P38 isoforms

The most extensive development of pharmacological inhibitors of MAPK cascades members has been for p38 (Table 1) [3]. Small-molecule inhibitors have been developed for two p38 isoforms (a and (3). Pyridinyl imidazole compounds have been known to block inflammation since the early 1970s. Structural analyses have revealed that p38 kinase inhibitors binds to the ATP-binding pocket of p38 thereby acting as competitive inhibitors. The p38 kinase inhibitor SB202190 is able to bind both the low-activity nonphosphorylated... 

A MAP kinase module is composed of three kinases where MAP kinase kinase kinase (MAPKKK) will phosphorylate and induce a MAP kinase kinase (MAPKK), which will then phosphorylate and activate a MAP kinase. MAP kinase phosphory-lates either transcription factors that are nonkinase proteins or other kinases that are called MAP kinase-activating protein kinases (MK). There are four distinct classes of MAP kinases, which include ERKs, C-Jun-N-terminal kinases, p38 isoforms and ERK5. 

Figure 3 Effect of hypoxia on p38 and p38y activity. PC12 cells were transfected with FLAG-tagged p38 isoforms and exposed to either normoxia (C, 21% O2) or hypoxia (H, 5% O2) for 6 hr. (a) Enzyme activity of various p38 isofoims was determined in immune complex kinase assays by determining the amount of 32p incorporated into myelin basic protein (mbp). (b) Whole-cell lysates were immunoblotted with antibody against the FLAG tag. Protein kinase activity of the various p38 isofoims after exposure to normoxia (black bars) or hypoxia (gray bars) is expressed as average percent of control SE (n = 6-9).

Enslen, H., Raingeaud, J. and Davis, R.J. 1998. Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6. J. Biol. Chem. 273 1741-1748... 

Morrison DL, Yee A, Paddon HB, Vilimek D, Aebersold R, Pelech SL. 2000. Regulation of the meiosis-inhibited protein kinase, a p38(MAPK) isoform, during meiosis and following fertilization of seastar oocytes. J Biol Chem 275(44) 34236-34244. 

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