Find GDNF Products Interaction Network for GDNF GDNF Details

Related Pathways Amyotrophic Lateral Sclerosis Signaling View All Pathways

Synonyms: AI385739, ATF1, ATF2, GDNF, GDNPF, HFB1-GDNF

GDNF-Family Ligands and Receptor Interactions

The glial cell line-derived neurotrophic factor family, a family of the transforming growth factor-beta (TGF-beta) superfamily, is composed of glial cell line-derived neurotrophic factor (GDNF), neurturin (NTN/NRTN), persephin (PSP,PSPN), and artemin (ART/ARTN/enovin). GDNF family proteins are differentially involved in the development and maintenance of sensory, enteric, sympathetic and parasympathetic neurons and a variety of non-neural tissues. GDNF is an especially potent survival factor for dopaminergic, noradrenergic and spinal motor neurons. GDNF family growth members have functions outside the nervous system. NTN, ART, and PSP are also expressed in the developing kidney. GDNF has critical roles outside the nervous system in the regulation of kidney morphogenesis and spermatogenesis. GDNF has been shown to promote ureteric branching in developing kidney.

Each member of the GDNF family binds preferentially to a glycosylphosphatidylinositol (GPI)-anchored protein receptor dynamically associated with the plasma membrane. The GDNF family receptor family is composed of GFRalpha1 (GFRα1, GDNFR-alpha); GFRalpha2 (GFRα2/TrnR2/GDNFR-beta/NTNR-alpha/RETL2); GFRalpha3 (GFRα3); and GFRalpha4 (GFRα4). GFR alpha-2 is highly expressed in cortex, basal forebrain, and specific layers of the olfactory bulb, and poorly expressed in substantia nigra, cerebellum, and motor nuclei. GFRalpha-3 is expressed in fetal and adult mouse heart, brain, lung and kidney. GFRalpha-4 is expressed at low levels in different brain areas in the adult as well as in some peripheral tissues including testis and heart. GDNF family member binding preferences are GDNF to GFRα1; neurturin to GFRα2; artemin to GFRα3; and persephin to GFRα4. The ligand receptor pairing is not stringent. GDNF binds to GFRα2 and GFRα3 with lower efficiencies than it binds to GFRα1.

The GDNF family ligands, typically by not exclusively, transmit their signals through multi-component complexes composed of a ligand, its GFRalpha receptor and the receptor tyrosine kinase, c-Ret. Ret is a common element of these ligand signaling complexes. Ret is a proto-oncogene that strongly activates anti-apoptotic signals through the activation of the phosphoinositol-3 kinases (PI3-K)/PDK/AKT(PKB) and the Ras/Raf/MEK/ERK pathways. Ret is also able to activate phospholipase Cgamma (PLCgamma) which elevates intracellular calcium and facilitates activation of members of the conventional and novel protein kinase C (PKC) family. GDNF family ligand receptor complexes are not restricted to signaling through Ret. GDNF:GFRalpha1 can bind to NCAM in cells lacking RET and activate Fyn and FAK. Under some conditions GDNF:GFRalpha complexes directly activate src kinase.

RET is expressed in neuroendocrine cells and derivative tumors. Tissues affected by mutations in RET are typically derived from neural crest during development. Activating RET mutations are found in inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2), associated with medullary thyroid carcinoma and pheochromocytoma.