TAK1-mediated serine/threonine phosphorylation of epidermal growth factor receptor via p38/extracellular signal-regulated kinase: NF-κB-independent survival …

M Nishimura, MS Shin, P Singhirunnusorn… - … and cellular biology, 2009 - Taylor & Francis
M Nishimura, MS Shin, P Singhirunnusorn, S Suzuki, M Kawanishi, K Koizumi, I Saiki…
Molecular and cellular biology, 2009Taylor & Francis
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 …
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.
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