IκB kinase-induced interaction of TPL-2 kinase with 14-3-3 is essential for Toll-like receptor activation of ERK-1 and -2 MAP kinases
| Autor: | Sven Kjaer, Stephen J. Smerdon, Stephen R. Martin, Christine Brender, Steven C. Ley, Abduelhakem Ben-Addi, Agnes Mambole-Dema, Julia Janzen |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Lipopolysaccharides
Mitogen-Activated Protein Kinase 3 MAP Kinase Signaling System Immunoblotting IκB kinase Mice TANK-binding kinase 1 Proto-Oncogene Proteins Serine Animals Humans Kinase activity Phosphorylation CHUK Cells Cultured MAPK14 Mice Knockout Mitogen-Activated Protein Kinase 1 Multidisciplinary MAP kinase kinase kinase Chemistry Tumor Necrosis Factor-alpha Macrophages Toll-Like Receptors I-Kappa-B Kinase NF-kappa B p50 Subunit MAP Kinase Kinase Kinases Molecular biology Cell biology I-kappa B Kinase Enzyme Activation Mice Inbred C57BL HEK293 Cells PNAS Plus 14-3-3 Proteins Protein Binding |
| Popis: | The MEK-1/2 kinase TPL-2 is critical for Toll-like receptor activation of the ERK-1/2 MAP kinase pathway during inflammatory responses, but it can transform cells following C-terminal truncation. IκB kinase (IKK) complex phosphorylation of the TPL-2 C terminus regulates full-length TPL-2 activation of ERK-1/2 by a mechanism that has remained obscure. Here, we show that TPL-2 Ser-400 phosphorylation by IKK and TPL-2 Ser-443 autophosphorylation cooperated to trigger TPL-2 association with 14-3-3. Recruitment of 14-3-3 to the phosphorylated C terminus stimulated TPL-2 MEK-1 kinase activity, which was essential for TPL-2 activation of ERK-1/2. The binding of 14-3-3 to TPL-2 was also indispensible for lipopolysaccharide-induced production of tumor necrosis factor by macrophages, which is regulated by TPL-2 independently of ERK-1/2 activation. Our data identify a key step in the activation of TPL-2 signaling and provide a mechanistic insight into how C-terminal deletion triggers the oncogenic potential of TPL-2 by rendering its kinase activity independent of 14-3-3 binding. |
| Databáze: | OpenAIRE |
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