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U0126: An Inhibitor of MKK/ERK Signal
Transduction in Mammalian Cells
By Natalie G. Ahn, Ph.D., and Nicholas S. Tolwinski, B.A.,
Department of Chemistry and Biochemistry and Howard Hughes Medical Institute, University
of Colorado
Kevin Hsiao, M.S., and Said A. Goueli, Ph.D., Promega Corporation
Editor's Note: Multiple names are in use for many of the
proteins in the kinase signaling pathways. For clarity in this report, the authors have
chosen to use the term "MKK," for mitogen-activated protein kinase kinase. The
other term in common use for this enzyme is MEK (MAP/ERK kinase). ERK is the acronym for
extracellular signal-regulated protein kinase, which is synonymous with MAPK.
The MAPK signaling pathway remains the focus of intensive research
because it plays a pivotal role in mediation of cellular responses to a variety of
signaling molecules. Due to the complex nature of this pathway and the multiplicity of the
various enzymes that undergo simultaneous alteration in their structure or functions, it
is important to develop biochemical reagents that are highly specific and highly selective
to individual enzymes in the signaling pathway. MEK Inhibitor U0126 is such a reagent
since it specifically inhibits MKK1/2, in both the inactive and active forms. In contrast,
PD098059 only inhibits the activation of MKK1/2. U0126, which inhibits a human MKK1-G1C
mutant enzyme with an IC50 of less than 200nM as well as the activation of
ERK1/2 in cells at 10µM, is at least 50-fold more potent than PD098059. Thus,
U0126 can serve as a powerful tool to investigate the activation of ERK1/2 by MKK1/2.
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