GDNF-induced cell signaling and neurite outgrowths are differentially mediated by GFRalpha1 isoforms.
Glial cell line-derived neurotrophic factor (GDNF) transduces signal and promotes neurite outgrowths in diverse neurons through the interactions of GDNF family receptor alpha 1 (GFRalpha1) and other co-receptors including Ret receptor tyrosine kinase and NCAM. GFRalpha1 is alternatively spliced into two isoforms, GFRalpha1a and GFRalpha1b, with five amino acids difference. In this study, we found that both GFRalpha1a and GFRalpha1b were expressed in various human tissues. Interestingly, when stimulated with GDNF, GFRalpha1a but not GFRalpha1b promoted neurite outgrowth in neuroblastoma cells through the activations of ERK1/2, Rac1 and Cdc42. Remarkably, in cells co-expressing GFRalpha1a and GFRalpha1b, GDNF inhibited neurite outgrowths. The inhibitory activity of GFRalpha1b was dependent on RhoA and ROCK activation. Furthermore, GFRalpha1b but not GFRalpha1a activated Rho and various ROCK downstream effectors LIMK1/2, cofilin and MLC2. This study demonstrates the hitherto unrecognized roles of GFRalpha1 isoforms in the activation of distinct signaling pathways and in neurite outgrowths.
Yoong
Li Foong
LF
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Lower Kent Ridge Road, 119260, Singapore.
Wan
Guoqiang
G
Too
Heng-Phon
HP
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016501:Neurites / Q000502:physiology*; D009447:Neuroblastoma; D051101:Neurturin / Q000494:pharmacology; D020033:Protein Isoforms / Q000378:metabolism*; D012234:Rho Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors; D051765:Early Growth Response Transcription Factors
D004268:DNA-Binding Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D051101:Neurturin; D020033:Protein Isoforms; D012234:Rho Factor; D014157:Transcription Factors; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; C494988:Gfra1 protein, mouse; C495056:Nrtn protein, mouse; C569958:KLF10 protein, mouse; D051741:Kruppel-Like Transcription Factors; D051765:Early Growth Response Transcription Factors