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Interleukin-6-induced STAT3 transactivation and Ser727 phosphorylation involves Vav, Rac-1 and the kinase SEK-1/MKK-4

J J Schuringa1, L J Jonk, W H Dokter

  • 1Department of Genetics, Biological Center, Kerklaan 30, 9751 NN, Haren, The Netherlands.

The Biochemical Journal
|March 23, 2000
PubMed

Insights

Interleukin-6 (IL-6) stimulation activates signal transducer and activator of transcription 3 (STAT3) phosphorylation and transactivation via the SEK-1/MKK-4 pathway, independent of ERK-1 and JNK-1. P38 kinase acts as a negative regulator.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Signal transduction

Background:

  • Signal transducer and activator of transcription 3 (STAT3) is a key transcription factor involved in various cellular processes.
  • Interleukin-6 (IL-6) is a cytokine that activates STAT3 signaling.
  • Mitogen-activated protein (MAP) kinases, including ERK-1, JNK-1, and p38, are involved in cellular responses to stimuli.

Purpose of the Study:

  • To investigate the role of MAP kinase family members in IL-6-induced STAT3 phosphorylation and transactivation.
  • To identify the specific signaling cascade components involved in IL-6-mediated STAT3 activation.

Main Methods:

  • HepG2 cells were stimulated with IL-6.
  • Inhibitors of MAP kinase pathway (PD98059, SB203580) were used.
  • Dominant-negative constructs of Raf and SEK-1/MKK-4 were overexpressed.
  • STAT3 phosphorylation and transactivation were assessed.
  • Upstream components of SEK-1/MKK-4 were identified.

Main Results:

  • IL-6-induced STAT3 activation was independent of ERK-1 and JNK-1.
  • SEK-1/MKK-4 was activated by IL-6, and its inhibition reduced STAT3 phosphorylation and transactivation.
  • Vav, Rac-1, and MEKK were identified as upstream components of the IL-6-induced SEK-1/MKK-4 cascade.
  • p38 kinase inhibition increased STAT3 transactivation, suggesting a negative regulatory role.

Conclusions:

  • IL-6-induced STAT3 transactivation and Ser(727) phosphorylation are mediated by a gp130 receptor-signalling cascade involving Vav, Rac-1, MEKK, and SEK-1/MKK-4.
  • ERK-1 and JNK-1 are not involved in this specific IL-6-induced STAT3 activation pathway.
  • p38 kinase negatively regulates IL-6-induced STAT3 transactivation through an uncharacterized mechanism.

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