The first member of the p38 MAPK family was independently identified by four groups as a 38 kDa protein (p38) that was rapidly phosphorylated on tyrosine in response to LPS (lipopolysaccharide) stimulation, as a target of pyridinylimidazole drugs[CSBP (cytokine-suppressive anti-inflammatory drug-binding protein)] that inhibited the production of pro-inflammatory cytokines, and as an activator [RK (reactivating kinase)] of MAPKAP-K2/MK2 (MAPK-activated protein kinase 2) in cells stimulated with heat shock, arsenite or IL (interleukin)-1. . The four p38 MAPKs are encoded by different genes and have different tissue expression patterns, with p38α being ubiquitously expressed at significant levels in most cell types, whereas the others seem to be expressed in a more tissue-specific manner; for example, p38β in brain, p38γ in skeletal muscle and p38δ in endocrine glands.  p38 MAPKs are activated by dual phosphorylation in the activation loop sequence Thr-Gly-Tyr. 
In response to appropriate stimuli, threonine and tyrosine residues can be phosphorylated by three dualspecificity MKKs/MAP2Ks (MAPK kinases). Different stimuli such as growth factors, inflammatory cytokines or a wide variety of environmental stresses can activate p38 MAPKs. A number of representative downstream targets, including protein kinases, cytosolic substrates, transcription factors and chromatin remodellers, are CHOP, DLK1, EEA1, eEF2K,  eIF4E, HMG-14, NHE-1, PLA2,PSD95, Sap1, STAT, TAO, TPL2, TTP,ZAK1, ZNHIT1. An alternative mechanism of p38 MAPK activation operates in T-lymphocytes and involves tyrosine phosphorylation of p38α, which results in its autophosphorylation on the activation loop. In some cases, p38α appears to be activated by autophosphorylation, which might be stimulated by its association with proteins such as TAB1, independently of both MAP2Ks and tyrosine phosphorylation. The interplay between p38α and several signalling pathways are including JNK, ERK1/2, NF-κB, Wnt/GSK3β, Akt and G-protein-coupled receptors (GPCRs). Most of the studies have focused on p38α, establishing its implication in tissue homoeostasis and several pathologies from inflammation and the immune response to cancer, heart and neurodegenerative diseases.

References

1.Cuadrado A, Nebreda AR. Biochem J. 2010;429(3):403–417.