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.
Proc Natl Acad Sci U S A
; 111(23): E2394-403, 2014 Jun 10.
Article
em En
| MEDLINE
| ID: mdl-24912162
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Proteínas Proto-Oncogênicas
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Proteína Quinase 1 Ativada por Mitógeno
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MAP Quinase Quinase Quinases
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Proteína Quinase 3 Ativada por Mitógeno
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Proteínas 14-3-3
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Quinase I-kappa B
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Receptores Toll-Like
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article