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J. Biol. Chem., Vol. 281, Issue 15, 10567-10576, April 14, 2006

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Activation of the Erk8 Mitogen-activated Protein (MAP) Kinase by RET/PTC3, a Constitutively Active Form of the RET Proto-oncogene^*

Carlo Iavarone¹, Mario Acunzo¹, Francesca Carlomagno, Annunziata Catania, Rosa M. Melillo, Stella M. Carlomagno, Massimo Santoro, and Mario Chiariello²

From the Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università degli Studi di Napoli "Federico II" and the Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (CNR), Via Pansini 5, 80131 Napoli, Italy

Mitogen-activated protein (MAP) kinases have a central role in several biological functions, including cell adhesion and spreading, chemotaxis, cell cycle progression, differentiation, and apoptosis. Extracellular signal-regulated kinase 8 (Erk8) is a large MAP kinase whose activity is controlled by serum and the c-Src non-receptor tyrosine kinase. Here, we show that RET/PTC3, an activated form of the RET proto-oncogene, was able to activate Erk8, and we demonstrate that such MAP kinase participated in RET/PTC3-dependent stimulation of the c-jun promoter. By using RET/PTC3 molecules mutated in specific tyrosine autophosphorylation sites, we characterized Tyr⁹⁸¹, a known binding site for c-Src, as a major determinant of RET/PTC3-induced Erk8 activation, although, surprisingly, the underlying mechanism did not strictly depend on the activity of Src. In contrast, we present evidence that RET/PTC3 acts on Erk8 through Tyr⁹⁸¹-mediated activation of c-Abl. Furthermore, we localized the region responsible for the modulation of Erk8 activity by the RET/PTC3 and Abl oncogenes in the Erk8 C-terminal domain. Altogether, these results support a role for Erk8 as a novel effector of RET/PTC3 and, therefore, RET biological functions.

Received for publication, December 16, 2005

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY994058 [GenBank] .

^* This work was supported by Associazione Italiana per la Ricerca sul Cancro. 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.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Istituto di Endocrinologia e Oncologia Sperimentale (IEOS), Consiglio Nazionale delle Ricerche (CNR), Via Pansini 5, 80131, Napoli, Italy. Tel.: 39-081-7462022; Fax: 39-081-7703285; E-mail: chiariel{at}unina.it.

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