R. Howes et al., IN-VIVO ANALYSIS OF ARGOS STRUCTURE-FUNCTION - SEQUENCE REQUIREMENTS FOR INHIBITION OF THE DROSOPHILA EPIDERMAL GROWTH-FACTOR RECEPTOR, The Journal of biological chemistry, 273(7), 1998, pp. 4275-4281
The Drosophila Argos protein is the only known extracellular inhibitor
of the epidermal growth factor receptor (EGFR), It is structurally re
lated to the activating ligands, in that it is a secreted protein with
a single epidermal growth factor (EGF) domain, To understand the mech
anism of Argos inhibition, we have investigated which regions of the p
rotein are essential, A series of deletions were made and tested in vi
vo; furthermore, by analyzing chimeric proteins between Argos and the
activating ligand, Spitz (a transforming growth factor-alpha-like fact
or), we have examined what makes one inhibitory and the other activati
ng, Our results reveal that Argos has structural requirements that dif
fer from all known EGFR activating ligands; domains flanking the EGF d
omain are essential for its function, We have also defined the importa
nt regions of the atypical Argos EGF domain, The extended B-loop is ne
cessary, whereas the C-loop can be replaced with the equivalent Spitz
region without substantially affecting Argos function, Comparison of t
he argos genes from Drosophila melanogaster and the housefly, Musca do
mestica, supports our structure-function analysis, These studies are a
prerequisite for understanding how Argos inhibits the Drosophila EGFR
and provide a basis for designing mammalian EGFR inhibitors.