A GPI-LINKED PROTEIN THAT INTERACTS WITH RET TO FORM A CANDIDATE NEURTURIN RECEPTOR

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(1-6). GDNF mediates its a ctions through a multicomponent receptor system composed of a ligand-b inding glycosyl-phosphatidylinositol (GPI)-linked protein (designated GDNFR-alpha) and the trans-membrane protein tyrosine kinase Ret(7-12). In contrast, the mechanism by which the NTN signal is transmitted is not well understood. Here we describe the identification and tissue di stribution of a GPI-linked protein (designated NTNR-alpha) that is str ucturally related to GDNFR-alpha. We further demonstrate that NTNR-alp ha binds NTN (K-d-10 pM) but not GDNF with high affinity; that GDNFR-a lpha binds to GDNF but not NTN with high affinity; and that cellular r esponses to NTN require the presence of NTNR-alpha. Finally, we show t hat NTN, in the presence of NTNR-alpha, induces tyrosine-phosphorylati on 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 signa lling and ligand-binding components, respectively, of a receptor for N TN and define a novel family of receptors for neurotrophic and differe ntiation factors composed of a shared transmembrane protein tyrosine k inase and a ligand-specific GPI-linked protein.