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 p38α/CSBP. The novel kinase, p38δ, has a nucleotide sequence encoding a protein of 365 amino acids with a putative TGY dual phosphorylation motif. Dot-blot analysis of p38δ mRNA in 50 human tissues revealed a distribution profile of p38δ that differs from p38α. p38δ is highly expressed in salivary gland, pituitary gland, and adrenal gland, whereas p38α is highly expressed in placenta, cerebellum, bone marrow, thyroid gland, peripheral leukocytes, liver, and spleen. Like p38α, p38δ is activated by cellular stress and proinflammatory cytokines. p38δ phosphorylates ATF-2 and PHAS-I, but not MAPK-activated protein kinase-2 and -3, knownin vivo and in vitro substrates of p38α. We also observed that p38δ was strongly activated by MKK3 and MKK6, while p38α was preferentially activated by MKK6. Other experiments showed that a potent p38α kinase inhibitor AMG 2372 minimally inhibited the kinase activity of p38δ. Taken together, these data indicate that p38δ is a new member of the p38 MAPK family and that p38δ likely has functions distinct from that of p38α.