Mitogen-activated protein kinases (MAPKs) are protein Ser/Thr kinases that convert extracellular stimuli into a wide range of cellular responses. MAPKs are among the most ancient signal transduction pathways and are widely used throughout evolution in many physiological processes (396
). All eukaryotic cells possess multiple MAPK pathways, which coordinately regulate gene expression, mitosis, metabolism, motility, survival, apoptosis, and differentiation. In mammals, 14 MAPKs have been characterized into seven groups (Fig. ). Conventional MAPKs comprise the extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun amino (N)-terminal kinases 1/2/3 (JNK1/2/3), p38 isoforms (α, β, γ, and δ), and ERK5 (reviewed in references 54
, and 264
). Atypical MAPKs have nonconforming particularities and comprise ERK3/4, ERK7, and Nemo-like kinase (NLK) (reviewed in reference 71
). By far the most extensively studied groups of mammalian MAPKs are the ERK1/2, JNKs, and p38 isoforms, but recent studies have shed some light on the regulation and function of other groups of MAPKs.
FIG. 1. Schematic representation of the overall structures of conventional and atypical MAPKs. All MAPKs contain a Ser/Thr kinase domain flanked by N- and C-terminal regions of different lengths. Different additional domains are also present in some MAPKs, including (more ...)
Each group of conventional MAPKs is composed of a set of three evolutionarily conserved, sequentially acting kinases: a MAPK, a MAPK kinase (MAPKK), and a MAPKK kinase (MAPKKK) (Fig. ). The MAPKKKs, which are protein Ser/Thr kinases, are often activated through phosphorylation and/or as a result of their interaction with a small GTP-binding protein of the Ras/Rho family in response to extracellular stimuli. MAPKKK activation leads to the phosphorylation and activation of a MAPKK, which then stimulates MAPK activity through dual phosphorylation on Thr and Tyr residues within a conserved Thr-X-Tyr motif located in the activation loop of the kinase domain subdomain VIII (Fig. ). Phosphorylation of these residues is essential for enzymatic activities, as was originally demonstrated for ERK2 (288
FIG. 2. MAPK signaling cascades leading to activation of the MAPKAPKs. Mitogens, cytokines, and cellular stresses promote the activation of different MAPK pathways, which in turn phosphorylate and activate the five subgroups of MAPKAPKs, including RSK, MSK, MNK, (more ...)
Less is known about the exact molecular mechanisms involved in activation of atypical MAPKs, as they do not share many characteristics of conventional MAPKs (71
). One determining feature of atypical MAPKs is that these proteins are not organized into classical three-tiered kinase cascades. In addition, the Thr-X-Tyr motif is absent in ERK3/4 and NLK, where a Gly or Glu residue replaces the Tyr. ERK7 contains the motif Thr-Glu-Tyr in its activation loop, but phosphorylation of these residues appears to be catalyzed by ERK7 itself, rather than by an upstream MAPKK. Nevertheless, once activated, conventional and atypical MAPKs phosphorylate target substrates on Ser or Thr followed by a Pro residue, making them Pro-directed kinases, and therefore have limited specificity in their consensus phosphorylation motifs. In addition to the transient kinase-substrate interaction, MAPK substrate selectivity is also conferred by specific interaction domains termed docking sites. Scaffolding proteins also mediate MAPK cascade specificity by simultaneously binding several components and organizing pathways in specific modules.
The wide range of functions regulated by the MAPKs is mediated through phosphorylation of several substrates, including members of a family of protein kinases termed MAPK-activated protein kinases (MAPKAPKs) (Fig. ) (123
). This family comprises the p90 ribosomal S6 kinases (RSKs) (48
), mitogen- and stress-activated kinases (MSKs) (14
), MAPK-interacting kinases (MNKs) (44
), MAPK-activated protein kinase 2/3 (MK2/3) (293
), and MK5 (267
). MAPKAPK family members represent an additional enzymatic and amplification step in the MAPK catalytic cascades. In addition, they control a wide range of biological functions and thereby increase the range of action regulated by activated MAPK modules. This article gives an overview of the different groups of mammalian MAPKs, as well as describing our current understanding of the properties, regulation, and function of the MAPK-activated protein kinases.