Search results for: Epigen (EPGN), human recombinant
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EGF-mediated suppression of cell extrusion during mucosal damage attenuates opportunistic fungal invasion.
Severe and often fatal opportunistic fungal infections arise frequently following mucosal damage caused by trauma or cytotoxic chemotherapy. Interaction of fungal pathogens with epithelial cells that comprise mucosae is a key early event associated with invasion, and, therefore, enhancing epithelial defense mechanisms may mitigate infection. Here, we establish a model of mold and yeast infection mediated by inducible epithelial cell loss in larval zebrafish. Epithelial cell loss by extrusion promotes exposure of laminin associated with increased fungal attachment, invasion, and larval lethality, whereas fungi defective in adherence or filamentation have reduced virulence. Transcriptional profiling identifies significant upregulation of the epidermal growth factor receptor ligand epigen (EPGN) upon mucosal damage. Treatment with recombinant human EPGN suppresses epithelial cell extrusion, leading to reduced fungal invasion and significantly enhanced survival. These data support the concept of augmenting epithelial restorative capacity to attenuate pathogenic invasion of fungi associated with human disease.Sebastian Wurster, Oscar E Ruiz, Krystin M Samms, Alexander M Tatara, Nathaniel D Albert, Philip H Kahan, Anh Trinh Nguyen, Antonios G Mikos, Dimitrios P Kontoyiannis, George T Eisenhoffer
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#15611079 2004/12/17
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Epigen, the last ligand of ErbB receptors, reveals intricate relationships between affinity and mitogenicity.
Four ErbB receptors and multiple growth factors sharing an epidermal growth factor (EGF) motif underlie transmembrane signaling by the ErbB family in development and cancer. Unlike other ErbB proteins, ErbB-2 binds no known EGF-like ligand. To address the existence of a direct ligand for ErbB-2, we applied algorithms based on genomic and cDNA structures to search sequence data bases. These searches reidentified all known EGF-like growth factors including Epigen (EPG), the least characterized ligand, but failed to identify novel factors. The precursor of EPG is a widely expressed transmembrane glycoprotein that undergoes cleavage at two sites to release a soluble EGF-like domain. A recombinant EPG cannot stimulate cells singly expressing ErbB-2, but it acts as a mitogen for cells expressing ErbB-1 and co-expressing ErbB-2 in combination with the other ErbBs. Interestingly, soluble EPG is more mitogenic than EGF, although its binding affinity is 100-fold lower. Our results attribute the anomalous mitogenic power of EPG to evasion of receptor-mediated depletion of ligand molecules, as well as to inefficient receptor ubiquitylation and down-regulation. In conclusion, EPG might represent the last EGF-like growth factor and define a category of low affinity ligands, whose bioactivity differs from the more extensively studied high affinity ligands.Bose S Kochupurakkal, Daniel Harari, Ayelet Di-Segni, Galia Maik-Rachline, Ljuba Lyass, Gal Gur, Gabriele Kerber, Ami Citri, Sara Lavi, Raya Eilam, Vered Chalifa-Caspi, Zelig Eshhar, Eli Pikarsky, Ronit Pinkas-Kramarski, Sarah S Bacus, Yosef Yarden