Molecular cloning and characterization of a novel p38 mitogen-activated protein kinase

The p38 mitogen-activated protein kinases (MAPK) are activated by cellular stresses and play an important role in regulating gene expression. We have isolated a cDNA encoding a novel protein kinase that has significant homology (57% amino acid identity) to human p38 alpha/CSBP. The novel kinase, p38 delta, has a nucleotide sequence encoding a protein of 365 amino acids with a putative TGY dual phosphorylation motif. Dot-blot analysis of p38 delta mRNA in 50 human tissues revealed a distribution profile of p38 delta that differs from p38 alpha. p38 delta is highly expressed in salivary gland, pituitary gland, and adrenal gland, whereas p38 alpha is highly expressed in placenta, cerebellum, bone marrow, thyroid gland, peripheral leukocytes, liver, and spleen. Like p38 alpha, p38 delta is activated by cellular stress and proinflammatory cytokines. p38 delta phosphorylates AFT-2 and PHAS-I, but not MAPK-activated protein kinase-2 and -3, known in vivo and in vitro substrates of p38 alpha. We also observed that p38 delta was strongly activated by MKK3 and MKK6, while p38 alpha was preferentially activated by MKK6. Other experiments showed that a potent p38 alpha kinase inhibitor AMG 2372 minimally inhibited the kinase activity of p38 delta. Taken together, these data indicate that p38 delta is a new member of the p38 MAPK family and that p38 delta likely has functions distinct from that of p38 alpha.