Characterization of the Structure and Function of the Fourth Member of p38 Group Mitogen-activated Protein Kinases, p38δ*

We have cloned and characterized a new member of the p38 group of mitogen-activated protein kinases here termed p38δ. Sequence comparisons revealed that p38δ is approximately 60% identical to the other three p38 isoforms but only 40–45% to the other mitogen-activated protein kinase family members. It contains the TGY dual phosphorylation site present in all p38 group members and is activated by a group of extracellular stimuli including cytokines and environmental stresses that also activate the other three known p38 isoforms. However, unlike the other p38 isoforms, the kinase activity of p38δ is not blocked by the pyridinyl imidazole, 4-(4-fluorophenyl)-2–2(4-hydroxyphenyl)-5-(4-pyridyl)-imidazole (identicalto SB202190). p38δ can be activated by MKK3 and MKK6, known activators of the other isoforms. Nonetheless, in-gel kinase assays provide evidence for additional activators. The data presented herein show that p38δ has many properties that are similar to those of other p38 group members. Nonetheless important differences exist among the four members of the p38 group of enzymes, and thus each may have highly specific, individual contributions to biologic events involving activation of the p38 pathways.

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