GDNF family ligand dependent STAT3 activation is mediated by specific alternatively spliced isoforms of GFRα2 and RET.

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. 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 duanyu18133 in primary cortical neuron and neuronal cell lines. Remarkably, duanyu18133 phosphorylation was found to be mediated specifically by GFRα2c and RET9 isoforms. Furthermore, serine but not tyrosine dominant negative mutant of duanyu18133 impaired NRTN induced neurite outgrowth, indicative of the role of duanyu18133 as a downstream mediator of NRTN function. Similar to NGF, the NRTN induced was localized to the mitochondria but not to the nucleus. Mitochondrial duanyu18133 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 duanyu18133 and the transcription independent mechanism whereby the mitochondria localized P-Ser-duanyu18133 mediated NRTN induced neurite outgrowth.

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