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J. Biol. Chem., Vol. 278, Issue 46, 45101-45108, November 14, 2003

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Calcium/Calmodulin-dependent Protein Kinase II Binds to Raf-1 and Modulates Integrin-stimulated ERK Activation^*

Maddalena Illario, Anna Lina Cavallo, K. Ulrich Bayer, Tiziana Di Matola, Gianfranco Fenzi¶, Guido Rossi||, and Mario Vitale¶**

From the Dipartimento di Biologia e Patologia Cellulare e Molecolare, ^¶Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università Federico II, and ^||Istituto di Endocrinologia ed Oncologia Sperimentale "G. Salvatore" del Consiglio Nazionale delle Ricerche (G.R.), Napoli, 80131 Italy, and Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado 80262

Integrin activation generates different signalings in a cell type-dependent manner and stimulates cell proliferation through the Ras/Raf-1/Mek/Erk pathway. In this study, we demonstrate that integrin stimulation by fibronectin (FN), besides activating the Ras/Erk pathway, generates an auxiliary calcium signal that activates calmodulin and the Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). This signal regulates Raf-1 activation by Ras and modulates the FN-stimulated extracellular signal-regulated kinase (Erk-1/2). The binding of soluble FN to integrins induced increase of intracellular calcium concentration associated with phosphorylation and activation of CaMKII. In two different cell lines, inhibition of CaMKII activity by specific inhibitors inhibited Erk-1/2 phosphorylation. Whereas CaMK inhibition affected neither integrin-stimulated Akt phosphorylation nor p21Ras or Mek-1 activity, it was necessary for Raf-1 activity. FN-induced Raf-1 activity was abrogated by the CaMKII specific inhibitory peptide ant-CaNtide. Integrin activation by FN induced the formation of a Raf-1/CaMKII complex, abrogated by inhibition of CaMKII. Active CaMKII phosphorylated Raf-1 in vitro. This is the first demonstration that CaMKII interplays with Raf-1 and regulates Erk activation induced by Ras-stimulated Raf-1. These findings also provide evidence supporting the possible existence of cross-talk between other intracellular pathways involving CaMKII and Raf-1.

Received for publication, May 22, 2003 , and in revised form, August 11, 2003.

^* This work has been supported in part by Ministero dell'Istruzione, dell'Università e della Ricerca (to M. V.) and Fondazione Italiana per la Ricerca sul Cancro (to T. D. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Via S. Pansini, 5 Napoli, 80131 Italy. Tel.: 39-0817463046; Fax: 39-0817701016; E-mail: mavitale{at}unina.it.

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