Previous Article | Next Article 
Molecular and Cellular Biology, April 2000, p. 2727-2733, Vol. 20, No. 8
Banting and Best Department of Medical
Research,1 Department of Molecular and
Medical Genetics,2 and Department of
Radiation Oncology,3 University of Toronto,
Toronto, Ontario M5G 1X5, Canada
Received 20 September 1999/Returned for modification 4 November
1999/Accepted 27 January 2000
Ras-GRF2 (GRF2) is a widely expressed, calcium-activated regulator
of the small-type GTPases Ras and Rac. It is a multidomain protein
composed of several recognizable sequence motifs in the following order
(NH2 to COOH): pleckstrin homology (PH), coiled-coil, ilimaquinone (IQ), Dbl homology (DH), PH, REM (Ras exchanger motif), PEST/destruction box, Cdc25. The DH and Cdc25 domains possess guanine
nucleotide exchange factor (GEF) activity and interact with Rac and
Ras, respectively. The REM-Cdc25 region was found to be sufficient for
maximal activation of Ras in vitro and in vivo caused Ras and
extracellular signal-regulated kinase (ERK) activation independent of
calcium signals, suggesting that, at least when expressed ectopically,
it contains all of the determinants required to access and activate Ras
signaling. Additional mutational analysis of GRF2 indicated that the
carboxyl PH domain imparts a modest inhibitory effect on Ras GEF
activity and probably normally participates in intermolecular
interactions. A variant of GRF2 missing the Cdc25 domain did not
activate Ras and functions as an inhibitor of wild-type GRF2,
presumably by competing for interactions with molecules other than
calmodulin, Ras, and ligands of the PH domain. The binding of
calmodulin was found to require several amino-terminal domains of GRF2
in addition to the IQ sequence, and no correlation between calmodulin
binding by GRF2 and its ability to directly activate Ras and indirectly
stimulate the mitogen-activated protein (MAP) kinase ERK in response to
calcium was found. The precise role of the GRF2-calmodulin association, therefore, remains to be determined. A GRF2 mutant missing the IQ
sequence was competent for Ras activation but failed to couple this to
stimulation of the ERK pathway. This demonstrates that Ras-GTP
formation is not sufficient for MAP kinase signaling. We conclude that
in addition to directly activating Ras, GRF2, and likely other GEFs,
promote the assembly of a protein network able to couple the GTPase
with particular effectors.
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Calmodulin-Independent Coordination of Ras and
Extracellular Signal-Regulated Kinase Activation by Ras-GRF2
*
Corresponding author. Mailing address: MDS Ocata Inc.,
600 University Ave., Suite 1075, Toronto, ON M5G 1X5, Canada. Phone: (416) 586-4800, ext. 2544. Fax: (416) 586-8869. E-mail:
m.moran{at}ocata.com.
Molecular and Cellular Biology, April 2000, p. 2727-2733, Vol. 20, No. 8
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Calvo, F., Crespo, P.
(2009). Structural and Spatial Determinants Regulating TC21 Activation by RasGRF Family Nucleotide Exchange Factors. Mol. Biol. Cell
20: 4289-4302
[Abstract] [Full Text] -
Rondaij, M. G., Bierings, R., van Agtmaal, E. L., Gijzen, K. A., Sellink, E., Kragt, A., Ferguson, S. S. G., Mertens, K., Hannah, M. J., van Mourik, J. A., Fernandez-Borja, M., Voorberg, J.
(2008). Guanine exchange factor RalGDS mediates exocytosis of Weibel-Palade bodies from endothelial cells. Blood
112: 56-63
[Abstract] [Full Text] -
Ruiz, S., Santos, E., Bustelo, X. R.
(2007). RasGRF2, a Guanosine Nucleotide Exchange Factor for Ras GTPases, Participates in T-Cell Signaling Responses. Mol. Cell. Biol.
27: 8127-8142
[Abstract] [Full Text] -
Liao, J., Planchon, S. M., Wolfman, J. C., Wolfman, A.
(2006). Growth Factor-dependent AKT Activation and Cell Migration Requires the Function of c-K(B)-Ras Versus Other Cellular Ras Isoforms. J. Biol. Chem.
281: 29730-29738
[Abstract] [Full Text] -
Cully, M., Shiu, J., Piekorz, R. P., Muller, W. J., Done, S. J., Mak, T. W.
(2005). Transforming Acidic Coiled Coil 1 Promotes Transformation and Mammary Tumorigenesis. Cancer Res.
65: 10363-10370
[Abstract] [Full Text] -
Grill, B., Schrader, J. W.
(2002). Activation of Rac-1, Rac-2, and Cdc42 by hemopoietic growth factors or cross-linking of the B-lymphocyte receptor for antigen. Blood
100: 3183-3192
[Abstract] [Full Text] -
Dumont, J. E., Dremier, S., Pirson, I., Maenhaut, C.
(2002). Cross signaling, cell specificity, and physiology. Am. J. Physiol. Cell Physiol.
283: C2-C28
[Abstract] [Full Text] -
de Hoog, C. L., Koehler, J. A., Goldstein, M. D., Taylor, P., Figeys, D., Moran, M. F.
(2001). Ras Binding Triggers Ubiquitination of the Ras Exchange Factor Ras-GRF2. Mol. Cell. Biol.
21: 2107-2117
[Abstract] [Full Text] -
Baouz, S., Jacquet, E., Accorsi, K., Hountondji, C., Balestrini, M., Zippel, R., Sturani, E., Parmeggiani, A.
(2001). Sites of Phosphorylation by Protein Kinase A in CDC25Mm/GRF1, a Guanine Nucleotide Exchange Factor for Ras. J. Biol. Chem.
276: 1742-1749
[Abstract] [Full Text]
Copyright © 2009 by the American Society for Microbiology. For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»