Feedback control of the protein kinase TAK1 by SAPK2a/p38

Peter C. F. Cheung, David G. Campbell, Angel R. Nebreda, Philip Cohen

    Research output: Contribution to journalArticle

    214 Citations (Scopus)

    Abstract

    NOTE: THE MATHEMATICAL SYMBOLS/SPECIAL CHARACTERS IN THIS ABSTRACT CANNOT BE DISPLAYED CORRECTLY ON THIS PAGE. PLEASE REFER TO THE ABSTRACT IN THE PUBLISHER'S WEBSITE FOR AN ACCURATE DISPLAY. TAB1, a subunit of the kinase TAK1, was phosphorylated by SAPK2a/p38? 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-? (TNF-?), 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? 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-?, IL-1 or osmotic shock was also enhanced in embryonic fibroblasts from SAPK2a/p38-?deficient mice, while incubation of these cells with SB 203580 had no effect. Our results suggest that TAB1 participates in a SAPK2a/p38?-mediated feedback control of TAK1, which not only limits the activation of SAPK2a/p38? but synchronizes its activity with other signalling pathways that lie downstream of TAK1 (JNK and IKK).
    Original languageEnglish
    Pages (from-to)5793-5805
    Number of pages13
    JournalThe EMBO Journal
    Volume22
    Issue number21
    DOIs
    Publication statusPublished - 2003

    Keywords

    • p38
    • SB 203580
    • Stress-activated protein kinase (SAPK)
    • TAB1
    • TAK1
    • SAPK

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