TNF and MAP kinase signalling pathways - PubMed (original) (raw)

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TNF and MAP kinase signalling pathways

Guadalupe Sabio et al. Semin Immunol. 2014 Jun.

Abstract

The binding of tumour necrosis factor α (TNFα) to cell surface receptors engages multiple signal transduction pathways, including three groups of mitogen-activated protein (MAP) kinases: extracellular-signal-regulated kinases (ERKs); the cJun NH2-terminal kinases (JNKs); and the p38 MAP kinases. These MAP kinase signalling pathways induce a secondary response by increasing the expression of several inflammatory cytokines (including TNFα) that contribute to the biological activity of TNFα. MAP kinases therefore function both upstream and down-stream of signalling by TNFα receptors. Here we review mechanisms that mediate these actions of MAP kinases during the response to TNFα.

Keywords: ERK; JNK; MAP kinase; TNF; p38 MAP kinase.

Copyright © 2014 Elsevier Ltd. All rights reserved.

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Figures

Figure 1

Figure 1. MAP kinase pathways

A general feature of MAPK pathways is a canonical cascade consisting of a MAPK kinase kinases (MAP3K), a MAPK kinase (MAP2K) and a MAPK. Three groups of MAP kinases can be defined: ERK (extracellular signal-regulated kinase); JNK (c-Jun N-terminal kinase); and p38 MAP kinases. These pathways can be activated by many stimuli, including growth factors, inflammatory cytokines, and a wide spectrum of cellular stresses. The MAP kinases can phosphorylate downstream targets, including protein kinases, cytosolic substrates, and transcription factors.

Figure 2

Figure 2. Activation of MAP kinases by TNFα

TNFα causes the activation of ERK, JNK, and p38 MAP kinases. TNFα-stimulated ERK activation is primarily mediated by the TAK1-IKK2-TPL2 pathway. In contrast, TNFα-stimulated activation of stress-activated MAP kinases (p38 and JNK) is mediated by multiple pathways, including those engaged by ASK1, MLK, TAK1, and TPL2.

Figure 3

Figure 3. MAP kinases control of TNFα biosynthesis

MAPK regulates TNFα expression by several mechanisms. Tnfα gene transcription can be regulated by ERK, JNK and p38α MAP kinases (and by down-stream protein kinases, including MSK1/2). In addition, the ERK pathway regulates Tnfα mRNA export to the cytoplasm, Tnfα mRNA stability, Tnfα mRNA translation initiation (mediated by MNK), and TNFα shedding by TACE phosphorylation. The p38α MAP kinase pathway regulates Tnfα mRNA translation initiation and Tnfα mRNA stability (mediated by the MNK and MK2/3 pathways). Moreover, the p38γ/δ MAP kinase pathway controls TNFα translation elongation by phosphorylation and inactivation of eukaryotic elongation factor 2 Kinase (eEF2K).

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