Abstract
TAB1, a subunit of the kinase TAK1, was phosphorylated by SAPK2a/p38alpha 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/p38alpha 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/p38alpha-deficient mice, while incubation of these cells with SB 203580 had no effect. Our results suggest that TAB1 participates in a SAPK2a/p38alpha-mediated feedback control of TAK1, which not only limits the activation of SAPK2a/p38alpha but synchronizes its activity with other signalling pathways that lie downstream of TAK1 (JNK and IKK).
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing*
-
Animals
-
Benzamides / pharmacology
-
Binding Sites
-
Carrier Proteins / antagonists & inhibitors
-
Carrier Proteins / chemistry
-
Carrier Proteins / metabolism
-
Cell Line
-
Enzyme Activation / drug effects
-
Enzyme Inhibitors / pharmacology
-
Feedback
-
Humans
-
Imidazoles / pharmacology
-
Intracellular Signaling Peptides and Proteins*
-
MAP Kinase Kinase Kinases / antagonists & inhibitors
-
MAP Kinase Kinase Kinases / chemistry
-
MAP Kinase Kinase Kinases / metabolism*
-
Mice
-
Mitogen-Activated Protein Kinases / metabolism*
-
Models, Biological
-
Phosphorylation
-
Protein Subunits
-
Pyridines / pharmacology
-
Recombinant Proteins / chemistry
-
Recombinant Proteins / metabolism
-
Two-Hybrid System Techniques
-
p38 Mitogen-Activated Protein Kinases
Substances
-
2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
-
Adaptor Proteins, Signal Transducing
-
Benzamides
-
Carrier Proteins
-
Enzyme Inhibitors
-
Imidazoles
-
Intracellular Signaling Peptides and Proteins
-
Protein Subunits
-
Pyridines
-
Recombinant Proteins
-
TAB1 protein, MAPKKK activator, vertebrate
-
TAB1 protein, human
-
Mitogen-Activated Protein Kinases
-
p38 Mitogen-Activated Protein Kinases
-
MAP Kinase Kinase Kinases
-
MAP kinase kinase kinase 7
-
SB 203580