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Abstract
The Snail gene product is a transcriptional repressor of E-cadherin expression and an inducer of the epithelial-to-mesenchymal transition in several epithelial tumor cell lines. This report presents data indicating that Snail function is controlled by its intracellular location. The cytosolic distribution of Snail depended on export from the nucleus by a CRM1-dependent mechanism, and a nuclear export sequence (NES) was located in the regulatory domain of this protein. Export of Snail was controlled by phosphorylation of a Ser-rich sequence adjacent to this NES. Modification of this sequence released the restriction created by the zinc finger domain and allowed nuclear export of the protein. The phosphorylation and subcellular distribution of Snail are controlled by cell attachment to the extracellular matrix. Suspended cells presented higher levels of phosphorylated Snail and an augmented extranuclear localization with respect to cells attached to the plate. These findings show the existence in tumor cells of an effective and fine-tuning nontranscriptional mechanism of regulation of Snail activity dependent on the extracellular environment.
ACKNOWLEDGMENTS
We greatly appreciate the advice of Francesc Posas and Jose Aramburu and the help of Arrate Mallabiabarrena with the confocal microscopy. We thank Gabriel Gil, Mercè Martín, and Mireia Duñach for the generous gift of plasmids. The technical assistance of M. Carmen Torns, Marta Garrido, and Francisco Sánchez-Aguilera is greatly appreciated.
This study was supported by grants awarded to A.G.H. by the Ministerio de Ciencia y Tecnología (PM99-0132), the Fundación Científica de la Asociación Española Contra el Cáncer, and the Direcció General de Recerca of the Generalitat de Catalunya (2001/SSSGR410). B.M.-S. and S. G. were recipients of predoctoral fellowships from the Ministerio de Ciencia y Tecnología. D.D., A.V.-S., and I.P. were recipients of predoctoral fellowships from the Instituto Carlos III, the Universitat Pompeu Fabra, and the Ministerio de Educación, respectively.