GDNF triggers a novel Ret-independent Src kinase family-coupled signaling via a GPI-linked GDNF receptor α1

Glial cell line-derived neurotrophic factor (GDNF) has potentially great clinical importance in the treatment of Parkinson's disease and several other neurodegenerative diseases, however its intracellular signaling mechanisms are poorly understood. Here we show that upon GDNF binding glycosylphosphatidylinositol (GPI)-linked GDNF receptor alpha 1 (GFR alpha 1) activates cytoplasmic Src family tyrosine kinase(s) in Ret tyrosine kinase-deficient cultured mouse dorsal root ganglion neurons and in two Ret-negative cell lines. GFR alpha 1-mediated Src-type kinase activation subsequently triggers phosphorylation of mitogen-activated protein kinase, cAMP response element binding protein and phospholipase C gamma, We therefore conclude that GDNF can activate intracellular signaling pathways Ret-independently via GPI-linked GFR alpha 1. (C) 1999 Federation of European Biochemical Societies.