Glial cell line-derived growth factor (GDNF), neurturin (NTN), persephin (PSP) and artemin, distant members of the TGF-beta superfamily, are neurotrophic factors for a variety of neuronal populations in the central and peripheral nervous systems. The bioactivities of GDNF and NTN are mediated through a receptor complex composed of the non ligand-binding signaling subunit (c-Ret receptor tyrosine kinase) and either of two ligand binding subunits, GDNF receptor alpha -1 (GFR alpha -1, also known as Trn R1) or GFR alpha -2 (also known as Trn R2). GFR alpha -1 and -2 are members of a family of at least four cysteine-rich glycosyl-phosphatidylinositol (GPI)-linked cell surface proteins that share conserved placements of many of their cysteine residues. Binding of GDNF or NTN to membrane-associated GFR alpha -1 or GFR alpha -2 initiates the association with and activation of the Ret tyrosine kinase.
Mouse GFR alpha -2 cDNA encodes a 463 amino acid (aa) residue protein with a putative N-terminal 21 aa residue hydrophobic signal peptide. Like other GPI-linked proteins, rat GFR alpha -2 has a C-terminal hydrophobic region which is preceded by a 3 aa residue (SGS) GPI-binding site. Human GFR alpha -2 shares 96.5% amino acid identity with mouse GFR alpha -2. The expression of the various GFR alpha s are differentially regulated in the central and peripheral nervous system, suggesting complementary roles for the GFR alpha s in mediating the activities of the GDNF family of neurotrophic factors.
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