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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2600-2609. Prepublished online as a Blood First Edition Paper on May 30, 2007; DOI 10.1182/blood-2006-01-028647. This Article Full Text Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: blood-2006-01-028647v1 110/7/2600    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Galietta, A. Articles by Gambacorti-Passerini, C. Search for Related Content PubMed PubMed Citation Articles by Galietta, A. Articles by Gambacorti-Passerini, C. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA NPM/ALK binds and phosphorylates the RNA/DNA-binding protein PSF in anaplastic large-cell lymphoma Annamaria Galietta1,2,9, Rosalind H. Gunby1, Sara Redaelli1, Paola Stano2, Cristiana Carniti2, Angela Bachi3, Philip W. Tucker4, Carmen J. Tartari1,2, Ching-Jung Huang4, Emanuela Colombo5, Karen Pulford6, Miriam Puttini1, Rocco G. Piazza1, Holger Ruchatz2, Antonello Villa7, Arianna Donella-Deana8, Oriano Marin8, Danilo Perrotti9, and Carlo Gambacorti-Passerini2,10 1 Department of Clinical Medicine, University of Milano-Bicocca, Monza, Italy; 2 Department of Experimental Oncology, The National Cancer Institute of Milan, Milan, Italy; 3 Dipartimento di Biotecnologie (DIBIT), San Raffaele Scientific Institute, Milan, Italy; 4 Molecular Genetics and Microbiology, University of Texas at Austin, TX; 5 Department of Experimental Oncology, The European Institute of Oncology, Milan, Italy; 6 Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford, United Kingdom; 7 Microscopy and Image Analysis Consortium, Department of Neuroscience, University of Milano-Bicocca, Monza, Italy; 8 Department of Biological Chemistry, Institute of Neuroscience of the Italian National Research Council (CNR), Section of Padua, University of Padua, Italy; 9 Department of Microbiology, Immunology, Virology, and Medical Genetics, Human Cancer Genetics Program and The Ohio State University Comprehensive Cancer Center, Columbus; 10 Department of Oncology, McGill University, Montreal, QC, Canada The oncogenic fusion tyrosine kinase nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) induces cellular transformation in anaplastic large-cell lymphomas (ALCLs) carrying the t(2;5) chromosomal translocation. Protein-protein interactions involving NPM/ALK are important for the activation of downstream signaling pathways. This study was aimed at identifying novel NPM/ALK-binding proteins that might contribute to its oncogenic transformation. Using a proteomic approach, several RNA/DNA-binding proteins were found to coimmunoprecipitate with NPM/ALK, including the multifunctional polypyrimidine tract binding proteinassociated splicing factor (PSF). The interaction between NPM/ALK and PSF was dependent on an active ALK kinase domain and PSF was found to be tyrosine-phosphorylated in NPM/ALK-expressing cell lines and in primary ALK+ ALCL samples. Furthermore, PSF was shown to be a direct substrate of purified ALK kinase domain in vitro, and PSF Tyr293 was identified as the site of phosphorylation. Y293F PSF was not phosphorylated by NPM/ALK and was not delocalized in NPM/ALK+ cells. The expression of ALK fusion proteins induced delocalization of PSF from the nucleus to the cytoplasm and forced overexpression of PSF-inhibited proliferation and induced apoptosis in cells expressing NPM/ALK. PSF phosphorylation also increased its binding to RNA and decreased the PSF-mediated suppression of GAGE6 expression. These results identify PSF as a novel NPM/ALK-binding protein and substrate, and suggest that PSF function may be perturbed in NPM/ALK-transformed cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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