THE N-TERMINAL GLOBULAR DOMAIN OF EPH RECEPTORS IS SUFFICIENT FOR LIGAND-BINDING AND RECEPTOR SIGNALING

The Eph family of receptor protein-tyrosine kinases (RTKs) have recent ly been implicated in patterning and wiring events in the developing n ervous system, Eph receptors are unique among other RTKs in that they fall into two large subclasses that show distinct ligand specificities and for the fact that they themselves might function as 'ligands', th ereby activating bidirectional signaling. To gain insight into the mec hanisms of ligand-receptor interaction, we have mapped the ligand bind ing domain in Eph receptors. By using a series of deletion and domain substitution mutants, we now report that an N-terminal globular domain of the Nuk/Cek5 receptor is the ligand binding domain of the transmem brane ligand Lerk2, Using focus formation assays, we show that the Cek 5 globular domain is sufficient to confer Lerk2-dependent transforming activity on the Cek9 orphan receptor, Extending our binding studies t o other members of both subclasses of receptors, it became apparent th at the same domain is used for binding of both transmembrane and glyco sylphosphatidyl-anchored ligands, Our studies have determined the firs t structural elements involved in ligand-receptor interaction and will allow more fine-tuned genetic experiments to elucidate the mechanism of action of these important guidance molecules.