Argos inhibits epidermal growth factor receptor signalling by ligand sequestration

Daryl E. Klein, Valerie M. Nappi, Gregory T. Reeves, Stanislav Y. Shvartsman and Mark A. Lemmon ()
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Daryl E. Klein: University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories
Valerie M. Nappi: University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories
Gregory T. Reeves: Princeton University, Carl Icahn Laboratory
Stanislav Y. Shvartsman: Princeton University, Carl Icahn Laboratory
Mark A. Lemmon: University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories

Nature, 2004, vol. 430, issue 7003, 1040-1044

Abstract: Abstract The epidermal growth factor receptor (EGFR) has critical functions in development and in many human cancers1,2,3. During development, the spatial extent of EGFR signalling is regulated by feedback loops comprising both well-understood activators and less well-characterized inhibitors3,4. In Drosophila melanogaster the secreted protein Argos functions as the only known extracellular inhibitor of EGFR5, with clearly identified roles in multiple stages of development3. Argos is only expressed when the Drosophila EGFR (DER) is activated at high levels6, 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.

Date: 2004
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DOI: 10.1038/nature02840

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