Roget, K., Ben-Addi, A., Mambole-Dema, A., Gantke, T., Yang, H.-T., Janzen, J., Morrice, N., Abbott, D. and Ley, S. C. (2012) I B Kinase 2 regulates TPL-2 activation of extracellular signal-regulated kinases 1 and 2 by direct phosphorylation of TPL-2 serine 400. Molecular and Cellular Biology, 32(22), pp. 4684-4690. (doi: 10.1128/MCB.01065-12)
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Abstract
Tumor progression locus 2 (TPL-2) functions as a MEK-1/2 kinase, which is essential for Toll-like receptor 4 (TLR4) activation of extracellular signal-regulated kinase 1 and 2 (ERK-1/2) mitogen-activated protein (MAP) kinases in lipopolysaccharide (LPS)-stimulated macrophages and for inducing the production of the proinflammatory cytokines tumor necrosis factor and interleukin-1β. In unstimulated cells, association of TPL-2 with NF-κB1 p105 prevents TPL-2 phosphorylation of MEK-1/2. LPS stimulation of TPL-2 MEK-1/2 kinase activity requires TPL-2 release from p105. This is triggered by IκB kinase 2 (IKK-2) phosphorylation of the p105 PEST region, which promotes p105 ubiquitination and degradation by the proteasome. LPS activation of ERK-1/2 additionally requires transphosphorylation of TPL-2 on serine 400 in its C terminus, which controls TPL-2 signaling to ERK-1/2 independently of p105. However, the identity of the protein kinase responsible for TPL-2 serine 400 phosphorylation remained unknown. In the present study, we show that TPL-2 serine 400 phosphorylation is mediated by IKK2. The IKK complex therefore regulates two of the key regulatory steps required for TPL-2 activation of ERK-1/2, underlining the close linkage of ERK-1/2 MAP kinase activation to upregulation of NF-κB-dependent transcription.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Morrice, Dr Nicholas |
| Authors: | Roget, K., Ben-Addi, A., Mambole-Dema, A., Gantke, T., Yang, H.-T., Janzen, J., Morrice, N., Abbott, D., and Ley, S. C. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Molecular and Cellular Biology |
| Publisher: | American Society for Microbiology |
| ISSN: | 0270-7306 |
| ISSN (Online): | 1098-5549 |
| Published Online: | 17 September 2012 |
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