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Regulation of Ras signaling specificity by protein kinase C

Domenii publicaţii > Biologie + Tipuri publicaţii > Articol în revistã ştiinţificã

Autori: Rusanescu G, Gotoh T, Tian XJ, Feig LA

Editorial: MOL CELL BIOL, 21 (8), p.2650-2658, 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-CEF 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.