TAK1-Mediated Serine/Threonine Phosphorylation of Epidermal Growth Factor Receptor via p38/Extracellular Signal-Regulated Kinase: NF-κB-Independent Survival Pathways in Tumor Necrosis Factor Alpha Signaling

Abstract

The kinase TAK1, a mitogen-activated protein kinase kinase kinase (MAP3K), has been widely accepted as a key kinase activating NF-κB and MAPKs in tumor necrosis factor alpha (TNF-α) 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-α. Experiments using chemical inhibitors and small interfering RNA demonstrated that TNF-α-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-κB antiapoptotic pathway. These results demonstrated that TAK1 controls two different signaling pathways, IκB kinase-NF-κB and MAPK-EGFR, leading to the survival of cells exposed to the death signal from the TNF-α receptor.

ACKNOWLEDGMENTS

We are grateful to N. Yanaka and K. Ono for the generous gifts of pEGFP-N1 and 5Z-7-oxozeaenol, respectively.

This work was supported in part by Grants-in-Aid for Scientific Research (C) (no. 19590063) and for the Cooperative Link of Unique Science and Technology for Economy Revitalization from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, and grants from the Sumitomo Foundation and Tamura Science Foundation.