Mitogen-activated protein (MAP) kinase cascades represent one of the major signal systems used by eukaryotic cells to transduce extracellular signals into cellular responses. Four MAP kinase subgroups have been identified in humans: ERK, JNK (SAPK), ERK5 (BMK), and p38. Here we characterize a new MAP kinase, p38β. p38β is a 372-amino acid protein most closely related to p38. It contains a TGY dual phosphorylation site, which is required for its kinase activity. Like p38, p38β is activated by proinflammatory cytokines and environmental stress. A comparison of events associated with the activation of p38β and p38 revealed differences, most notably in the preferred activation of p38β by MAP kinase kinase 6 (MKK6), whereas p38 was activated nearly equally by MKK3, MKK4, and MKK6. Moreover, in vitro and in vivo experiments showed a strong substrate preference by p38β for activating transcription factor 2 (ATF2). Enhancement of ATF2-dependent gene expression by p38β was ∼20-fold greater than that of p38 and other MAP kinases tested. The data reported here suggest that while closely related, p38β and p38 may be regulated by differing mechanisms and may exert their actions on separate downstream targets. Mitogen-activated protein (MAP) kinase cascades represent one of the major signal systems used by eukaryotic cells to transduce extracellular signals into cellular responses. Four MAP kinase subgroups have been identified in humans: ERK, JNK (SAPK), ERK5 (BMK), and p38. Here we characterize a new MAP kinase, p38β. p38β is a 372-amino acid protein most closely related to p38. It contains a TGY dual phosphorylation site, which is required for its kinase activity. Like p38, p38β is activated by proinflammatory cytokines and environmental stress. A comparison of events associated with the activation of p38β and p38 revealed differences, most notably in the preferred activation of p38β by MAP kinase kinase 6 (MKK6), whereas p38 was activated nearly equally by MKK3, MKK4, and MKK6. Moreover, in vitro and in vivo experiments showed a strong substrate preference by p38β for activating transcription factor 2 (ATF2). Enhancement of ATF2-dependent gene expression by p38β was ∼20-fold greater than that of p38 and other MAP kinases tested. The data reported here suggest that while closely related, p38β and p38 may be regulated by differing mechanisms and may exert their actions on separate downstream targets.

Characterization of the Structure and Function of a New Mitogen-activated Protein Kinase (p38β)