GDNF-INDUCED ACTIVATION OF THE RET PROTEIN-TYROSINE KINASE IS MEDIATED BY GDNFR-ALPHA, A NOVEL RECEPTOR FOR GDNF

We report the expression cloning and characterization of GDNFR-alpha, a novel glycosylphosphatidylinositol-linked cell surface receptor for glial cell line-derived neurotrophic factor (GDNF). GDNFR-alpha binds GDNF specifically and mediates activation of the Ret protein-tyrosine kinase (PTK). Treatment of Neuro-2a cells expressing GDNFR-alpha with GDNF rapidly stimulates Ret autophosphorylation. Ret is also activated by treatment with a combination of GDNF and soluble GDNFR-alpha in ce lls lacking GDNFR-alpha, and this effect is blocked by a soluble Ret-F c 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-tra nsducing complex including GDNF, GDNFR-alpha, and the Ret PTK is propo sed.