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- Title
Feedback control of the protein kinase TAK1 by SAPK2a/p38α.
- Authors
Peter C.F. Cheung; David G. Campbell; Angel R. Nebreda; Philip Cohen
- Abstract
TAB1, a subunit of the kinase TAK1, was phosphorylated by SAPK2a/p38α at Ser423, Thr431 and Ser438 in vitro. TAB1 became phosphorylated at all three sites when cells were exposed to cellular stresses, or stimulated with tumour necrosis factor-α (TNF-α), interleukin-1 (IL-1) or lipopolysaccharide (LPS). The phosphorylation of Ser423 and Thr431 was prevented if cells were pre-incubated with SB 203580, while the phosphorylation of Ser438 was partially inhibited by PD 184352. Ser423 is the first residue phosphorylated by SAPK2a/p38α that is not followed by proline. The activation of TAK1 was enhanced by SB 203580 in LPS-stimulated macrophages, and by proinflammatory cytokines or osmotic shock in epithelial KB cells or embryonic fibroblasts. The activation of TAK1 by TNF-α, IL-1 or osmotic shock was also enhanced in embryonic fibroblasts from SAPK2a/p38α-deficient mice, while incubation of these cells with SB 203580 had no effect. Our results suggest that TAB1 participates in a SAPK2a/p38α-mediated feedback control of TAK1, which not only limits the activation of SAPK2a/p38α but synchronizes its activity with other signalling pathways that lie downstream of TAK1 (JNK and IKK).
- Publication
EMBO Journal, 2003, Vol 22, Issue 21, p5793
- ISSN
0261-4189
- Publication type
Academic Journal
- DOI
10.1093/emboj/cdg552