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Negatively Regulates Raf-1 Activity by Interactions
with the Raf-1 Cysteine-rich Domain
(Received for publication, April 21, 1997, and in revised form, June 10, 1997)
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and
From the Although Raf-1 is a critical effector of Ras
signaling and transformation, the mechanism by which Ras promotes Raf-1
activation is complex and remains poorly understood. We recently
reported that Ras interaction with the Raf-1 cysteine-rich domain
(Raf-CRD, residues 139-184) may be required for Raf-1 activation. The
Raf-CRD is located in the NH2-terminal negative
regulatory domain of Raf-1 and is highly homologous to cysteine-rich
domains found in protein kinase C family members. Recent studies
indicate that the structural integrity of the Raf-CRD is also critical
for Raf-1 interaction with 14-3-3 proteins. However, whether 14-3-3 proteins interact directly with the Raf-CRD and how this interaction
may mediate Raf-1 function has not been determined. In the present
study, we demonstrate that 14-3-3 Department of Pharmacology and the
¶ Department of Biochemistry and Biophysics, Lineberger
Comprehensive Cancer Center, University of North Carolina, Chapel Hill,
North Carolina 27599 and the Department of Pharmacology, Emory
University School of Medicine, Atlanta, Georgia 30322
binds directly to the isolated
Raf-CRD. Moreover, mutation of Raf-1 residues 143-145 impairs binding
of 14-3-3, but not Ras, to the Raf-CRD. Introduction of mutations that
impair 14-3-3 binding resulted in full-length Raf-1 mutants with
enhanced transforming activity. Thus, 14-3-3 interaction with the
Raf-CRD may serve in negative regulation of Raf-1 function by
facilitating dissociation of 14-3-3 from the NH2 terminus
of Raf-1 to promote subsequent events necessary for full activation of
Raf-1.
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