Cross interference with TNF-alpha-induced TAK1 activation via EGFR-mediated p38 phosphorylation of TAK1-binding protein 1.
Transforming growth factor-alpha-activated kinase 1 (TAK1) has been widely recognized as a kinase that regulates multiple intracellular signaling pathways evoked by cytokines and immune receptor activation. We have recently reported that tumor necrosis factor-alpha (TNF-alpha) triggers internalization of epidermal growth factor receptor (EGFR) through a TAK1-p38alpha signaling pathway, which results in a transient suppression of the EGFR. In the present study, we investigated the pathway of intracellular signaling in the opposite direction. Ligand-induced activation of EGFR caused phosphorylation of the TAK1-binding proteins TAB1 and TAB2 in a TAK1-independent manner. EGFR-mediated phosphorylation of TAB1 was completely inhibited by a chemical inhibitor and siRNA of p38alpha. The phosphorylation of TAB1 was occurred at Ser-423 and Thr-431, the residues underlying the p38-mediated feedback inhibition of TAK1. In contrast, phosphorylation of TAB2 was sustained, and largely resistant to p38 inhibition. The inducible phosphorylation of TAB1 interfered with a response of EGF-treated cells to TNF-alpha-induced TAK1 activation, which led to the reduction of NF-kappaB activation. Collectively, these results demonstrated that EGFR activation interfered with TNF-alpha-induced TAK1 activation via p38-mediated phosphorylation of TAB1.
Shin
Myoung-Sook
MS
Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan.
Shinghirunnusorn
Pattama
P
Sugishima
Yumiko
Y
Nishimura
Miki
M
Suzuki
Shunsuke
S
Koizumi
Keiichi
K
Saiki
Ikuo
I
Sakurai
Hiroaki
H
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
D048868:Adaptor Proteins, Signal Transducing; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D008156:Luciferases; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D010744:Phosphoric Monoester Hydrolases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C486300:TAB1 protein, human; C512478:EGFR protein, human