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STAT3 as a downstream mediator of Trk signaling and functions

Yu Pong Ng1, Zelda H Cheung, Nancy Y Ip

  • 1Department of Biochemistry, Biotechnology Research Institute, and Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.

The Journal of Biological Chemistry
|April 14, 2006
PubMed

Insights

Signal transducer and activator of transcription 3 (STAT3) is a novel signal transducer for TrkA, mediating nerve growth factor (NGF) functions. STAT3 activation is crucial for neurotrophin-induced gene transcription, cell growth, and neurite outgrowth.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Signaling

Background:

  • Signal transducer and activator of transcription 3 (STAT3) regulates gene transcription in response to cytokines and growth factors.
  • Recent evidence suggests STAT3 activation downstream of receptor-tyrosine kinases.
  • The role of STAT3 in neurotrophin signaling pathways remains incompletely understood.

Purpose of the Study:

  • To identify novel signaling molecules involved in neurotrophin pathways.
  • To investigate the role of STAT3 as a signal transducer for TrkA, the receptor for nerve growth factor (NGF).
  • To elucidate the downstream functions mediated by STAT3 activation in response to neurotrophins.

Main Methods:

  • Investigated STAT3 activation downstream of TrkA receptor-tyrosine kinase.
  • Utilized RNA interference to knock down STAT3 expression in PC12 cells.
  • Assessed NGF-induced gene transcription, cyclin D1 expression, and growth arrest.
  • Examined the effect of STAT3 inhibition on brain-derived neurotrophic factor-promoted neurite outgrowth in primary hippocampal neurons.

Main Results:

  • Identified STAT3 as a novel signal transducer for TrkA, activated by NGF.
  • NGF-induced TrkA activation led to STAT3 phosphorylation at Ser-727, enhancing its DNA binding and transcriptional activity.
  • STAT3 knockdown attenuated NGF-induced immediate early gene transcription and cyclin D1 expression, inhibiting NGF-induced growth arrest.
  • Inhibition of STAT3 suppressed brain-derived neurotrophic factor-promoted neurite outgrowth in primary hippocampal neurons.

Conclusions:

  • STAT3 is a critical downstream signaling component of neurotrophin signaling pathways.
  • STAT3 mediates key neurotrophin functions, including gene transcription, cell cycle regulation, and neurite outgrowth.
  • These findings establish STAT3 as an essential mediator of neurotrophin actions.

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