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Molecular and Cellular Biology, April 2001, p. 2650-2658, Vol. 21, No. 8
Department of Biochemistry, Tufts University
School of Medicine, Boston, Massachusetts
Received 7 June 2000/Returned for modification 21 July
2000/Accepted 30 January 2001
Ras proteins have the capacity to bind to and activate at least
three families of downstream target proteins: Raf kinases, phosphatidylinositol 3 (PI 3)-kinase, and Ral-specific guanine nucleotide exchange factors (Ral-GEFs). We have previously shown that
the Ras/Ral-GEF and Ras/Raf pathways oppose each other upon nerve
growth factor stimulation, with the former promoting proliferation and
the latter promoting cell cycle arrest. Moreover, the pathways are not
activated equally. While the Ras/Raf/Erk signaling pathway is induced
for hours, the Ras/Ral-GEF/Ral signaling pathway is induced for only
minutes. Here we show that this preferential down-regulation of Ral
signaling is mediated, at least in part, by protein kinase C (PKC). In
particular, we show that PKC activation by phorbol ester treatment of
cells blocks growth factor-induced Ral activation while it enhances Erk
activation. Moreover, suppression of growth factor-induced PKC
activation enhances and prolongs Ral activation. PKC does not influence
the basal activity of the Ral-GEF designated Ral-GDS but suppresses its
activation by Ras. Interestingly, Ras binding to the C-terminal Ras
binding domain of Ral-GDS is not affected by PKC activity. Instead,
suppression of Ral-GDS activation occurs through the region N terminal
to the catalytic domain, which becomes phosphorylated in response to
phorbol ester treatment of cells. These findings identify a role for
PKC in determining the specificity of Ras signaling by its ability to
differentially modulate Ras effector protein activation.
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.8.2650-2658.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Regulation of Ras Signaling Specificity by Protein
Kinase C
*
Corresponding author. Mailing address: Department of
Biochemistry, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111. Phone: (617) 969-4657. Fax: (617) 636-2409. E-mail:
lfeig{at}opal.tufts.edu.
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