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Molecular and Cellular Biology, April 2001, p. 2650-2658, Vol. 21, No. 8
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

Gabriel Rusanescu, Takaya Gotoh, Xuejun Tian, and Larry A. Feig*

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.

* 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.

Molecular and Cellular Biology, April 2001, p. 2650-2658, Vol. 21, No. 8
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.8.2650-2658.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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