TRAF6 and C-SRC induce synergistic AP-1 activation via PI3-kinase-AKT-JNK pathway.
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.
Funakoshi-Tago
Megumi
M
Department of Biochemistry, Kyoritsu College of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
Tago
Kenji
K
Sonoda
Yoshiko
Y
Tominaga
Shin-Ichi
S
Kasahara
Tadashi
T
D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007375:Interleukin-1; D016209:Interleukin-8; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016760:Proto-Oncogene Proteins c-fos; D016392:Proto-Oncogene Proteins pp60(c-src); D048029:TNF Receptor-Associated Factor 6; D018808:Transcription Factor AP-1; C494918:AKT1 protein, human