Differential effects of glial cell line-derived neurotrophic factor and neurturin in RET/GFRalpha1-expressing cells.
The c-ret protooncogene, RET, encodes a receptor tyrosine kinase. RET is activated by members of the glial cell line-derived neurotrophic factor (GDNF) family of ligands, which include GDNF, neurturin, artemin, and persephin. The ligands bind RET through GDNF family receptor alpha, termed GFRalpha1-4. Despite the importance of RET signaling in the development of the enteric nervous system and the kidney, the differential signaling mechanisms between RET ligands are poorly established. It has been suggested that signal specificity is achieved through binding of the ligand to its preferred GFRalpha. To compare the signaling profiles of GDNF and neurturin, we have identified a cell line, NG108-15, which endogenously expresses RET and GFRalpha1 but not GFRalpha2-4. Immunoblot data showed that GDNF caused a transient activation, whereas neurturin caused a sustained activation, of both p44/p42 MAP kinases and PLCgamma. Under serum starvation, NG108-15 cells differentiate and form neurites. Neurturin but not GDNF stimulated neurite outgrowth, which could be blocked by the selective PLC inhibitor U73122. On the other hand, GDNF but not neurturin promoted cell survival, and this could be blocked by the p44/p42 MAP kinase inhibitor PD98059. Our findings not only show the differential signaling of GDNF and neurturin but also suggest that this can be achieved through binding to the same GFRalpha subtype, leading to distinct biological responses.
Lee
Rebecca Hui Kwan
RH
Department of Paediatrics and Adolescent Medicine, the University of Hong Kong, Pokfulam, Hong Kong SAR, People's Republic of China.
Wong
Wai Lap
WL
Chan
Chin Ho
CH
Chan
Siu Yuen
SY
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology*; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics* / Q000502:physiology*; D015151:Immunoblotting; D008024:Ligands; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051101:Neurturin / Q000494:pharmacology*; D010766:Phosphorylation; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000502:physiology*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008024:Ligands; D051101:Neurturin; D014443:Tyrosine; D012313:RNA; D051096:Proto-Oncogene Proteins c-ret; D048052:Mitogen-Activated Protein Kinase 3