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.

Early Secreted Antigenic Target of 6-kDa of Mycobacterium tuberculosis Stimulates IL-6 Production by Macrophages through Activation of STAT3

“…The phosphorylated STAT3 was located both in the nucleus and cytoplasm though with dominance in the cytoplasm (Fig. 2B), consistent with a previous report that activated STAT3 is not only localized in the nucleus but also in the cytoplasm, probably in mitochondria31.…”

“…2B). This is consistent with a previous report showing both mitochondrial and nuclear localization of active STAT3 in the cells31. The EMSA data showed that STAT3 and NF-κB from macrophages stimulated with ESAT-6 bound to both the STAT3 consensus binding site and IL-6 proximal promoter, clearly demonstrating the functional significance of activated STAT3 by ESAT-6 (Fig.…”

GDNF secreted from adipose-derived stem cells stimulates VEGF-independent angiogenesis

“…RPI-1 is a competitive inhibitor of the ATP-dependent RET kinase receptor that is involved in GDNF signaling [31, 32]. As expected, addition of the RPI-1 potently blocked capillary network formation induced by GDNF, indicating that activation of the RET co-receptor was required for the angiogenic properties of GDNF (Figure 6).…”

“…All of these data strongly suggest that GDNF induces new vessel growth independently of the VEGF angiogenesis pathway. Interestingly, Ret was reported to mediate neurturin (NRTN)-, a member of the GDNF family of ligands (GFL), induced phosphorylation of the signal transducers and activators of transcription 3 (STAT3) [46]. STAT3 played a critical role in oncogenesis and angiogenesis [47, 48].…”

Toward a new STATe: The role of STATs in mitochondrial function

“…As an example, mitochondrial STAT3 is required to drive neurite outgrowth in response to a variety of ligands including nerve growth factor [26,27]. Coupled with the fact that the mitochondrion is the central player in mediating cell death and survival pathways, mitochondrial STAT3 may play a role in cancer biology.…”