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The Drosophila Argos protein is the only known extracellular inhibitor of the epidermal growth factor receptor (EGFR). It is structurally related to the activating ligands, in that it is a secreted protein with a single epidermal growth factor (EGF) domain. To understand the mechanism of Argos inhibition, we have investigated which regions of the protein are essential. A series of deletions were made and tested in vivo; furthermore, by analyzing chimeric proteins between Argos and the activating ligand, Spitz (a transforming growth factor-alpha-like factor), we have examined what makes one inhibitory and the other activating. Our results reveal that Argos has structural requirements that differ from all known EGFR activating ligands; domains flanking the EGF domain are essential for its function. We have also defined the important regions of the atypical Argos EGF domain. The extended B-loop is necessary, whereas the C-loop can be replaced with the equivalent Spitz region without substantially affecting Argos function. Comparison of the argos genes from Drosophila melanogaster and the housefly, Musca domestica, supports our structure-function analysis. These studies are a prerequisite for understanding how Argos inhibits the Drosophila EGFR and provide a basis for designing mammalian EGFR inhibitors.


Journal article


J Biol Chem

Publication Date





4275 - 4281


Amino Acid Sequence, Animals, Conserved Sequence, Drosophila Proteins, Drosophila melanogaster, Epidermal Growth Factor, Eye, Eye Proteins, Gene Expression Regulation, Developmental, Houseflies, Membrane Proteins, Microscopy, Electron, Scanning, Molecular Sequence Data, Nerve Tissue Proteins, Receptor, Epidermal Growth Factor, Recombinant Fusion Proteins, Sequence Alignment, Sequence Deletion, Structure-Activity Relationship, Wings, Animal