CHARACTERIZATION OF A MULTICOMPONENT RECEPTOR FOR GDNF

GLIAL-CELL-LINE-DERIVED neurotrophic factor (GDNF)(1) is a potent surv ival factor for central and peripheral neurons(2-6), and is essential for the development of kidneys and the enteric nervous system(7-9). De spite the potential clinical and physiological importance of GDNF, its mechanism of action is unknown. Here we show that physiological respo nses to GDNF require the presence of a novel glycosyl-phosphatidylinos itol (GPI)-linked protein (designated GDNFR-alpha) that is expressed o n GDNF-responsive cells and binds GDNF with a high affinity. We furthe r demonstrate that GDNF promotes the formation of a physical complex b etween GDNFR-alpha and the orphan tyrosine kinase receptor Ret(10-12), thereby inducing its tyrosine phosphorylation. These findings support the hypothesis that GDNF uses a multi-subunit receptor system in whic h GDNFR-alpha and Ret function as the ligand-binding and signalling co mponents, respectively.