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(Received for publication, July 9, 1996)
From the A stress-activated, serine/threonine
kinase, p38 (also known as HOG1 or MPK2) belongs to a subgroup of
mitogen-activated protein kinase (MAPK) superfamily molecules. An
activity to activate p38 (p38 activator activity) as well as p38
activity itself were greatly stimulated by hyperosmolar media in mouse
lymphoma L5178Y cells. The activator activity has been purified by
sequential chromatography. A 36-kDa polypeptide that was coeluted with
the activity in the final chromatography step was identified as MAPK
kinase 6 (MAPKK6) by protein microsequencing analysis. Monoclonal
and polyclonal antibodies raised against recombinant MAPKK6
recognized specifically the 36-kDa MAPKK6 protein but did not
cross-react with MKK3 proteins. The use of these anti-MAPKK6 antibodies
revealed that two major peaks of the p38 activator activity in the
first chromatography step reside in the activated MAPKK6. Using a
genetic screen in yeast, we isolated MKK3b, an alternatively spliced
form of MKK3. Like MKK3 and MAPKK6, MKK3b was shown to be a specific
activator for p38 and was activated by osmotic shock when expressed in
COS7 cells. Immunoblotting analysis revealed that MAPKK6 is expressed
highly in HeLa and KB cells and scarcely in PC12 cells, whereas MKK3
and MKK3b are expressed in all cells examined. Immunodepletion of
MAPKK6 from the extracts obtained from L5178Y cells and KB cells
exposed to hyperosmolar media depleted them of almost all of the p38
activator activity, indicating that MAPKK6 is a major activator for p38
in an osmosensing pathway in these cells. In addition, MAPKK6 was
activated strongly by tumor necrosis factor-
Volume 271, Number 43,
Issue of October 25, 1996
pp. 26981-26988
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
ACTIVATION OF MITOGEN-ACTIVATED PROTEIN KINASE KINASE 6 BY
OSMOTIC SHOCK, TUMOR NECROSIS FACTOR-
, AND
H2O2
,
,
,
,
,
Department of Genetics and Molecular
Biology, Institute for Virus Research, Kyoto University, Sakyo-ku,
Kyoto 606-01, § Central Laboratories for Key Technology,
Kirin Brewery Company Limited, Kanazawa-ku, Yokohama 236, the
¶ Department of Molecular Biology, Faculty of Science, Nagoya
University, Chikusa-ku, Nagoya 464-01, and the 
Department of
Anatomy, Nagoya University School of Medicine, 65 Tsurumai-cho,
Showa-ku, Nagoya 466, Japan
,
H2O2, and okadaic acid and moderately by
cycloheximide in KB cells. Thus, there are at least three members of
p38 activator, MKK3, MKK3b, and MAPKK6, and MAPKK6 may function as a
major activator for p38 when expressed.
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N. Reunanen, J. Westermarck, L. Hakkinen, T. H. Holmstrom, I. Elo, J. E. Eriksson, and V.-M. Kahari Enhancement of Fibroblast Collagenase (Matrix Metalloproteinase-1)Gene Expression by Ceramide Is Mediated by Extracellular Signal-regulated and Stress-activated Protein Kinase Pathways J. Biol. Chem., February 27, 1998; 273(9): 5137 - 5145. [Abstract] [Full Text] [PDF]
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