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 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.
Klein
Daryl E
DE
Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA.
Nappi
Valerie M
VM
Reeves
Gregory T
GT
Shvartsman
Stanislav Y
SY
Lemmon
Mark A
MA
D000818:Animals; D001665:Binding Sites; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005136:Eye Proteins / Q000378:metabolism*; D008024:Ligands; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D018010:Receptors, Invertebrate Peptide / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction
D029721:Drosophila Proteins; D005136:Eye Proteins; D008024:Ligands; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D018010:Receptors, Invertebrate Peptide; C075638:aos protein, Drosophila; C076026:spi protein, Drosophila; D004815:Epidermal Growth Factor; D011494:Protein Kinases; C066532:Egfr protein, Drosophila; D066246:ErbB Receptors