Argos inhibits epidermal growth factor receptor signalling by ligand sequestration

The epidermal growth factor receptor (EGFR) has critical functions in development and in many human cancers. During development, the spatial extent of EGFR signalling is regulated by feedback loops comprising both well-understood activators and less well-characterized inhibitors. In Drosophila melan...

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Bibliographic Details
Published in:	Nature Vol. 430; no. 7003; pp. 1040 - 1044
Main Authors:	Klein, D.E, Nappi, V.M, Reeves, G.T, Shvartsman, S.Y, Lemmon, M.A
Format:	Journal Article
Language:	English
Published:	London Nature Publishing 26-08-2004 Nature Publishing Group
Subjects:	Animals Antineoplastic agents binding proteins Binding Sites Biochemistry Biological and medical sciences Cancer Developmental stages Down-Regulation Drosophila melanogaster Drosophila melanogaster - metabolism Drosophila Proteins - antagonists & inhibitors Drosophila Proteins - metabolism Electron Spin Resonance Spectroscopy epidermal growth factor Epidermal Growth Factor - antagonists & inhibitors Epidermal Growth Factor - metabolism ErbB Receptors - antagonists & inhibitors ErbB Receptors - metabolism Eye Proteins - metabolism General aspects Ligands Medical sciences Membrane Proteins - antagonists & inhibitors Membrane Proteins - metabolism Nerve Tissue Proteins - metabolism Pharmacology. Drug treatments Protein Binding Protein Kinase Inhibitors Protein Kinases - metabolism Proteins receptors Receptors, Invertebrate Peptide - antagonists & inhibitors Receptors, Invertebrate Peptide - metabolism Signal Transduction Antineoplastic agent Ligand Insecta Epidermal growth factor receptor Drosophilidae Signal transduction Growth factor receptor Arthropoda Secretory protein Antagonist Invertebrata Drosophila melanogaster Diptera Biological receptor
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Summary:	The epidermal growth factor receptor (EGFR) has critical functions in development and in many human cancers. During development, the spatial extent of EGFR signalling is regulated by feedback loops comprising both well-understood activators and less well-characterized inhibitors. In Drosophila melanogaster the secreted protein Argos functions as the only known extracellular inhibitor of EGFR, with clearly identified roles in multiple stages of development. Argos is only expressed when the Drosophila EGFR (DER) is activated at high levels, and downregulates further DER signalling. Although there is ample genetic evidence that Argos inhibits DER activation, the biochemical mechanism has not been established. Here we show that Argos inhibits DER signalling without interacting directly with the receptor, but instead by sequestering the DER-activating ligand Spitz. Argos binds tightly to the EGF motif of Spitz and forms a 1:1 (Spitz:Argos) complex that does not bind DER in vitro or at the cell surface. Our results provide an insight into the mechanism of Argos function, and suggest new strategies for EGFR inhibitor design.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0028-0836 1476-4687
DOI:	10.1038/nature02840