TRAF6 and C-SRC induce synergistic AP-1 activation via PI3-kinase-AKT-JNK pathway

Eur J Biochem. 2003 Mar;270(6):1257-68. doi: 10.1046/j.1432-1033.2003.03487.x.


Interleukin-1 (IL-1) induces multiple genes via activation of transcription factors that include NF-kappa B and activator protein-1 (AP-1). We found that IL-1-mediated c-Src activation was required for AP-1 activation, but not for NF-kappa B activation and also revealed that c-Src-induced AP-1 activation was enhanced synergistically by the coexpression of TNF receptor associated factor 6 (TRAF6). In addition, c-Src interacts with TRAF6 in response to IL-1 and this interaction is required for c-Src activity. However, neither dominant negative mutants of TRAF6 (TRAF6 DN) nor kinase-dead mutant of c-Src (c-Src KD) counteracted each-induced AP-1 activation, suggesting no hierarchy between these two molecules. During the TRAF6 and c-Src-induced AP-1 activation, phosphatidylinositol 3 (PI3)-kinase, its downstream signaling molecule, Akt and c-Jun N-terminal kinase (JNK) were significantly activated and inhibition of these kinase activities down-regulated AP-1 activation through the suppression of c-fos expression. Furthermore, TRAF6 and c-Src-induced JNK activation was significantly inhibited by PI3-kinase inhibitor or a dominant negative mutant of Akt (Akt DN). Taken together, our results demonstrate that c-Src and TRAF6 are key mediators of IL-1-induced AP-1 activation and provide evidence of cross talk between c-Src and TRAF6 molecules through PI3 kinase-Akt-JNK pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Enzyme Activation
  • Enzyme Inhibitors / metabolism
  • Gene Expression Regulation
  • Humans
  • Interleukin-1 / metabolism
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein-Serine-Threonine Kinases*
  • Proteins / genetics
  • Proteins / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins pp60(c-src) / genetics
  • Proto-Oncogene Proteins pp60(c-src) / metabolism*
  • Signal Transduction / physiology*
  • TNF Receptor-Associated Factor 6
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism*


  • Enzyme Inhibitors
  • Interleukin-1
  • Interleukin-8
  • Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-fos
  • TNF Receptor-Associated Factor 6
  • Transcription Factor AP-1
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins pp60(c-src)
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases