GFRα-2 and GFRα-3 are two new receptors for ligands of the GDNF family

The receptor for glial cell line-derived neurotrophic factor (GDNF) consists of GFR alpha-1 and Ret. Neurturin is a GDNF-related neurotrophin whose receptor is presently unknown. Here we report that neurturin can bind to either GFR alpha-1 or GFR alpha-2, a novel receptor related to GFR alpha-1. Both GFR alpha-1 and GFR alpha-2 mediate neurturin-induced Ret phosphorylation. GDNF can also bind to either GFR alpha-1 or GFR alpha-2, and activate Ret in the presence of either binding receptor. Although both ligands interact with both receptors, cells expressing GFR alpha-1 bind GDNF more efficiently than neurturin, while cells expressing GFR alpha-2 bind neurturin preferentially. Crosslinking and Ret activation data also suggest that while there is cross-talk, GFR alpha-1 is the primary receptor for GDNF and GFR alpha-2 exhibits a preference for neurturin. We have also cloned a cDNA that apparently codes for a third member of the GFR alpha receptor family. This putative receptor, designated GFR alpha-3, is closely related in amino acid sequence and is nearly identical in the spacing of its cysteine residues to both GFR alpha-1 and GFR alpha-2. Analysis of the tissue distribution of GFR alpha-1, GFR alpha-2, GFR alpha-3, and Ret by Northern blot reveals overlapping but distinct patterns of expression. Consistent with a role in GDNF function, the GFR alpha s and Ret are expressed in many of the same tissues, suggesting that GFR alpha s mediate the action of GDNF family ligands in vivo.