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Article

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Published version

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1998-08-21

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Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/177102

Calmodulin inhibitor W13 induces sustained activation of ERK2 and expression of p21CIP1

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https://doi.org/10.1074/jbc.273.34.22145

Abstract

One of the major signaling pathways by which extracellular signals induce cell proliferation and differentiation involves the activation of extracellular signal-regulated kinases (ERKs). Because calmodulin is essential for quiescent cells to enter cell cycle, the role of calmodulin on ERK2 activation was studied in cultured fibroblasts. Serum, phorbol esters, or active Ras induced ERK2 activation in NIH 3T3 fibroblasts. This activation was not inhibited by calmodulin blockade. Surprisingly, inhibition of calmodulin prior to fetal bovine serum addition prolonged activation of ERK2. Furthermore, inactivation of calmodulin in serum-starved cells induced ERK2 phosphorylation that was dependent on MAP kinase kinase (MEK). Inactivation of calmodulin in serum-starved cells also induced activation of Ras, Raf, and MEK. On the contrary, tyrosine phosphorylation of tyrosine kinase receptors was not observed. These results indicate that calmodulin inhibits ERK2 activation pathway at the level of Ras. Calmodulin inhibition induced overexpression of p21(cip1) which was dependent on MEK activity. We propose that inhibition of Ras by calmodulin prevents the activation of ERK2 at low serum concentration. Thus, entering into the cell cycle after serum addition would imply the overcoming of the inhibitory effect of calmodulin and consequently ERK2 activation. Furthermore, down-regulation of Ras by calmodulin may be also important to determine the duration of ERK2 activation and to prevent a high p21(cip1) expression that would lead to an inhibition of cell proliferation.

Subject

Calmodulina, Metabolisme, Ciclines, Sulfamides

Subject (English)

Calmodulin, Metabolism, Cyclins, Sulfonamides

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Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Biomedicina)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

Citation

BOSCH I RODRÍGUEZ, Marta, et al. Calmodulin inhibitor W13 induces sustained activation of ERK2 and expression of p21CIP1. Journal of Biological Chemistry. 1998. Vol. 273, num. 34, pags. 22145-22150. ISSN 0021-9258. [consulted: 8 of August of 2026]. Available at: https://hdl.handle.net/2445/177102

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