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Blood, 15 February 2004, Vol. 103, No. 4, pp. 1464-1471. Prepublished online as a Blood First Edition Paper on October 16, 2003; DOI 10.1182/blood-2003-04-1038. This Article Full Text (PDF) All Versions of this Article: 2003-04-1038v1 103/4/1464    most recent Alert me when this article is cited Alert me if a correction is posted 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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Cussac, D. Articles by Payrastre, B. Search for Related Content PubMed PubMed Citation Articles by Cussac, D. Articles by Payrastre, B. Social Bookmarking                   What's this? Submitted April 3, 2003 Accepted October 7, 2003 Nucleophosmin-anaplastic lymphoma kinase of anaplastic large-cell lymphoma recruits, activates and uses pp60c-src to mediate its mitogenicity Daniel Cussac, Catherine Greenland, Serge Roche, Ren-Yuan Bai, Justus Duyster, Stephan W Morris, George Delsol, Michele Allouche, and Bernard Payrastre* Departement d'Oncogenese et Signalisation dans les Cellules Hematopoietiques, INSERM, Unite 563, Toulouse, France CRBM, CNRS UPR 1086, Montpellier, France Department of Internal Medicine III, Laboratory of Leukemogenesis, Technical University of Munich, Munich, Germany Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA * Corresponding author; email: payrastr{at}toulouse.inserm.fr. Anaplastic large-cell lymphomas (ALCLs) are lymphomas of T/null phenotype often associated with a chromosomal translocation, t(2;5)(p23;q35). This translocation leads to the expression of a hydrid protein consisting of the N-terminal portion of nucleophosmin (NPM) and the intracellular domain of the anaplastic lymphoma kinase (ALK). NPM-ALK possesses a constitutive tyrosine kinase activity responsible for its oncogenic property through activation of downstream effectors such as PLC- and the type I A phosphoinositide 3-kinase. Here, we show that the Src-kinases, particularly pp60c-src, associate with and are activated by NPM-ALK expression in various cells, and in cell lines established from patients with ALCL. The kinase activity and the tyrosine 418 of NPM-ALK are required for its association with Src-kinases. Y418F mutation of NPM-ALK impaired its association with Src-kinases and strongly reduced the proliferation rate of Ba/F3 cells. In agreement, Src-kinase inhibitors or pp60c-src siRNA significantly decreased the proliferation rate of NPM-ALK positive ALCL cell lines. Moreover, using active or inactive forms of pp60c-src and NPM-ALK, we provide evidence that NPM-ALK is a potential substrate of pp60c-src. Overall, our data place Src-kinases as new important downstream effectors of NPM-ALK and attractive potential therapeutic targets for new ALCL treatment. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. S. Lim, M. L. Carlson, D. K. Crockett, G. C. Fillmore, D. R. Abbott, O. F. Elenitoba-Johnson, S. R. Tripp, G. Z. Rassidakis, L. J. Medeiros, P. Szankasi, et al. The proteomic signature of NPM/ALK reveals deregulation of multiple cellular pathways Blood, August 20, 2009; 114(8): 1585 - 1595. [Abstract] [Full Text] [PDF] P. Shi, R. Lai, Q. Lin, A. S. Iqbal, L. C. Young, L. W. Kwak, R. J. Ford, and H. M. 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