GDNF Family Ligand-Receptor Interactions

Neurotrophic factors are a broad set of peptide growth factors that tightly regulate many critical aspects of the ontogeny of neurons, such as the number of neurons in a given population, neurite branching and synaptogenesis, adult synaptic plasticity and maturation of electrophysiological properties. Neurotrophic factors include neurotrophins, neurokines and GDNF family ligands. The GDNF family, consisting of GDNF, NRTN, ARTN and PSPN are distant members of the TGF-β superfamily that maintain several neuronal populations in the CNS, including midbrain dopamine neurons. In addition, GDNF, NRTN and ARTN support the survival and regulate the differentiation of many peripheral neurons, including sympathetic, parasympathetic, sensory and enteric neurons.Unlike other members of the TGF-β superfamily which signal through receptor serine-threonine kinases, the cellular responses to GDNF family ligands are mediated by a multi-component receptor complex consisting of Ret (an RTK) and a family of GPI-linked ligand-binding subunits known as GFR-α. GFR-α proteins have unique binding affinities for each GDNF family ligand. GDNF, NRTN, and ARTN specifically bind to GFR-α1, GFR-α2 and GFR-α3. The GDNF family ligands first form a high-affinity complex with one of the four GFR-α proteins. The GDNF-GFR complex then brings two molecules of Ret together. Ret autophosphorylates its tyrosine domains that then serve as docking sites for SH2 domain-containing target molecules. A number of signaling pathways are transduced: the PI3K/AKT1 pathway which is crucial for both neuronal survival and neurite outgrowth, the Ras/Raf/MEK/ERK pathway involved in proliferation, the PLC-γ pathway which regulates the intracellular level of Ca2+ ions via increased IP3, and DOK which is tyrosine phosphorylated by Ret and binds p120-GAP to play a role in mitogenic signaling. GDNF has several roles outside the nervous system. It functions as a morphogen in kidney development and regulates spermatogonial differentiation. GDNF is currently the most potent protein for the treatment of Parkinson's disease.