News and Publications

The p38 MAP Kinase Signal Transduction Pathway

M. Zhao, L. New, Y. Li, W. Zhu, W. Basset, X. Wang, J. Downey, J. Han

The signal transduction pathways that use mitogen-activated protein (MAP) kinases have an important role in a variety of cellular responses, including growth, stress-induced gene expression, and compensation for alterations in the environment. The p38 MAP kinase pathway is 1 of 4 MAP kinase pathways that have been determined. The 4 MAP kinases are designated p38 or p38, p38ß, p38, and p38; all 4 have been categorized as part of the p38 group of MAP kinases. This group of kinases can be activated by physical or chemical stress and by proinflammatory cytokines. The upstream kinases for p38 isoforms are MAP kinase kinase 3 and MAP kinase kinase 6. Several downstream substrates of p38 have been detected, including transcription factors, protein kinases, and enzymes. Studies from this and other laboratories have revealed that activation of the p38 pathway is involved in many pathologic changes that occur during inflammatory, immunologic, and cardiovascular diseases.

During the past year, we have continued to search for substrates for p38. We have identified and cloned a new serine/threonine kinase: p38 regulated/activated protein kinase (PRAK). PRAK is a 471 amino acid protein with 20--30% sequence identity to the known MAP kinase--regulated protein kinases RSK1/2/3, MNK1/2, and MAPKAPK2/3. PRAK was expressed in all human tissues and cell lines that we examined. In HeLa cells, PRAK was activated in response to cellular stress and proinflammatory cytokines. The in vitro and in vivo data indicate that PRAK is strictly regulated by p38ß. We have mapped the regulatory phosphorylation site of PRAK to threonine 182. Phosphorylation of PRAK on this site by p38 leads to enzymatic activation of PRAK. The known substrate for PRAK so far is small heat-shock protein 27. An in-gel kinase assay indicated that PRAK is a major stress-activated kinase that can phosphorylate this small heat-shock protein, suggesting a potential role of PRAK in mediating stress-induced phosphorylation of this protein.

We showed previously that the transactivation activity of the transcription factor MEF2C is regulated by p38 MAP kinase. We have extended our study to other members of the MEF2 family of transcription factors. We found that MEF2A, but not MEF2B or MEF2D, is a substrate for p38. Among the 4 members of the p38 group, p38 is the most potent kinase for MEF2A. Threonine 312 and threonine 319 in MEF2A are the regulatory sites phosphorylated by p38. Phosphorylation of MEF2A in MEF2A/MEF2D heterodimers enhances MEF2-dependent gene expression. Thus, the p38 MAP kinase pathway can discriminate between different MEF2 isoforms and thereby regulate MEF2-dependent genes.

Currently, our research work focuses on regulation and function of the different p38 group members, determination of the downstream target of p38-regulated protein kinases, the role of the p38 pathway in the cell cycle and apoptosis, and the mechanism used by the p38 pathway to control the expression of cytokine genes.

PUBLICATIONS

Downey, J.S., Han, J. Cellular activation mechanisms in septic shock. Front. Biosci. 3:468, 1998.

Han, J., Bohuslav, J., Jiang, Y., Kravchenko, V.V., Li, Z., Richter, B., Ulevitch, R.J. CD14 dependent mechanisms of cell activation. In: Endotoxin and Sepsis. Levin, J., et al. (Eds.). Wiley, New York, 1998, p. 157.

Jiang, Y., Gram, H., Zhoa, M., New, L., Gu, J., Feing, L., Di Padova, F., Ulevich, R.J., Han, J. Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinases, p38. J. Biol. Chem. 272:30122, 1997.

Kato, Y., Kravchenko, V.V., Tapping, R.T., Han, J., Ulevich, R.J., Lee, J.D. BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEFC. EMBO J. 16:7054, 1997.

Ludwig, S., Hoffmeyer, A., Gobeler, M., Kilian, K., Hafner, H., Neufeld, B., Han, J., Rapp, U.R. The stress inducer arsenite activates mitogen activated protein kinases ERK1/2 via a MKK6/p38 dependent pathway. J. Biol. Chem. 273:1917, 1998.

New, L., Han, J. The p38 MAP kinase pathway and its biological function. Trends Cardiovasc. Med., in press.

New, L., Jiang, Y., Zhao, M., Liu, K., Flood, L.J., Kato, Y., Parry, G.C.N., Han, J. PRAK, a novel protein kinase regulated by the p38 MAP kinase. EMBO J., in press.

Wang, Y., Huang, S., Sah, V.P., Ross, J., Jr., Brown, J.H., Han, J., Chien, K.R. Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen activated protein kinase family. J. Biol. Chem. 273:2161, 1998.

Wang, Y., Su, B., Sah, V.P., Brown, J.H., Han, J., Chien, K.R. Cardiac hypertrophy induced by mitogen-activated protein kinase kinase 7, a specific activator for c-jun N-terminal kinase in ventricular muscle cells. J. Biol. Chem. 273:5423, 1998.