Feedback control of the protein kinase TAK1 by SAPK2a/p38

• Published in: The EMBO journal Vol. 22; no. 21; pp. 5793 - 5805
• Main Author: Cheung, P. C.F.
• Format: Journal Article
• Language: English
• Published: Heidelberg Blackwell Publishing Ltd 03.11.2003
• ISSN: 1460-2075; 0261-4189; 1460-2075
• DOI: 10.1093/emboj/cdg552

TAB1, a subunit of the kinase TAK1, was phosphorylated by SAPK2a/p38[alpha] 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-[alpha] (TNF-[alpha]), 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/p38[alpha] 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-[alpha], IL-1 or osmotic shock was also enhanced in embryonic fibroblasts from SAPK2a/p38[alpha]-deficient mice, while incubation of these cells with SB 203580 had no effect. Our results suggest that TAB1 participates in a SAPK2a/p38[alpha]-mediated feedback control of TAK1, which not only limits the activation of SAPK2a/p38[alpha] but synchronizes its activity with other signalling pathways that lie downstream of TAK1 (JNK and IKK).