Conserved signaling pathways that activate the mitogen-activated protein kinases MAPKs are involved in relaying extracellular stimulations to intracellular responses. The MAPKs coordinately regulate cell proliferation differentiation motility and survival which are functions also known to be mediated by members of a growing family of MAPK-activated protein kinases MKs formerly known as MAPKAP kinases. The MKs are related serinethreonine kinases that respond to mitogenic and stress stimuli through proline-directed phosphorylation and activation of the kinase domain by extracellular signal-regulated kinases 1 and 2 and p38 MAPKs. There are currently 11 vertebrate MKs in five subfamilies based on primary sequence homology: the ribosomal S6 kinases the mitogen- and stress-activated kinases the MAPK-interacting kinases MAPK-activated protein kinases 2 and 3 and MK5. In the last 5 years several MK substrates have been identified which has helped tremendously to identify the biological role of the members of this family. Together with data from the study of MK-knockout mice the identities of the MK substrates indicate that they play important roles in diverse biological processes including mRNA translation cell proliferation and survival and the nuclear genomic response to mitogens and cellular stresses. In this article we review the existing data on the MKs and discuss their physiological functions based on recent discoveries. Cells recognize and respond to extracellular stimuli by engaging specific intracellular programs such as the signaling cascade that leads to activation of the mitogen-activated protein kinases MAPKs. All eukaryotic cells possess multiple MAPK pathways which coordinately regulate diverse cellular activities running the gamut from gene expression mitosis and metabolism to motility survival and apoptosis and differentiation. To date five distinct groups of MAPKs have been characterized in mammals: extracellular signal-regulated kinases ERKs 1 and 2 ERK12 c-Jun amino-terminal kinases JNKs 1 2 and 3 p38 isoforms and ERKs 3 and 4 and ERK5 reviewed in references 25 and 103. Since Saccharomyces cerevisiae possesses six different MAPKs the relative complexity of the human genome suggests that there are probably several additional vertebrate MAPK subfamilies 118. The most extensively studied groups of vertebrate MAPKs to date are the ERK12 JNKs and p38 kinases. MAPKs can be activated by a wide variety of different stimuli but in general ERK1 and ERK2 are preferentially activated in response to growth factors and phorbol esters while the JNK and p38 kinases are more responsive to stress stimuli ranging from osmotic shock and ionizing radiation to cytokine stimulation reviewed in reference 147 Fig. 1. Although each MAPK has unique characteristics a number of features are shared by the MAPK pathways studied to date. Each family of MAPKs is composed of a set of three evolutionarily conserved sequentially acting kinases: a MAPK a MAPK kinase MAPKK and a MAPKK kinase MAPKKK. The MAPKKKs which are serinethreonine kinases are often activated through phosphorylation andor as a result of their interaction with a small GTP-binding protein of the RasRho family in response to extracellular stimuli 36 98. MAPKKK activation leads to the phosphorylation and activation of a MAPKK which then stimulates MAPK activity through dual phosphorylation on threonine and tyrosine residues located in the activation loop of kinase subdomain VIII. Once activated MAPKs phosphorylate target substrates on serine or threonine residues followed by a proline however substrate selectivity is often conferred by specific interaction motifs located on physiological substrates. Furthermore MAPK cascade specificity is also mediated through interaction with scaffolding proteins which organize pathways in specific modules through simultaneous binding of several components. |
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