title: GDNF family ligand dependent STAT3 activation is mediated by specific alternatively spliced isoforms of GFRα2 and RET.
abstract: Neurturin (NRTN), a member of the GDNF family of ligands (GFL), is currently investigated in a series of clinical trials for Parkinson's disease. NRTN signals through its cognate receptor GFRα2 and co-receptor RET to induce neurite outgrowth, but the underlying mechanism remains to be better understood. STAT3 was previously shown to be activated by oncogenic RET, independent of ligand and GFRα. In this study, we demonstrated that NRTN induced serine(727) but not tyrosine(705) phosphorylation of STAT3 in primary cortical neuron and neuronal cell lines. Remarkably, STAT3 phosphorylation was found to be mediated specifically by GFRα2c and RET9 isoforms. Furthermore, serine but not tyrosine dominant negative mutant of STAT3 impaired NRTN induced neurite outgrowth, indicative of the role of STAT3 as a downstream mediator of NRTN function. Similar to NGF, the NRTN induced P-Ser-STAT3 was localized to the mitochondria but not to the nucleus. Mitochondrial STAT3 was further found to be intimately involved in NRTN induced neurite outgrowth. Collectively, these findings demonstrated the hitherto unrecognized and novel role of specific GFRα2 and RET isoforms in mediating NRTN activation of STAT3 and the transcription independent mechanism whereby the mitochondria localized P-Ser-STAT3 mediated NRTN induced neurite outgrowth.
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore; Bioprocessing Technology Institute, Agency for Science Technology and Research (A*STAR), Singapore.
authors.forename: Lihan
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore; Chemical Pharmaceutical Engineering, Singapore-Massachusetts Institute of Technology Alliance, Singapore; Bioprocessing Technology Institute, Agency for Science Technology and Research (A*STAR), Singapore. Electronic address: heng-phon_too@nuhs.edu.sg.
authors.forename: Heng-Phon
authors.initials: HP
authors.lastname: Too
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D051101:Neurturin / Q000494:pharmacology*; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008024:Ligands; D019006:Neural Cell Adhesion Molecules; D051101:Neurturin; D020033:Protein Isoforms; D050796:STAT3 Transcription Factor; D010768:Phosphoserine; D051096:Proto-Oncogene Proteins c-ret; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: GDNF; GDNF family ligand; GDNF family receptor alpha; GFL; GFRα; GFRα2; Mitochondrial STAT3; NCAM; NRTN; Neurturin; RE arranged during Transformation; RET; Receptor isoform; STAT3; Signal Transducer and Activator of Transcription 3; glial cell line-derived neurotrophic factor; neural cell adhesion molecule