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(Received for publication, April 10, 1996, and in revised form, July 18, 1996)
From the Mammalian cells contain at least three signaling
systems which are structurally related to the mitogen-activated protein
kinase (MAPK) pathway. Growth factors acting through Ras primarily
stimulate the Raf/MEK/MAPK cascade of protein kinases. In contrast,
many stress-related signals such as heat shock, inflammatory cytokines, and hyperosmolarity induce the MEKK/SEK(MKK4)/SAPK(JNK) and/or the MKK3
or MKK6/p38hog pathways. Physiological agonists of these
pathway types are either qualitatively or quantitatively distinct,
suggesting few common proximal signaling elements, although past
studies performed in vitro, or in cells using transient
over-expression, reveal interaction between the components of all three
pathways. These studies suggest a high degree of cross-talk apparently
not seen in vivo. We have examined the possible molecular
basis of the differing agonist profiles of these three MAPK pathways.
We report preferential association between MAP kinases and their
activators in eukaryotic cells. Furthermore, using the yeast 2-hybrid
system, we show that association between these components can occur
independent of additional eukaryotic proteins. We show that SAPK(JNK)
or p38hog activation is specifically impaired by co-expression
of cognate dominant negative MAP kinase kinase mutants, demonstrating
functional specificity at this level. Further divergence and insulation
of the stress pathways occurs proximal to the MAPK kinases since activation of the MAPK kinase kinase MEKK results in SAPK(JNK) activation but does not cause p38hog phosphorylation.
Therefore, in intact cells, the three MAPK pathways may be
independently regulated and their components show specificity in their
interaction with cognate cascade members. The degree of intermolecular
specificity suggests that mammalian MAPK signaling pathways may remain
distinct without the need for specific scaffolding proteins to
sequester components of individual pathways.
Volume 271, Number 47,
Issue of November 22, 1996
pp. 29876-29881
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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Department of Medicine and The Ontario
Cancer Institute Princess Margaret Hospital, 610 University Ave.,
Toronto, Ontario, M5G 2M9 Canada and ¶ The Institute of
Pathology, Case Western Reserve University, Cleveland, Ohio 44106
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G. Alonso, C. Ambrosino, M. Jones, and A. R. Nebreda Differential Activation of p38 Mitogen-activated Protein Kinase Isoforms Depending on Signal Strength J. Biol. Chem., December 15, 2000; 275(51): 40641 - 40648. [Abstract] [Full Text] [PDF]
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