The respective MAPKAPKs activated by the MAPKs are show in light gray next to the cognate MAPK. Different additional domains are also present in some MAPKs, including a transactivation domain (TAD), a nuclear localization sequence (NLS), a region conserved in ERK3 and ERK4 (C34), and a domain rich in Ala, His, and Glu (AHQr). All MAPKs contain a Ser/Thr kinase domain flanked by N- and C-terminal regions of different lengths. Schematic representation of the overall structures of conventional and atypical MAPKs. 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. Atypical MAPKs have nonconforming particularities and comprise ERK3/4, ERK7, and Nemo-like kinase (NLK) (reviewed in reference 71). 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, 198, and 264). In mammals, 14 MAPKs have been characterized into seven groups (Fig. All eukaryotic cells possess multiple MAPK pathways, which coordinately regulate gene expression, mitosis, metabolism, motility, survival, apoptosis, and differentiation. MAPKs are among the most ancient signal transduction pathways and are widely used throughout evolution in many physiological processes ( 396). Mitogen-activated protein kinases (MAPKs) are protein Ser/Thr kinases that convert extracellular stimuli into a wide range of cellular responses. Here we review the mechanisms of MAPKAPK activation by the different MAPKs and discuss their physiological roles based on established substrates and recent discoveries. These enzymes have diverse biological functions, including regulation of nucleosome and gene expression, mRNA stability and translation, and cell proliferation and survival. There are five MAPKAPK subfamilies: the p90 ribosomal S6 kinase (RSK), the mitogen- and stress-activated kinase (MSK), the MAPK-interacting kinase (MNK), the MAPK-activated protein kinase 2/3 (MK2/3), and MK5 (also known as p38-regulated/activated protein kinase ). The MAPKAPKs are related enzymes that respond to extracellular stimulation through direct MAPK-dependent activation loop phosphorylation and kinase activation.

Together, the MAPKs regulate a large number of substrates, including members of a family of protein Ser/Thr kinases termed MAPK-activated protein kinases (MAPKAPKs). There are additional, atypical MAPK enzymes, including ERK3/4, ERK7/8, and Nemo-like kinase (NLK), which have distinct regulation and functions. The best known are the conventional MAPKs, which include the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun amino-terminal kinases 1 to 3 (JNK1 to -3), p38 (α, β, γ, and δ), and ERK5 families. In mammals, there are more than a dozen MAPK enzymes that coordinately regulate cell proliferation, differentiation, motility, and survival. Summary: The mitogen-activated protein kinases (MAPKs) regulate diverse cellular programs by relaying extracellular signals to intracellular responses.

Kinases with known consensus sequences