GDNF – a stranger in the TGF‐β superfamily?

Glial cell line‐derived neurotrophic factor (GDNF) family, consisting of GDNF, neurturin, artemin and persephin are distant members of the transforming growth factor‐β (TGF‐β) superfamily. Unlike other members of the TGF‐β 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 α (GFRα) and then the GDNF family ligand–GFRα complex binds to and stimulates autophosphorylation of Ret. Alternatively, a preassociated complex between GFRα and Ret could form the binding site for the GDNF family ligand. GFRα1, GFRα2, GFRα3 and GFRα4 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 GFRα1 in the absence of Ret. GPI‐anchored GFRα receptors are localized in plasma membrane to lipid rafts. GDNF binding to GFRα1 also recruits Ret to the lipid rafts and triggers association with Src, which is required for effective downstream signalling, leading to differ