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J Biol Chem, Vol. 275, Issue 12, 8854-8862, March 24, 2000
§
From the Department of Biological Chemistry and the
Ras plays an important role in a variety of
cellular functions, including growth, differentiation, and oncogenic
transformation. For instance, Ras participates in the activation of
Raf, which phosphorylates and activates mitogen-activated protein
kinase kinase (MEK), which then phosphorylates and activates
extracellular signal-regulated kinase (ERK), a mitogen-activated
protein (MAP) kinase. Activation of MAP kinase appears to be essential
for propagating a wide variety of extracellular signals from the plasma
membrane to the nucleus. N17Ras, a GDP-bound dominant negative mutant, is used widely as an interfering mutant to assess Ras function in
vivo. Surprisingly, we observed that expression of N17Ras
inhibited the activity and phosphorylation of Elk-1, a physiological
substrate of MAP kinases, in response to phorbol myristate acetate. The activity and phosphorylation of the MAP kinase hemagglutinin epitope (HA)-ERK1 were not affected by N17Ras in response to the same stimulus.
Additionally, expression of N17Ras, but not L61S186Ras, a GTP-bound
interfering mutant, inhibited MEK-induced Elk-1 phosphorylation, suggesting that inhibition of Elk-1 may be unique to GDP-bound Ras
mutants. Finally, we observed that V12Ras-induced focus formation in
NIH3T3 cells is inhibited by coexpression of GDP-bound Ras mutants,
such as N17, A15, and N17N69. Therefore, N17Ras and V12 Ras may be
codominant with respect to Elk-1 activation and cellular transformation. These results indicate that N17Ras appears to have at
least two distinguishable functions: interference with endogenous Ras
activation and inhibition of Elk-1 and transfomation. Furthermore, our
data imply the possibility that GDP-bound Ras, like N17Ras, may have a
direct role in signal transduction.
Institute of Gerontology, University of Michigan Medical
School, Ann Arbor, Michigan 48109
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