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J. Biol. Chem., Vol. 275, Issue 48, 37303-37306, December 1, 2000
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,
From the Departments of Cell Biology and Pharmacology, University
of Texas Southwestern Medical Center, Dallas, Texas 75390
The Raf family of serine/threonine protein
kinases is intimately involved in the transmission of cell regulatory
signals controlling proliferation and differentiation. The best
characterized Raf substrates are MEK1 and MEK2. The activation of
MEK1/2 by Raf is required to mediate many of the cellular responses to
Raf activation, suggesting that MEK1/2 are the dominant Raf effector
proteins. However, accumulating evidence suggests that there are
additional Raf substrates and that subsets of Raf-induced regulatory
events are mediated independently of Raf activation of MEK1/2. To
examine the possibility that there is bifurcation at the level of Raf in activation of MEK1/2-dependent and MEK1/2-independent
cell regulatory events, we engineered a kinase-active Raf1 variant (RafBXB(T481A)) with an amino acid substitution that disrupts MEK1
binding. We find that disruption of MEK1/2 association uncouples Raf
from activation of ERK1/2, induction of serum-response
element-dependent gene expression, and induction of growth
and morphological transformation. However, activation of
NF-
B-dependent gene expression and induction of neurite
differentiation were unimpaired. In addition, Raf-dependent activation of p90 ribosomal S6 kinase was only slightly
impaired. These results support the hypothesis that Raf kinases utilize multiple downstream effectors to regulate distinct cellular activities.
Supported by Pharmacological Sciences Training Grant G1907062- 25.
§
To whom correspondence should be addressed. Tel.: 214-648-2861;
Fax: 214-648-8694; E-mail: white08@utsw.swmed.edu.
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