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 language | English |
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Pages (from-to) | 5793-5805 |
Number of pages | 13 |
Journal | The EMBO Journal |
Volume | 22 |
Issue number | 21 |
DOIs | |
Publication status | Published - 2003 |
Keywords
- p38
- SB 203580
- Stress-activated protein kinase (SAPK)
- TAB1
- TAK1
- SAPK