p38 MAPK is the archetypal member of the third MAPK-related pathway in mammalian cells. Like SAPK/JNK it is activated primarily by cellular stresses and not mitogenic stimuli. p38 is similar to the product of the budding yeast HOG1 gene which is part of the response to hyperosmolarity. A Xenopus homologue, termed XMpk2 has also been isolated. The activation domains of both p38 and HOG1 contain the sequence TGY, which represent the tyrosine and threonine residues required for activation (targetted by MKK3 and MKK6). The first report of the p38 sequence was: Han J, Lee JD, Bibbs L and Ulevitch RJ (1994) A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265, 808-810
Shortly thereafter, Lee et al. reported the cloning of a target for an anti-inflammatory drug (SB203580) which was identical to p38 which they termed CSBP (two splice variants were found). See: Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, McNulty D, Blumenthal MJ, Heys JR, Landvatter SW, Strickler JE, McLaughlin MM, Siemens IR, Fisher SM, Livi GP, White JR, Adams JL and Young PR (1994) A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372, 739-743
The crystal structure of p38 has been reported: Wilson et al., J. Biol. Chem. 271, 27696-27700 (1996).
A number of other p38 relatives have recently been identified which all contain the signature Thr-Gly-Tyr activation domain sequence. These incude:
SAPK3 and ERK6 appear to be homologous and are regulated by MKK6 phosphorylation: Cuenda, A., Cohen, P., Buee-Scherrer and V. Goedert, M. (1997) Activation of stress activated protein kinase-3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6); comparison of the specificities of SAPK3 and SAPK2 (RK/p38). EMBO J. 16, 295-305.
The physiological role of the different p38 isoforms (which are derived from three genes as well as differential splicing, like the SAPK family) is still unclear but there is some suggestion that they may differentially couple to MKK3 or MKK6 and have subtly distinct substrate specificities. p38beta is inhibited by SB203580 but this drug has no effect on ERK6.
Among the identified targets for p38 are MAPKAPK-2 and the transcription factors, CHOP/GADD153 (Wang and Ron,Science (1997) 272, 1347-1349), MEF2C (Han et al., Nature (1997), 386, 296-299) and ATF2.