Feedback control of the protein kinase TAK1 by SAPK2a/p38α

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).

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