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PMID:23872421

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Citation

Zhou, L and Too, HP (2013) GDNF family ligand dependent STAT3 activation is mediated by specific alternatively spliced isoforms of GFRα2 and RET. Biochim. Biophys. Acta 1833:2789-2802

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.

Links

PubMed Online version:10.1016/j.bbamcr.2013.07.004

Keywords

Alternative Splicing/drug effects; Alternative Splicing/genetics; Animals; Cell Nucleus/drug effects; Cell Nucleus/metabolism; Extracellular Signal-Regulated MAP Kinases/metabolism; Glial Cell Line-Derived Neurotrophic Factor Receptors/genetics; Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism; Ligands; Mice; Mitochondria/drug effects; Mitochondria/metabolism; Neural Cell Adhesion Molecules/metabolism; Neurites/drug effects; Neurites/metabolism; Neurturin/pharmacology; PC12 Cells; Phosphorylation/drug effects; Phosphoserine/metabolism; Protein Isoforms/genetics; Protein Isoforms/metabolism; Protein Transport/drug effects; Proto-Oncogene Proteins c-ret/genetics; Proto-Oncogene Proteins c-ret/metabolism; Rats; STAT3 Transcription Factor/metabolism; src-Family Kinases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:RET

acts_upstream_of_or_within

GO:0033141: positive regulation of peptidyl-serine phosphorylation of STAT protein

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0000031)

Seeded From UniProt

complete

MOUSE:RET

acts_upstream_of_or_within

GO:0033141: positive regulation of peptidyl-serine phosphorylation of STAT protein

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0000031)

Seeded From UniProt

complete

MOUSE:RET

NOT|acts_upstream_of_or_within

GO:0033139: regulation of peptidyl-serine phosphorylation of STAT protein

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RET

acts_upstream_of_or_within

GO:0033141: positive regulation of peptidyl-serine phosphorylation of STAT protein

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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