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Tpl2 (tumor progression locus 2) phosphorylation at Thr290 is induced by lipopolysaccharide via an Ikappa-B Kinase-beta-dependent pathway and is required for Tpl2 activation by external signals.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2005 May 27; Vol. 280 (21), pp. 20442-8. Date of Electronic Publication: 2005 Mar 18. - Publication Year :
- 2005
-
Abstract
- The serine-threonine protein kinase encoded by the tumor progression locus 2 (Tpl2) proto-oncogene transduces Toll-like receptor and death receptor signals in a variety of cell types. Here we show that Tpl2 undergoes phosphorylation at Thr(290) both in cells overexpressing Tpl2 and in cells stimulated with lipopolysaccharide (LPS) or tumor necrosis factor-alpha and that phosphorylation on this site parallels Tpl2 activation. Reconstitution of Tpl2(-/-) macrophages with wild type Tpl2 or Tpl2 T290D restored ERK activation by LPS, whereas reconstitution of the same cells with Tpl2 T290A did not, suggesting that phosphorylation at Thr(290) is required for the physiological activation of Tpl2 by external signals. Both the wild type Tpl2 and the kinase-inactive mutant Tpl2 K167M undergo Thr(290) phosphorylation, suggesting that Thr(290) may be a site of trans-phosphorylation rather than auto-phosphorylation. Pretreatment of 293 cells and primary macrophages with the Ikappa-B kinase-beta (IKKbeta) inhibitor PS-1145 blocked Tpl2 phosphorylation at Thr(290), suggesting that phosphorylation depends on IKKbeta, an obligatory positive regulator of Tpl2. We conclude that Tpl2 phosphorylation at Thr(290) is induced by LPS, depends on IKKbeta, and is required for the physiological activation of Tpl2 by external signals.
- Subjects :
- Animals
Binding Sites
Bone Marrow Cells
Cells, Cultured
Enzyme Inhibitors pharmacology
Extracellular Signal-Regulated MAP Kinases metabolism
Heterocyclic Compounds, 3-Ring pharmacology
I-kappa B Kinase
Immunosorbent Techniques
MAP Kinase Kinase Kinases genetics
Macrophages metabolism
Mice
Mice, Knockout
Mutagenesis, Site-Directed
Phosphorylation
Protein Serine-Threonine Kinases antagonists & inhibitors
Protein Serine-Threonine Kinases genetics
Proto-Oncogene Proteins genetics
Pyridines pharmacology
RNA, Small Interfering
Signal Transduction
Structure-Activity Relationship
Transfection
Tumor Necrosis Factor-alpha pharmacology
Lipopolysaccharides pharmacology
MAP Kinase Kinase Kinases chemistry
MAP Kinase Kinase Kinases physiology
Protein Serine-Threonine Kinases metabolism
Proto-Oncogene Proteins chemistry
Proto-Oncogene Proteins physiology
Threonine metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 280
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 15778223
- Full Text :
- https://doi.org/10.1074/jbc.M413554200