Wang - One of the best experts on this subject based on the ideXlab platform.
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placental productions and expressions of soluble endoglin soluble fms like Tyrosine Kinase Receptor 1 and placental growth factor in normal and preeclamptic pregnancies
The Journal of Clinical Endocrinology and Metabolism, 2008Co-Authors: Yang Gu, David F Lewis, Yuping WangAbstract:Context: Increased production of antiangiogenic factors soluble endoglin (sEng) and soluble fms-like Tyrosine Kinase Receptor-1 (sFlt-1) by the placenta contributes to the pathophysiology in preeclampsia (PE). Objective: Our objective was to determine the differences in endoglin (Eng), fms-like Tyrosine Kinase Receptor-1 (Flt-1), and placental growth factor (PlGF) expressions between normal and PE placentas and sEng, sFlt-1, and PlGF production by trophoblast cells (TC) cultured under lowered oxygen conditions. Methods: TCs isolated from normal and PE placentas were cultured under regular (5% CO2/air) and lowered (2% O2/5% CO2/93% N2) oxygen conditions. sEng, sFlt-1, and PlGF productions were determined by ELISA. Protein expressions for Eng, Flt-1, and PlGF in the placental tissues were accessed by immunohistochemical staining and Western blot analysis. Deglycosylated Eng, Flt-1, and PlGF protein expressions in placental tissues were also examined. Results: PE TCs produced significantly more sEng, sFlt-1, and PlGF compared with those from normal TCs (P < 0.05). Under lowered oxygen conditions, PE TCs, but not normal TCs, released more sEng and sFlt-1. In contrast, both normal and PE TCs released less PlGF (P < 0.05). Enhanced expressions of Eng and Flt-1, as well as glycosylated Eng and Flt-1, were observed in PE placentas. Immunoblot also revealed that TCs released glycosylated sFlt-1, but not sEng, in culture. Conclusions: PE TCs produce more sEng, sFlt-1, and PlGF than normal TCs. Lowered oxygen conditions promote sEng and sFlt-1, but reduce PlGF, productions by PE TCs. More glycosylated sEng and sFlt-1 are present in PE placentas. Trophoblasts release glycosylated sFlt-1, but unglycosylated sEng, in culture.
Siavoush Dastmalchi - One of the best experts on this subject based on the ideXlab platform.
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Strategies of targeting the extracellular domain of RON Tyrosine Kinase Receptor for cancer therapy and drug delivery
Journal of Cancer Research and Clinical Oncology, 2016Co-Authors: Omid Zarei, Fulya Ustun-alkan, Silvia Benvenuti, Maryam Hamzeh-mivehroud, Siavoush DastmalchiAbstract:PurposeCancer is one of the most important life-threatening diseases in the world. The current efforts to combat cancer are being focused on molecular-targeted therapies. The main purpose of such approaches is based on targeting cancer cell-specific molecules to minimize toxicity for the normal cells. RON (Recepteur d’Origine Nantais) Tyrosine Kinase Receptor is one of the promising targets in cancer-targeted therapy and drug delivery.MethodsIn this review, we will summarize the available agents against extracellular domain of RON with potential antitumor activities.ResultsThe presented antibodies and antibody drug conjugates against RON in this review showed wide spectrum of in vitro and in vivo antitumor activities promising the hope for them entering the clinical trials.ConclusionDue to critical role of extracellular domain of RON in Receptor activation, the development of therapeutic agents against this region could lead to fruitful outcome in cancer therapy.
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Strategies of targeting the extracellular domain of RON Tyrosine Kinase Receptor for cancer therapy and drug delivery.
Journal of Cancer Research and Clinical Oncology, 2016Co-Authors: Omid Zarei, Fulya Ustun-alkan, Silvia Benvenuti, Maryam Hamzeh-mivehroud, Siavoush DastmalchiAbstract:Purpose Cancer is one of the most important life-threatening diseases in the world. The current efforts to combat cancer are being focused on molecular-targeted therapies. The main purpose of such approaches is based on targeting cancer cell-specific molecules to minimize toxicity for the normal cells. RON (Recepteur d’Origine Nantais) Tyrosine Kinase Receptor is one of the promising targets in cancer-targeted therapy and drug delivery.
