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(Received for publication, May 9, 1995; and in revised form, August 8, 1995)
PD 098059 has been shown previously to inhibit the
dephosphorylated form of mitogen-activated protein kinase kinase-1
(MAPKK1) and a mutant MAPKK1(S217E,S221E), which has low levels of
constitutive activity (Dudley, D. T., Pang, L., Decker, S. J., Bridges,
A. J., and Saltiel, A. R.(1995) Proc. Natl. Acad. Sci. U. S. A. 92, 7686-7689). Here we report that PD 098059 does not
inhibit Raf-activated MAPKK1 but that it prevents the activation of
MAPKK1 by Raf or MEK kinase in vitro at concentrations
(IC = 2-7 µM) similar to those
concentrations that inhibit dephosphorylated MAPKK1 or
MAPKK1(S217E,S221E). PD 098059 inhibited the activation of MAPKK2 by
Raf with a much higher IC
value (50 µM) and
did not inhibit the phosphorylation of other Raf or MEK kinase
substrates, indicating that it exerts its effect by binding to the
inactive form of MAPKK1. PD 098059 also acts as a specific inhibitor of
the activation of MAPKK in Swiss 3T3 cells, suppressing by 80-90%
its activation by a variety of agonists. The high degree of specificity
of PD 098059 in vitro and in vivo is indicated by its
failure to inhibit 18 protein Ser/Thr kinases (including two other
MAPKK homologues) in vitro by its failure to inhibit the in vivo activation of MAPKK and MAP kinase homologues that
participate in stress and interleukin-1-stimulated kinase cascades in
KB and PC12 cells, and by lack of inhibition of the activation of p70
S6 kinase by insulin or epidermal growth factor in Swiss 3T3 cells. PD
098059 (50 µM) inhibited the activation of p42
and isoforms of MAP kinase-activated protein kinase-1 in Swiss
3T3 cells, but the extent of inhibition depended on how potently c-Raf
and MAPKK were activated by any particular agonist and demonstrated the
enormous amplification potential of this kinase cascade. PD 098059 not
only failed to inhibit the activation of Raf by platelet-derived growth
factor, serum, insulin, and phorbol esters in Swiss 3T3 cells but
actually enhanced Raf activity. The rate of activation of Raf by
platelet-derived growth factor was increased 3-fold, and the subsequent
inactivation that occurred after 10 min was prevented. These results
indicate that the activation of Raf is suppressed and that its
inactivation is accelerated by a downstream component(s) of the MAP
kinase pathway.
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