Novel functions and signalling pathways for GDNF.
Glial-cell-line-derived neurotrophic factor (GDNF) was originally identified as a survival factor for midbrain dopaminergic neurons. GDNF and related ligands, neurturin (NRTN), artemin (ARTN) and persephin (PSPN), maintain several neuronal populations in the central nervous systems, including midbrain dopamine neurons and motoneurons. In addition, GDNF, NRTN and ARTN support the survival and regulate the differentiation of many peripheral neurons, including sympathetic, parasympathetic, sensory and enteric neurons. GDNF has further critical roles outside the nervous system in the regulation of kidney morphogenesis and spermatogenesis. GDNF family ligands bind to specific GDNF family receptor alpha (GFRalpha) proteins, all of which form receptor complexes and signal through the RET receptor tyrosine kinase. The biology of GDNF signalling is much more complex than originally assumed. The neurotrophic effect of GDNF, except in motoneurons, requires the presence of transforming growth factor beta, which activates the transport of GFRalpha1 to the cell membrane. GDNF can also signal RET independently through GFR1alpha. Upon ligand binding, GDNF in complex with GFRalpha1 may interact with heparan sulphate glycosaminoglycans to activate the Met receptor tyrosine kinase through cytoplasmic Src-family kinases. GDNF family ligands also signal through the neural cell adhesion molecule NCAM. In cells lacking RET, GDNF binds with high affinity to the NCAM and GFRalpha1 complex, which activates Fyn and FAK.
Sariola
Hannu
H
Institute of Biomedicine, University of Helsinki, PO Box 63 (Haartmaninkatu 8), FIN-00014, Finland. hannu.sariola@helsinki.fi
Saarma
Mart
M
D000818:Animals; D002470:Cell Survival; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008636:Mesencephalon / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D051101:Neurturin; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013091:Spermatogenesis / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism
C490886:ARTN protein, human; C495039:GDNF protein, human; C494987:GFRA1 protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; C495053:NRTN protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D051101:Neurturin; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; C110758:persephin; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases