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Differential effects of glial cell line‐derived neurotrophic factor and neurturin in RET/GFRα1‐expressing cells
Author(s) -
Lee Rebecca Hui Kwan,
Wong Wai Lap,
Chan Chin Ho,
Chan Siu Yuen
Publication year - 2006
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20701
Subject(s) - neurturin , glial cell line derived neurotrophic factor , gdnf family of ligands , neurotrophic factors , proto oncogene proteins c ret , biology , microbiology and biotechnology , receptor tyrosine kinase , cancer research , receptor , signal transduction , biochemistry
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 α, termed GFRα1–4 . 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 GFRα. To compare the signaling profiles of GDNF and neurturin, we have identified a cell line, NG108‐15, which endogenously expresses RET and GFRα1 but not GFRα2–4. Immunoblot data showed that GDNF caused a transient activation, whereas neurturin caused a sustained activation, of both p44/p42 MAP kinases and PLCγ. 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 GFRα subtype, leading to distinct biological responses. © 2005 Wiley‐Liss, Inc.