INHIBITION OF DROSOPHILA EGF RECEPTOR ACTIVATION BY THE SECRETED PROTEIN ARGOS

THE Drosophila homologue of the mammalian epidermal growth factor (EGF ) receptor (DER)(1,2) is a receptor tyrosine kinase involved in many s tages of fly development, including photoreceptor determination, and w ing-vein formation(3-9). Its primary activating ligand is the Spitz pr otein(10,11), which is similar to mammalian TGF-alpha (ref. 12), Argos is a secreted protein that, like Spitz, contains a single EGF motif(1 3-15). It is a repressor of cell determination in the eye, and acts in other tissues, including the wing(16-18) Because Argos has the opposi te effects to DER in the eye (the former blocks photoreceptor determin ation, the latter promotes it) we have tested whether it acts by block ing the DER pathway, We show that Argos does indeed repress this pathw ay in vivo and find that, in vitro, Argos protein can inhibit the acti vation of DER by Spitz, Thus the determination of cells by the DER pat hway is regulated by a balance between extracellular activating and in hibiting signals. This is the first in vivo example of an extracellula r inhibitor of a receptor tyrosine kinase.