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There are four p38 MAP kinases in mammals: α, β, γ and δ. Among all p38 MAPK isoforms, p38α is the best characterized and is expressed in most cell types. p38α MAPK was initially identify as a 38 kDa polypeptide that underwent tyrosine phosphorylation in response to endotoxin treatment and hyperosmolarity shock. Although all p38 isoforms are widely expressed, p38γ is most significantly expressed in skeletal muscle and p38δ is mainly found in testis, pancreas, kidney and small intestine.

The p38 MAPKs are strongly activated in vivo by environmental stresses and inflammatory cytokines, and less by serum and growth factors. Together with the JNK family, p38 MAPKs are also known as Stress-Activated Protein Kinases (SAPKs). The canonical activation of p38 MAPKs occurs via dual phosphorylation of their Thr–Gly–Tyr motif, in the activation loop, by MKK3 and MKK6. MKK3 and MKK6 (also called SKK3) are highly selective for p38 MAPKs and do not activate JNKs or ERK1/2. Upon activation, the dually phosphorylated p38 MAPK goes through characteristic global conformational changes that alters the alignment of the two kinase halves (N-terminal and C-terminal domains) of the folded protein and enhances access to substrate, which together increases enzymatic activity. MKK-independent mechanism of activation of p38α has been observed in T cells stimulated through the T cell antigen receptor (TCR). In this system, p38α is activated by an alternative mechanism in which TCR-mediated stimulation activates proximal tyrosine kinases that results in the phosphorylation of p38α on a noncanonical activating residue, Tyr323. This phosphorylation activates p38α. Many p38 MAPK targets have been described, both in the cytoplasm and in the nucleus, which indicates that multiple cellular functions are under their control. p38α MAPK was shown to be present in both the nucleus and the cytoplasm of quiescent cells, but upon cell stimulation, some evidence suggests that it translocates from the cytoplasm to the nucleus [81]. However, other data indicate that activated p38 MAPK is also present in the cytoplasm of stimulated cells.

There are three specific age-associated changes in the properties of the hepatic p38 MAPK signaling pathway components. These are: (a) increased levels of phosphorylation of the catalytic residues; (b) increased constitutive kinase activity; and (c) failure of the pathway to respond to the acute increase of oxidative stress generated by 3-NPA. the failure of the p38 pathway to respond to 3-NPA may be a factor in the increased susceptibility of aged tissues to oxidative damage and that ROS produced by mitochondrial dysfunction may play a key role in the age-associated change.