STAT3 as a downstream mediator of Trk signaling and functions

J Biol Chem. 2006 Jun 9;281(23):15636-44. doi: 10.1074/jbc.M601863200. Epub 2006 Apr 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Brain-Derived Neurotrophic Factor / pharmacology
  • Cells, Cultured
  • DNA Primers
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Immunohistochemistry
  • Nerve Growth Factor / pharmacology
  • Neurons / drug effects
  • Neurons / metabolism
  • PC12 Cells
  • Phosphorylation
  • Rats
  • Receptor, trkA / metabolism*
  • STAT3 Transcription Factor / metabolism
  • STAT3 Transcription Factor / physiology*
  • Signal Transduction / physiology*
  • Subcellular Fractions / metabolism
  • Transcription, Genetic / physiology

Substances

  • Brain-Derived Neurotrophic Factor
  • DNA Primers
  • STAT3 Transcription Factor
  • Nerve Growth Factor
  • Receptor, trkA