Sci. STKE, 6 March 2001
Protein Degradation GRF2 Regulated by Ubiquitination
Ras-GRF2 (GRF2) is a guanine nucleotide exchange factor (GEF) that activates the small guanosine triphosphatases (GTPases) Ras and Rac1 by promoting the exchange of GDP (inactive) for GTP (active). GRF2 contains several conserved protein domains and motifs including a destruction box (DB), and a Cdc25 domain that binds to Ras and contains the GEF activity. But how is the activity of GRF2 regulated so that an amplifying feed-forward cycle of Ras activation is prevented? de Hoog et al. found that deletion of the GRF2 DB motif, which presumably did not inhibit GRF2-Ras association, spared GRF2 from destruction in Ca2+- and ionomycin-treated cells. Cdc25 domain mutants of GRF2 that did not bind Ras were similarly protected from degradation, suggesting that GRF2 degradation required the DB motif and physical association with Ras. GRF2 was phosphorylated on serine or threonine near the DB motif, and GRF2 was ubiquitinated upon cell stimulation. Treatment of cells with proteasomal inhibitors inhibited GRF2 degradation, suggesting that the 26S proteasome is responsible for maintaining tight control of GRF2 levels, and consequently Ras activation by GRF2, in cells.
C. L. de Hoog, J. A. Koehler, M. D. Goldstein, P. Taylor, D. Figeys, M. F. Moran, Ras binding triggers ubiquitination of the Ras exchange factor Ras-GRF2. Mol. Cell. Biol. 21, 2107-2117 (2001). [Abstract] [Full Text]
Citation: GRF2 Regulated by Ubiquitination. Sci. STKE 2001, tw6 (2001).
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