title: STAT3 as a downstream mediator of Trk signaling and functions.
abstract: Signal transducer and activator of transcription 3 (STAT3) has long been shown to regulate gene transcription in response to cytokines and growth factors. Recent evidence suggests that STAT3 activation may also occur downstream of receptor-tyrosine kinase activation. In the current study we have identified STAT3 as a novel signal transducer for TrkA, the receptor-tyrosine kinase that mediates the functions of nerve growth factor (NGF). Activation of TrkA by NGF triggered STAT3 phosphorylation at Ser-727, and enhanced the DNA binding and transcriptional activities of STAT3. More importantly, neurotrophin-induced increase in STAT3 activation was observed to underlie several downstream functions of neurotrophin signaling. First of all, knockdown of STAT3 expression using the RNA interference approach attenuated NGF-induced transcription of immediate early genes in PC12 cells. Furthermore, reduced STAT3 expression in PC12 cells suppressed NGF-induced cyclin D1 expression, thereby inhibiting growth arrest normally triggered by NGF treatment. Finally, inhibition of STAT3 expression decreased brain-derived neurotrophic factor-promoted neurite outgrowth in primary hippocampal neurons. Together, our findings have identified STAT3 as an essential component of neurotrophin signaling and functions.
authors.affiliation: Department of Biochemistry, Biotechnology Research Institute, and Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
authors.forename: Yu Pong
authors.initials: YP
authors.lastname: Ng
authors.forename: Zelda H
authors.initials: ZH
authors.lastname: Cheung
authors.forename: Nancy Y
authors.initials: NY
authors.lastname: Ip
mesh_terms: D000818:Animals; D001483:Base Sequence; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002478:Cells, Cultured; D017931:DNA Primers; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013347:Subcellular Fractions / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017931:DNA Primers; D050796:STAT3 Transcription Factor; D020932:Nerve Growth Factor; D020917:Receptor, trkA