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J. Biol. Chem., Vol. 280, Issue 27, 25461-25469, July 8, 2005

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Cross-talk between Signaling Pathways Regulates Alternative Splicing

A NOVEL ROLE FOR JNK^*

Federico Pelisch, Matías Blaustein, Alberto R. Kornblihtt, and Anabella Srebrow¶

From the Laboratorio de Fisiología y Biología Molecular, Instituto de Fisiología, Biología Molecular y Neurociencias-Consejo Nacional de Investigaciones Científicas y Técnicas, Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II (C1428EHA) Buenos Aires, Argentina.

The regulation of alternative splicing by extracellular signals represents a key event in the control of gene expression. There is increasing evidence showing that many extracellular cues regulate alternative splicing. Nevertheless, the broad picture regarding the role of different signaling pathways and their interaction remains incomplete. Using the fibronectin gene as a model, we show that a laminin-rich basement membrane regulates the alternative splicing of two out of three regions of the transcript (extra domain I and type III connecting segment) in mammary epithelial cells, through a non-stress c-Jun N-terminal kinase (JNK) signaling pathway. We propose that dephosphorylation of the extracellular signal-regulated kinase is involved in this regulatory process. Furthermore, the laminin-rich basement membrane blocks the effect of a mammary mesenchymal cell-conditioned medium, which stimulates the inclusion of extra domain I and type III connectingsegmentthroughaphosphatidylinositol3-kinase-dependent cascade, indicating that JNK signaling can inhibit the phosphatidylinositol 3-kinase-mediated splicing regulation. These results implicate JNK in the regulation of alternative splicing and provide new evidence on how extracellular stimuli are converted into changes in splicing patterns, strengthening the view that the control of alternative splicing is as complex and relevant as transcriptional control, together accounting for the spatiotemporal requirements of gene expression.

Received for publication, October 22, 2004 , and in revised form, April 20, 2005.

^* This work was supported in part by grants from the Third World Academy of Sciences, the International Centre for Genetic Engineering and Biotechnology, Fundación Antorchas, Universidad de Buenos Aires, Agencia Nacional de Promoción Científica y Technológica, and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). 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.

Supported by fellowships from the Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and CONICET.

Investigator of the CONICET and an International Research Scholar of the Howard Hughes Medical Institute.

^¶ Investigator of the CONICET. To whom correspondence should be addressed. Tel.: 5411-4576-3368; Fax: 5411-4576-3321; E-mail: asrebrow{at}fbmc.fcen.uba.ar.

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