**1. Introduction**

Mitogen-activated protein kinases (MAPKs) are an evolutionarily conserved family of enzymes that link extracellular signals to the intracellular machinery in order to control a plethora of cellular processes including proliferation, cell survival, differentiation and apoptosis, among others. In fact, its deregulation is associated with many human diseases including inflammation, neurodegenerative disorders and cancer [1].

In mammals, four conventional MAPK subfamilies have been identified: extracellular signalregulated protein kinases 1/2 (ERK1/2), c-Jun N-terminal kinases 1-3 (JNK1/2/3), p38MAPKs (<sup>α</sup>, β, γ and δ), and the most recently discovered and least characterized ERK5 [1]. Each MAPK has its own activators, inhibitory phosphatases, substrates and scaffold proteins that allow the correct function of the different MAPK signaling pathways [2,3]. The diversity and specificity of MAPKs in cellular responses are achieved with a linear architecture, consisting of a module of three protein kinases: a MAPK kinase kinase (MAP3K or MKKKs) at the top, which phosphorylates a MAPK kinase (MAP2K, MKKs or MEKs) on specific serine (S) and threonine (T) residues. Eventually, there is a dual phosphorylation of

the T and tyrosine (Y) residues of the conserved T-X-Y motif, located in a loop close to the active site of the terminal MAPK [4].

In addition, there is the group of atypical MAPKs, including ERK3/4, ERK7, ERK8 and Nemo-like kinase (NLK) [5–8], whose regulation and activation is not related to the module of the three kinases described for the conventional ones.

#### **2. The p38MAPK Family**

In mammalian cells, the p38MAPK family includes four members: p38 α (MAPK14), p38β (MAPK11), p38 γ (MAPK12) and p38δ (MAPK13), which have a high degree of sequence homology at the amino acid level (>60%) [9]. p38MAPKs di ffer in their expression patterns and substrate specificities, suggesting diverse functions. The p38MAPKs are S/T proline-directed kinases with an activation motif, T-G-Y, in which the substrate specificity is not only determined by the targeted amino acids, but also by specific docking domains present on the substrate and by a specific substrate binding motif in the MAPK (for a recent review of the p38MAPK-mediated signaling see [10]). The primary MAP2Ks for the p38MAPKs modules are MKK3 and MKK6 [11], although initially it was also considered the activation through MKK4 [12]. Activation of MAP2Ks occurs by phosphorylation of two conserved S and T residues on their activation loop by a broad range of MAPK3s. The MAP3Ks of this pathway include ASK1 (apoptosis signal-regulating kinase 1), DLK1 (dual-leucine-zipper bearing kinase 1), TAK1 (transforming growth factor β-activated kinase 1), TAO (thousand and one amino acid) 1 and 2, TPL2 (tumor progression loci 2), MLK3 (mixed-lineage kinase 3), MEKK (3 and 4), and ZAK1 (leucine zipper and sterileα motif kinase 1) [13]. However, it has also been reported activation/inactivation of this signaling pathway by non-canonical mechanisms as in the case of T-cell receptor [14] or GRK2 [15].

The p38MAPK family can be divided into two subsets: on the one hand, p38 α and p38β, and on the other hand p38δ and p38 γ. This classification is based on their homology and their susceptibility to be inhibited by pyridinyl imidazoles (SB203580 and SB202190 compounds) at low concentrations. p38 α and p38β have a higher homology between them (75%) and both can be inhibited by pyridinyl imidazoles, whereas p38δ and p38 γ are 61% and 62% identical to p38 α, respectively, and are not susceptible to be inhibited by SB203580 and SB202190 [16,17]. The number of specific inhibitors for p38MAPK is rapidly growing, allowing for a better understanding of the biological role of each p38 family member [18]. Important substrates in the p38MAPK signaling pathway include downstream kinases such as MK2/3, PRAK MSK1 or MNK1/2, as well as various transcription factors including ATF1/2/6, c-Myc, c-Fos, GAT4A, MEF2A/C, SRF, STAT1, p53 and CHOP among others [19]. This diversity of factors associated with the p38MAPK signaling pathway gives a glimpse of the plethora of biological processes implicated in this pathway.
