Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/176995
Title: Calmodulin prevents activation of Ras by PKC in 3T3 fibroblasts
Author: Villalonga, Priam
López Alcalá, Cristina
Chiloeches, Antonio
Gil i Santano, Joan
Marais, Richard
Bachs Valldeneu, Oriol
Agell i Jané, Neus
Keywords: Calmodulina
Farmacologia
Metabolisme
Proteïnes quinases
Calmodulin
Pharmacology
Metabolism
Protein kinases
Issue Date: 4-Oct-2002
Publisher: American Society for Biochemistry and Molecular Biology
Abstract: We have shown previously (Villalonga, P., López- Alcalá, C., Bosch, M., Chiloeches, A., Rocamora, N., Gil, J., Marais, R., Marshall, C. J., Bachs, O., and Agell, N. (2001) Mol. Cell. Biol. 21, 7345-7354) that calmodulin negatively regulates Ras activation in fibroblasts. Hence, anti-calmodulin drugs (such as W13, trifluoroperazine, or W7) are able to induce Ras/ERK pathway activation under low levels of growth factors. We show here that cell treatment with protein kinase C (PKC) inhibitors abolishes W13-induced activation of Ras, Raf-1, and ERK. Consequently, PKC activity is essential for achieving the synergism between calmodulin inhibition and growth factors to activate Ras. Furthermore, whereas the activation of PKC by 12-O-tetradecanoylphorbol-13-acetate (TPA) does not induce Ras activation in 3T3 cells, activation is observed if calmodulin is simultaneously inhibited. This indicates that calmodulin is preventing Ras activation by PKC. Treatment of cells with epidermal growth factor receptor or platelet-derived growth factor receptor tyrosine kinase inhibitors does not abrogate the activation of Ras by calmodulin inhibition. This implies that epidermal growth factor receptor and platelet-derived growth factor receptor tyrosine kinase activities are dispensable for the activation of Ras by TPA plus W13, and, therefore, Ras activation is not a consequence of the transactivation of those receptors by the combination of the anti-calmodulin drug plus TPA. Furthermore, K-Ras, the isoform previously shown to bind to calmodulin, is the only one activated by TPA when calmodulin is inhibited. These data suggest that direct interaction between K-Ras and calmodulin may account for the inability of PKC to activate Ras in 3T3 fibroblasts. In vitro experiments showed that the phosphorylation of K-Ras by PKC was inhibited by calmodulin, suggesting that calmodulin-dependent modulation of K-Ras phosphorylation by PKC could be the mechanism underlying K-Ras activation in fibroblasts treated with TPA plus W13.
Note: Reproducció del document publicat a: https://doi.org/10.1074/jbc.M202245200
It is part of: Journal of Biological Chemistry, 2002, vol. 277, num. 40, p. 37927-37935
URI: http://hdl.handle.net/2445/176995
Related resource: https://doi.org/10.1074/jbc.M202245200
ISSN: 0021-9258
Appears in Collections:Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Biomedicina)
Articles publicats en revistes (Ciències Fisiològiques)

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