A high-affinity ErbB4Fc fusion protein is a potent antagonist of heregulin-mediated receptor activation
| Autor: | Colin W. Ward, Antony W. Burgess, Edouard C. Nice, John D. Bentley, Timothy E. Adams, Julie Rothacker, Terrance Grant Johns, Jacqueline F. Donoghue, Mathias Hafner, George O. Lovrecz, Eva J. Koziolek, Olan Dolezal |
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| Rok vydání: | 2012 |
| Předmět: |
Receptor
ErbB-4 Neuregulin-1 Recombinant Fusion Proteins Clinical Biochemistry Breast Neoplasms CHO Cells Receptors Fc Biology Cell Line Mice ErbB Receptors Endocrinology Epidermal growth factor ErbB Cricetinae Animals Humans ERBB3 Epidermal growth factor receptor Betacellulin Phosphorylation Extracellular Signal-Regulated MAP Kinases Melanoma Ovarian Neoplasms JNK Mitogen-Activated Protein Kinases Cell Biology Xenograft Model Antitumor Assays Fusion protein Molecular biology HEK293 Cells Ectodomain Immunoglobulin G MCF-7 Cells Cancer research biology.protein Intercellular Signaling Peptides and Proteins Female I-kappa B Proteins Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Growth Factors. 30:310-319 |
| ISSN: | 1029-2292 0897-7194 |
| Popis: | Ligand-mediated activation of ErbB3 and ErbB4 is implicated in the pathogenesis of several human malignancies including cancer of the ovary and melanoma. We have used the broad ErbB ligand specificity of ErbB4 to assemble and express an ErbB4 fusion protein comprising the first 497 amino acids of the mature ErbB4 ectodomain fused to the human IgG Fc constant region. The purified fusion protein, designated sErbB4.497.Fc, binds the ErbB receptor ligands betacellulin and heregulin-β1 (HRG-β1) with high affinity (K(D) = 130 pM), an increase in affinity of 10- to 20-fold, respectively, compared with sErbB4.615.Fc. sErbB4.497.Fc inhibited ligand-stimulated phosphorylation of epidermal growth factor receptor and ErbB2, and blocked HRG-β1 activation of the IKB/MAP/JNK/AKT signalling pathways. sErbB4.497.Fc inhibited HRG-β1-stimulated proliferation in MCF7 cells. In a mouse tumour xenograft model, sErbB4.497.Fc as a monotherapy modestly inhibited the growth of MDA-MB-231 breast cancer cells. sErbB4.497.Fc may be useful in an adjuvant setting in combination with conventional therapeutic agents. |
| Databáze: | OpenAIRE |
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