MAP Kinase Modules: Many Roads Home

MAP kinases are a family of enzymes that coordinate diverse cellular programs in response to signals relayed from the extracellular milieu. They are components of signalling pathways that have a common architecture, in which the MAP kinases themselves are the terminal members of a three-component linear kinase cascade. The MAP kinases are activated by dual phosphorylation on a conserved Thr-Xxx-Tyr motif in their activation loop by an upstream MAP kinase kinase (MAP2K). MAP2Ks are themselves activated by dual phosphorylation by MAP2K kinases (MAP3Ks). Confusingly, these enzymes have various alternative names, which are summarised in Table 1. Three families of MAP kinases have been identified: the extracellular signal regulated protein kinases, ERK1 and ERK2; the c-Jun NH2 terminal kinases, JNK1, JNK2 and JNK3; and the p38 MAP kinases, α, β, δ and γ. A handful of other MAP kinases, including ERK5 and ERK3, have been discovered that are less well understood and may have divergent properties [1,2]. Each of the MAP kinase families has at least two cognate MAP2Ks and multiple MAP3Ks. MAP2Ks display remarkable substrate specificity for their MAP kinases; several recognize only one or two MAP kinases and few if any other substrates. In contrast, MAP3Ks have the capacity to activate multiple MAP kinase cascades (Figure 1). The multiple mammalian MAP3Ks and MAP2Ks may have arisen because mammalian MAP kinases must sense a panoply of ligands and hence have evolved multiple components sensitive to ligand subsets. A recent study by Brancho et al. [3], who have investigated how MAP kinases are activated by diverse upstream pathway components and the consequences of these choices, has shed new light on the features of MAP kinase cascades that provide them their remarkable response specificity.