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Blood, 15 May 2006, Vol. 107, No. 10, pp. 4130-4138. Prepublished online as a Blood First Edition Paper on February 9, 2006; DOI 10.1182/blood-2005-06-2421. This Article Full Text (PDF) All Versions of this Article: 2005-06-2421v1 107/10/4130    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 Honorat, J.-F. Articles by Ragab-Thomas, J. Search for Related Content PubMed PubMed Citation Articles by Honorat, J.-F. Articles by Ragab-Thomas, J. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 17, 2005 Accepted January 27, 2006 SHP1 tyrosine phosphatase negatively regulates NPM-ALK tyrosine kinase signaling Jean-Francois Honorat, Ashraf Ragab, Laurence Lamant, Georges Delsol*, and Jeannie Ragab-Thomas Oncogenesis and Signaling in Hematopoietic Cells, INSERM, U.563-CPTP, Toulouse, France; Medecine, Univ Paul-Sabatier, Toulouse, France Oncogenesis and Signaling in Hematopoietic Cells, INSERM, U.563-CPTP, Toulouse, France; Medecine, Univ Paul-Sabatier, Toulouse, France; Service d'Anatomie Pathologique, CHU Purpan, Toulouse, France * Corresponding author; email: delsol.g{at}chu-toulouse.fr. Anaplastic Large Cell Lymphoma (ALCL) is frequently associated with the 2;5 translocation and expresses the NPM-ALK fusion protein which possesses a constitutive tyrosine kinase activity. We analysed SHP1 tyrosine-phosphatase expression and activity in three ALK-positive ALCL cell lines (Karpas 299, Cost and SU-DHL1) and in lymph node biopsies (n=40). We found an inverse correlation between the level of NPM-ALK phosphorylation and SHP1 phosphatase activity. Pull-down and co-immunoprecipitation experiments demonstrated a SHP1/NPM-ALK association. Furthermore, confocal microscopy performed on ALCL cell lines and biopsy specimens showed the co-localization of the two proteins in cytoplasmic bodies containing Y664-phosphorylated NPM-ALK. Dephosphorylation of NPM-ALK by SHP1 demonstrated that NPM-ALK was a SHP1 substrate. Down-regulation of SHP1 expression by RNAi in Karpas cells led to hyperphosphorylation of NPM-ALK, STAT3 activation and increase in cell proliferation. Furthermore, SHP1 over-expression in 3T3 fibroblasts stably expressing NPM-ALK led to the decrease of NPM-ALK phosphorylation, lower cell proliferation and tumor progression in nude mice. These findings show that SHP1 is a negative regulator of NPM-ALK signaling. The use of tissue microarrays revealed that 50% of ALK-positive ALCLs were positive for SHP1. Our results suggest that SHP1 could be a critical enzyme in ALCL biology and a potential therapeutic target. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Q. Zhang, H. Y. Wang, G. Bhutani, X. Liu, M. Paessler, J. W. Tobias, D. Baldwin, K. Swaminathan, M. C. Milone, and M. A. Wasik Lack of TNF{alpha} expression protects anaplastic lymphoma kinase-positive T-cell lymphoma (ALK+ TCL) cells from apoptosis PNAS, September 15, 2009; 106(37): 15843 - 15848. [Abstract] [Full Text] [PDF] J. K. C. Chan, L. Lamant, E. Algar, G. Delsol, W. Y. W. Tsang, K. C. Lee, K. Tiedemann, and C. W. Chow ALK+ histiocytosis: a novel type of systemic histiocytic proliferative disorder of early infancy Blood, October 1, 2008; 112(7): 2965 - 2968. 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Franko, C. Frantz, X. Shi, and R. Lai Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large-cell lymphoma Blood, October 15, 2006; 108(8): 2796 - 2803. [Abstract] [Full Text] [PDF] M. Fawal, F. Armstrong, S. Ollier, H. Dupont, C. Touriol, B. Monsarrat, G. Delsol, B. Payrastre, and D. Morello A "liaison dangereuse" between AUF1/hnRNPD and the oncogenic tyrosine kinase NPM-ALK Blood, October 15, 2006; 108(8): 2780 - 2788. [Abstract] [Full Text] [PDF]

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