Glial-cell-line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two 
structurally related, potent survival factors for sympathetic, sensory and 
central nervous system neurons. GDNF mediates its actions through a 
multicomponent receptor system composed of a ligand-binding 
glycosyl-phosphatidylinositol (GPI)-linked protein (designated GDNFR-alpha) and 
the transmembrane protein tyrosine kinase Ret. In contrast, the mechanism by 
which the NTN signal is transmitted is not well understood. Here we describe the 
identification and tissue distribution of a GPI-linked protein (designated 
NTNR-alpha) that is structurally related to GDNFR-alpha. We further demonstrate 
that NTNR-alpha binds NTN (K[d] approximately 10 pM) but not GDNF with high 
affinity; that GDNFR-alpha binds to GDNF but not NTN with high affinity; and 
that cellular responses to NTN require the presence of NTNR-alpha. Finally, we 
show that NTN, in the presence of NTNR-alpha, induces tyrosine-phosphorylation 
of Ret, and that NTN, NTNR-alpha and Ret form a physical complex on the cell 
surface. These findings identify Ret and NTNR-alpha as signalling and 
ligand-binding components, respectively, of a receptor for NTN and define a 
novel family of receptors for neurotrophic and differentiation factors composed 
of a shared transmembrane protein tyrosine kinase and a ligand-specific 
GPI-linked protein.