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Letters to Nature
Nature 430, 1040-1044 (26 August 2004) | doi:10.1038/nature02840; Received 18 May 2004; Accepted 7 July 2004
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Argos inhibits epidermal growth factor receptor signalling by ligand sequestration
Daryl E. Klein1,3, Valerie M. Nappi1,3, Gregory T. Reeves2, Stanislav Y. Shvartsman2 & Mark A. Lemmon1
- Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA
- Department of Chemical Engineering and the Lewis-Sigler Institute for Integrative Genomics, Princeton University, Carl Icahn Laboratory, Washington Road, Princeton, New Jersey 08544, USA
- These authors contributed equally to this work
Correspondence to: Mark A. Lemmon1 Correspondence and requests for materials should be addressed to M.A.L. (Email: mlemmon@mail.med.upenn.edu).
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.
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