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. 2013 Mar 26;4(2):101-33.
doi: 10.3390/genes4020101.

The Role of Mitogen-Activated Protein Kinase-Activated Protein Kinases (MAPKAPKs) in Inflammation

Ugo Moens  1 , Sergiy Kostenko  2 , Baldur Sveinbjørnsson  3
Affiliations

The Role of Mitogen-Activated Protein Kinase-Activated Protein Kinases (MAPKAPKs) in Inflammation

Ugo Moens et al. Genes (Basel). .

Abstract

Mitogen-activated protein kinase (MAPK) pathways are implicated in several cellular processes including proliferation, differentiation, apoptosis, cell survival, cell motility, metabolism, stress response and inflammation. MAPK pathways transmit and convert a plethora of extracellular signals by three consecutive phosphorylation events involving a MAPK kinase kinase, a MAPK kinase, and a MAPK. In turn MAPKs phosphorylate substrates, including other protein kinases referred to as MAPK-activated protein kinases (MAPKAPKs). Eleven mammalian MAPKAPKs have been identified: ribosomal-S6-kinases (RSK1-4), mitogen- and stress-activated kinases (MSK1-2), MAPK-interacting kinases (MNK1-2), MAPKAPK-2 (MK2), MAPKAPK-3 (MK3), and MAPKAPK-5 (MK5). The role of these MAPKAPKs in inflammation will be reviewed.

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Figures

Figure 1
Figure 1
Schematic presentation of the mammalian mitogen-activated protein kinase(MAPK) pathways. The conventional MAPK pathways, represented by MAPK/extracellular signal regulated kinase kinase (MEK), extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK), p38MAPK, and MEK5/ERK5 and the atypical MAPK pathways, including ERK3, ERK4, ERK7, ERK8, and Nemo-like kinase (NLK) are shown. The typical MAPK pathways consist of a module of three kinases that subsequently phosphorylate and activate each other: MAPK kinase kinase (MAP3K) phosphorylates MAPK kinase (MAP2K), which in turn phosphorylates MAPK. The MAPKs ERK1, ERK2 and ERK5 are typically activated by growth factors, while p38MAPK and JNK are predominantly induced by a variety of environmental stresses. JNK can also be activated by mitogens and pro-survival stimuli. Downstream of MAPK are substrates including other protein kinases referred to as MAPK-activated protein kinases (MAPKAPK). The MAPKAPK MK5/PRAK is target for the conventional p38 MAPK and the atypical ERK3/4 MAPKs.
Figure 2
Figure 2
MAPKAPK can interfere with inflammatory processes by different mechanisms. MAPKAPKs can control signalling pathways such as the nuclear factor-kappa B (NK-κB), JAK/STAT3 and IL6R/gp130 pathways. They can also affect biosynthesis of inflammatory modulators at the transcriptional level by modulating the activity of transcriptional activators (e.g., CREB, IRF3, p65, CBP/p300) or repressors (e.g., HSF1). MAPKAPK can also regulate the stability of transcripts by controlling the activity of mRNA binding proteins such as HuR, TTP, AUF1, hnRNP A0 and hnRNP A1. The MAPKAPK MAPKAPK-3 (MK3), MAPK-interacting kinases (MNK), the mitogen- and stress-activated kinases (MSK) and MK5 may also stimulate the enzymatic activity of cytoplasmic phospholipase A2 (cPLA2). Abbreviations: ATF1, activating transcription factor-1; AUF1, AU-rich element RNA-binding protein 1; CBP, CREB-binding protein; cPLA2, cytosolic phospholipase A2; CREB, cAMP response element-binding protein; gp130, glycoprotein 130; hnRNP, heterogeneous nuclear ribonucleoprotein; HSF1, heat-shock factor 1; HSP27, heat-shock protein 27; HuR, human antigen R; IKK, I kappa B kinase; IL6R, interleukin-6 receptor; IRF3, interferon regulatory factor 3; JAK, Janus kinase; p300, histone acetyltransferase; PIAS1, protein inhibitor of activated STAT1; STAT, signal transducer and activator of transcription; TTP, tristetraprolin. See text for details.
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