GDNF–Induced Activation of the Ret Protein Tyrosine Kinase Is Mediated by GDNFR-α, a Novel Receptor for GDNF

AbstractWe report the expression cloning and characterization of GDNFR-α, a novel glycosylphosphatidylinositol-linked cell surface receptor for glial cell line–derived neurotrophic factor (GDNF). GDNFR-α binds GDNF specifically and mediates activation of the Ret protein-tyrosine kinase (PTK). Treatment of Neuro-2a cells expressing GDNFR-α with GDNF rapidly stimulates Ret autophosphorylation. Ret is also activated by treatment with a combination of GDNF and soluble GDNFR-α in cells lacking GDNFR-α, and this effect is blocked by a soluble Ret–Fc fusion protein. Ret activation by GDNF was also observed in cultured embryonic rat spinal cord motor neurons, a cell type that responds to GDNF in vivo. A model for the stepwise formation of a GDNF signal-transducing complex including GDNF, GDNFR-α, and the Ret PTK is proposed