Argos inhibits epidermal growth factor receptor signalling by ligand sequestration

Nature
Daryl E KleinMark A Lemmon

Abstract

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.

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Citations

Jul 26, 2006·Journal of Mammary Gland Biology and Neoplasia·Colleen SweeneyKermit L Carraway
May 27, 2008·Nature·Daryl E KleinMark A Lemmon
Nov 25, 2006·Nature Reviews. Immunology·Alberto MantovaniMassimo Locati
Sep 22, 2006·Systems Biology·N YakobyS Y Shvartsman
Mar 2, 2010·Proceedings of the National Academy of Sciences of the United States of America·Marina Cardó-VilaRenata Pasqualini
Apr 26, 2013·Open Biology·Qiang ZhangMelvin E Andersen
Dec 14, 2012·Journal of Virology·Daryl E KleinStephen C Harrison
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