Inhibition of Drosophila EGF receptor activation by the secreted protein Argos

Abstract

THE Drosophila homologue of the mammalian epidermal growth factor (EGF) receptor (DER)^1,2 is a receptor tyrosine kinase involved in many stages of fly development, including photoreceptor determination, and wing-vein formation^3–9. Its primary activating ligand is the Spitz protein^10,11, which is similar to mammalian TGF-α (ref. 12). Argos is a secreted protein that, like Spitz, contains a single EGF motif^13–15. It is a represser of cell determination in the eye, and acts in other tissues, including the wing^16–18. Because Argos has the opposite effects to DER in the eye (the former blocks photoreceptor determination, the latter promotes it) we have tested whether it acts by blocking the DER pathway. We show that Argos does indeed repress this pathway in vivo and find that, in vitro, Argos protein can inhibit the activation of DER by Spitz. Thus the determination of cells by the DER pathway is regulated by a balance between extracellular activating and inhibiting signals. This is the first in vivo example of an extracellular inhibitor of a receptor tyrosine kinase.