Journal
EUROPEAN JOURNAL OF BIOCHEMISTRY
Volume 267, Issue 24, Pages 6968-6971Publisher
WILEY
DOI: 10.1046/j.1432-1327.2000.01826.x
Keywords
GDNF; neurturin; artemin; persephin; Ret; GFR alpha; dopamine neurons; motoneurons; ureteric branching; spermatogenesis
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Glial cell line-derived neurotrophic factor (GDNF) family, consisting of GDNF, neurturin, artemin and persephin are distant members of the transforming growth factor-beta (TGF-beta) superfamily. Unlike other members of the TGF-beta superfamily, which signal through the receptor serine-threonine kinases, GDNF family ligands activate intracellular signalling cascades via the receptor tyrosine kinase Ret. GDNF family ligands first bind to the glycosylphosphatidylinositol (GPI)-anchored GDNF family receptor alpha (GFR alpha) and then the GDNF family ligand-GFR alpha complex binds to and stimulates autophosphorylation of Ret. Alternatively, a preassociated complex between GFR alpha and Ret could form the binding site for the GDNF family ligand. GFR alpha1, GFR alpha2, GFR alpha3 and GFR alpha4 are the physiological coreceptors for GDNF, neurturin, artemin and persephin, respectively. Although all GDNF family ligands signal via activated Ret, GDNF can signal also via GFR alpha1 in the absence of Ret. GPI-anchored GFR alpha receptors are localized in plasma membrane to lipid rafts. GDNF binding to GFR alpha1 also recruits Ret to the lipid rafts and triggers association with Src, which is required for effective downstream signalling, leading to differentiation and neuronal survival. GDNF family ligands are potent survival factors for midbrain dopamine neurons, motoneurons, noradrenergic neurons, as well as for sympathetic, parasympathetic and sensory neurons. However, for most neuronal populations, except for motoneurons, TGF-beta is required as a cofactor for GDNF family ligand signalling. Because GDNF and neurturin can rescue dopamine neurons in the animal models of Parkinson disease, as well as motoneurons in vivo, hopes have been raised that GDNF family ligands may be new drugs for the treatment of neurodegenerative diseases. GDNF also has distinct functions outside the nervous system, promoting ureteric branching in kidney development and regulating spermatogenesis.
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