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Molecular and Cellular Biology, October 2009, p. 5529-5539, Vol. 29, No. 20
0270-7306/09/$08.00+0     doi:10.1128/MCB.00375-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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{triangledown}

Miki Nishimura, Myoung-Sook Shin, Pattama Singhirunnusorn, Shunsuke Suzuki, Miho Kawanishi, Keiichi Koizumi, Ikuo Saiki, and Hiroaki Sakurai*

Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan

Received 24 March 2009/ Returned for modification 6 May 2009/ Accepted 10 August 2009

The kinase TAK1, a mitogen-activated protein kinase kinase kinase (MAP3K), has been widely accepted as a key kinase activating NF-{kappa}B 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-{kappa}B antiapoptotic pathway. These results demonstrated that TAK1 controls two different signaling pathways, I{kappa}B kinase-NF-{kappa}B and MAPK-EGFR, leading to the survival of cells exposed to the death signal from the TNF-{alpha} receptor.

* Corresponding author. Mailing address: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Phone: 81-76-434-7636. Fax: 81-76-434-5058. E-mail: hsakurai{at}inm.u-toyama.ac.jp

{triangledown} Published ahead of print on 17 August 2009.

Molecular and Cellular Biology, October 2009, p. 5529-5539, Vol. 29, No. 20
0270-7306/09/$08.00+0     doi:10.1128/MCB.00375-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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