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Edited By: Karen Young Kreeger STRESSED OUT: Jöel Raingeaud, left, and Roger Davis found that the p38 MAP kinase is activated by inflammatory cytokines and environmental stress. J. Raingeaud, S. Gupta, J.S. Rogers, M. Dickens, J. Han, R.J. Ulevitch, R.J. Davis, "Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine," Journal of Biological Chemistry, 270:7420-6, 1995. (Cited in nearly 100 publications as of March 1997) Comments by Roger J. Davis, University of Massachusetts Medical School, Howard Hughes Medical Institute. The signal transduction pathways of mitogen-activated protein (MAP) kinases have been actively studied for some time. About three years ago, a new mammalian protein kinase encoded by the gene p38 was identified and cloned in Richard Ulevitch's lab at the Scripps Research Institute in La Jolla, Calif., by Jiahuai Han, a postdoctoral fellow on Ulevitch's research team (J. Han et al., Science, 265:808-11, 1994). The p38 kinase is similar in amino acid sequence to MAP kinases already described. This paper reports on the characterization of the p38 protein and demonstrates its function, work conducted primarily in the lab of Roger Davis at the University of Massachusetts Medical School. "One of the reasons why the paper is so frequently cited is that the findings establish many of the methods that are currently being used for studies of this protein," says Davis, a professor of molecu-lar medicine and a Howard Hughes Medical Institute investigator. "For example, we established the assays for examining the activity of this protein." The paper also describes one substrate for this protein kinase, a transcription factor called ATF2. "Subsequent papers have established that ATF2 mediates gene expression as a result of activation of the p38 kinase," remarks Davis. In another part of the study that investigated p38's function, Davis and postdoc Jöel Raingeaud demonstrated that p38 is activated by inflammatory cytokines and environmental stress through dual phosphorylation on two amino acids, tyrosine and threonine. "We showed that the p38 MAP kinase is a member of a larger family of kinases called the stress-activated MAP kinases," notes Davis. When cells come into contact with an outside stress such as extreme heat, they respond by changing the activity of certain molecules, such as the stress-activated MAP kinases. For this study, the authors used ultraviolet (UV) radiation and osmotic stress. "We show that the activation of these kinases is part of the stress response that cells undergo," explains Davis. Understanding what happens when a cell experiences a lack of oxygen or sunburn injury from too much heat or UV radiation is one of the many clinical applications for stress-response research, he adds. He speculates that another reason for the paper's frequent citation is associated with a clinical application currently under development. SmithKline Beecham, a Philadelphia-based pharmaceutical firm, has identified a drug that acts as an anti-inflammatory agent. "The target for this drug turned out to be the same protein-the p38 MAP kinase-that was the subject of this paper. For arthritic diseases, this drug appears to have some therapeutic benefit for the treatment of inflammation by inhibiting the secretion of inflammatory cytokines. Both in academia and industry, there's a lot of interest in this system for its therapeutic opportunity." Davis and his colleagues are still trying to tease all the biochemical information that they can from the p38 MAP kinase. "We're still working on trying to understand the function of this protein in vivo to define its downstream targets and mechanism of action," he says.

Signal Transduction

The Scientist Staff

Apr 27, 1997

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