Members of the EGF-CFC family play essential roles in embryonic development and have been implicated in tumorigenesis. The
TGF signals Nodal and Vg1/GDF1, but not Activin, require EGF-CFC
coreceptors to activate Activin receptors. We report that the TGF
signaling antagonist Lefty also acts through an EGF-CFC-dependent mechanism. Lefty inhibits Nodal and Vg1 signaling, but not Activin signaling. Lefty genetically interacts with EGF-CFC proteins and competes with Nodal for binding to these coreceptors. Chimeras between Activin and Nodal or Vg1 identify a 14 amino acid region that confers independence from EGF-CFC coreceptors and resistance to Lefty. These results indicate that coreceptors are targets for both TGF agonists and antagonists and suggest that subtle sequence variations in TGF signals result in greater ligand diversity.