CHARACTERIZATION OF THE STRUCTURE AND FUNCTION OF THE 4TH MEMBER OF P38 GROUP MITOGEN-ACTIVATED PROTEIN-KINASES, P38-DELTA

We have cloned and characterized a new member of the p38 group of mito gen-activated protein kinases here termed p38 delta. Sequence comparis ons revealed that p38 delta is approximately 60% identical to the othe r three p38 isoforms but only 40-45% to the other mitogen-activated pr otein kinase family members. It contains the TGY dual phosphorylation site present in all p38 group members and is activated by a group of e xtracellular stimuli including cytokines and environmental stresses th at also activate the other three known p38 isoforms. However, unlike t he other p38 isoforms, the kinase activity of p38 delta is not blocked by the pyridinyl imidazole, 4-(4-fluorophenyl)-2- 2(4-hydroxyphenyl)- 5-(4-pyridyl)-imidazole (identicalto SB202190). p38 delta can be activ ated by MKK3 and MKK6, known activators of the other isoforms. Nonethe less, in-gel kinase assays provide evidence for additional activators. The data presented herein show that p38 delta has many properties tha t are similar to those of other p38 group members. Nonetheless importa nt differences exist among the four members of the p38 group of enzyme s, and thus each may have highly specific, individual contributions to biologic events involving activation of the p38 pathways.