GDNF-Family Ligands and Receptor Interactions
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GDNF-Family Ligands and 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 (Glial-cell-line-derived Neurotrophic Factor) family ligands (GFLs). GDNF family, consisting of GDNF, NRTN (Neurturin), ARTN (Artemin) and PSPN (Persephin) are distant members of the TGF-Beta (Transforming Growth Factor-Beta) superfamily that maintain several neuronal populations in the CNS (Central Nervous Systems), 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 (Ref.1).

Unlike other members of the TGF-Beta superfamily, which signal through the receptor serine-threonine kinases, the cellular responses to GFLs are mediated by a multicomponent receptor complex consisting of Ret (Rearranged during transformation) receptor tyrosine kinase and a GPI (Glycosyl Phosphatidylinositol)-linked ligand-binding subunit known as GFR-Alpha (GDNF Family Receptor-Alpha) (Ref.2). GFR-Alpha proteins that have unique binding affinities for each GFL determine the ligand-binding specificity of GFLs. GDNF, NRTN, and ARTN specifically bind to GFR-Alpha1, GFR-Alpha2 and GFR-Alpha3. PSPN does not bind or activate any of the mammalian GFR-Alpha, but does bind to a protein currently only identified in chicken called GFR-Alpha4. The GFLs first form a high-affinity complex with one of the four GFR-Alpha proteins. The complex, containing GFL and GFR-Alpha homodimers, then brings two molecules of Ret together, triggering transphosphorylation of specific tyrosine residues in their tyrosine kinase domains and intracellular signaling (Ref.3). Upon ligand binding Ret autophosphorylates its tyrosine domains that then serve as docking sites for SH2 (Src Homology-2) domain-containing target molecules activating different intracellular pathways, which regulate cell survival, differentiation, proliferation, migration, chemotaxis, branching morphogenesis, neurite outgrowth and synaptic plasticity. Tyr1062 of Ret, which represents an intracytoplasmic docking site for multiple signaling molecules, is essential for Ret-mediated activation of PI3K (Phosphatidylinositol 3-Kinase). PI3K in turn, induces cell survival and neoplastic transformation mediated by Ret. IRS1/2 (Insulin Receptor Substrate-1/2) is tyrosine phosphorylated and associated with the p85 regulatory subunit of PI3K in response to Ret activation and results in the potentiation of Ret-mediated activation of Akt/PKB (Protein Kinase-B). Ret also associates with SHC (Src Homology domain-containing adaptor protein), GRB2 (Growth Factor Receptor-Bound Protein-2), SOS, PLC-Gamma (Phospholipase-C), Crk, Nck1, and activate the Ras-MAPK (Mitogen-Activated Protein Kinase) pathway (Ref.4). The MAPK pathway may be involved in ureteric branching during nephrogenesis and neurite outgrowth in the nervous system, but it also contributes to neuronal survival. The PI3K/Akt1 pathway is crucial for both neuronal survival and neurite outgrowth and the PLC-Gamma pathway regulates the intracellular level of Ca2+ ions by increasing the level of IP3 (Inositol (1,4,5) Trisphosphate) (Ref.3). Enigma also interacts with the short isoform of Ret and is involved in the assembly of an Actin filament-associated complex essential for transmission of Ret-mediated mitogenic signaling (Ref.6). DOK (Docking Protein) is constitutively tyrosine phosphorylated by Ret and binds p120-GAP (RasGAP) to play a role in mitogenic signaling.

GDNF can also signal Ret independently through GFR-Alpha1. Upon ligand binding, GDNF in complex with GFR-Alpha1 may interact with heparan sulphate glycosaminoglycans, such as syndecan to activate the Met receptor tyrosine kinase and trigger Src-family kinase activation and phosphorylation of ERK1/2 (Extracellular Signal-Regulated Kinase)/MAPK, PLC-Gamma and the transcription factor CREB (cAMP Response Element Binding protein), and induction of c-Fos mRNA expression (Ref.5). GDNF family ligands also signal through the NCAM (Neural Cell Adhesion Molecule). In cells lacking Ret, GDNF binds with high affinity to the NCAM and GFR-Alpha1 complex, which activates Fyn and FAK (Focal Adhesion Kinase).

GDNF and the related GFLs ARTN, NRTN and PSPN support several neuronal populations in the CNS, including midbrain dopamine neurons and motoneurons. In addition, GDNF has several roles outside the nervous system. It functions as a morphogen in kidney development and regulates spermatogonial differentiation. In the embryonic kidney, GDNF acts as a mesenchyme-derived signal promoting ureteric branching. In the testis, the GDNF dosage controls the cell fate decision of undifferentiated spermatogonia (Ref.3). GDNF is currently the most potent protein for the treatment of the Parkinsons disease. However, the molecular events leading to the degeneration of dopaminergic neurons are largely unclear. Unravelling the intracellular cascades that are activated in GDNF-deprived dopaminergic neurons would offer a unique opportunity to develop pharmacological inhibitors that specifically block these death pathways but leave other pathways untouched.