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.