Calmodulin Binds to K-Ras, but Not to H- or N-Ras, and Modulates Its Downstream Signaling

doi:10.1128/MCB.21.21.7345-7354.2001

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Molecular and Cellular Biology, November 2001, p. 7345-7354, Vol. 21, No. 21
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.21.7345-7354.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Calmodulin Binds to K-Ras, but Not to H- or N-Ras, and Modulates Its Downstream Signaling

Priam Villalonga,¹ Cristina López-Alcalá,¹ Marta Bosch,² Antonio Chiloeches,² Nativitat Rocamora,³ Joan Gil,⁴ Richard Marais,² Christopher J. Marshall,² Oriol Bachs,¹ and Neus Agell¹^,^*

Departament de Biologia Cellular i Anatomia Patològica, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona,¹ Institut Català d'Oncologia³ and Departament de Ciències Fisiològiques II, Campus de Bellvitge, Universitat de Barcelona,⁴ 08907 L'Hospitalet, Barcelona, Spain, and CRC Center for Cell and Molecular Biology, Institute of Cancer Research, London SW3 6JB, United Kingdom²

Received 20 February 2001/Returned for modification 23 March 2001/Accepted 27 July 2001

Activation of Ras induces a variety of cellular responses depending on the specific effector activated and the intensity andamplitude of this activation. We have previously shown that calmodulinis an essential molecule in the down-regulation of the Ras/Raf/MEK/extracellularlyregulated kinase (ERK) pathway in cultured fibroblasts and thatthis is due at least in part to an inhibitory effect of calmodulinon Ras activation. Here we show that inhibition of calmodulinsynergizes with diverse stimuli (epidermal growth factor, platelet-derivedgrowth factor, bombesin, or fetal bovine serum) to induce ERKactivation. Moreover, even in the absence of any added stimuli,activation of Ras by calmodulin inhibition was observed. To identifythe calmodulin-binding protein involved in this process, calmodulinaffinity chromatography was performed. We show that Ras and Raffrom cellular lysates were able to bind to calmodulin. Furthermore,Ras binding to calmodulin was favored in lysates with large amountsof GTP-bound Ras, and it was Raf independent. Interestingly, onlyone of the Ras isoforms, K-RasB, was able to bind to calmodulin.Furthermore, calmodulin inhibition preferentially activated K-Ras.Interaction between calmodulin and K-RasB is direct and is inhibitedby the calmodulin kinase II calmodulin-binding domain. Thus, GTP-boundK-RasB is a calmodulin-binding protein, and we suggest that thisbinding may be a key element in the modulation of Rassignaling.

^* Corresponding author. Mailing address: Dept. Biologia Cellular, Fac. Medicina, U. Barcelona, C/Casanova, 143, 08036 Barcelona,Spain. Phone: 34 934035267. Fax: 34 934021907. E-mail: agell{at}medicina.ub.es.

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