TAK1-mediated serine/threonine phosphorylation of epidermal growth factor receptor via p38/extracellular signal-regulated kinase: NF-{kappa}B-independent survival pathways in tumor necrosis factor alpha signaling.
The kinase TAK1, a mitogen-activated protein kinase kinase kinase (MAP3K), has been widely accepted as a key kinase activating NF-kappaB and MAPKs in tumor necrosis factor alpha (TNF-alpha) signaling. We have recently reported that TAK1 regulates the transient phosphorylation and endocytosis of epidermal growth factor receptor (EGFR) in a tyrosine kinase activity-independent manner. In the present study, we found that Thr-669 in the juxtamembrane domain and Ser-1046/1047 in the carboxyl-terminal regulatory domain were transiently phosphorylated in response to TNF-alpha. Experiments using chemical inhibitors and small interfering RNA demonstrated that TNF-alpha-mediated phosphorylation of Thr-669 and Ser-1046/7 were differently regulated via TAK1-extracellular signal-regulated kinase (ERK) and TAK1-p38 pathways, respectively. In addition, p38, but not ERK, was involved in the endocytosis of EGFR. Surprisingly, modified EGFR was essential to prevent apoptotic cellular responses; however, the EGFR pathway was independent of the NF-kappaB antiapoptotic pathway. These results demonstrated that TAK1 controls two different signaling pathways, IkappaB kinase-NF-kappaB and MAPK-EGFR, leading to the survival of cells exposed to the death signal from the TNF-alpha receptor.
Nishimura
Miki
M
Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Shin
Myoung-Sook
MS
Singhirunnusorn
Pattama
P
Suzuki
Shunsuke
S
Kawanishi
Miho
M
Koizumi
Keiichi
K
Saiki
Ikuo
I
Sakurai
Hiroaki
H
D000873:Anthracenes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000819:agonists / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013912:Threonine / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7; D015025:Zearalenone / Q000008:administration & dosage
D000873:Anthracenes; D002070:Butadienes; D004791:Enzyme Inhibitors; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D007093:Imidazoles; D007783:Lactones; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D009570:Nitriles; D011725:Pyridines; D011799:Quinazolines; D034741:RNA, Small Interfering; D012118:Resorcinols; D012694:Serine; D013912:Threonine; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C505734:7-oxozeanol; D015025:Zearalenone; C113580:U 0126; C432165:pyrazolanthrone; C093642:SB 203580; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline
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