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Blood, 1 January 2005, Vol. 105, No. 1, pp. 259-265. Prepublished online as a Blood First Edition Paper on August 26, 2004; DOI 10.1182/blood-2004-07-2708. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-07-2708v1 105/1/259    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Middendorp, S. Articles by Hendriks, R. W. Search for Related Content PubMed PubMed Citation Articles by Middendorp, S. Articles by Hendriks, R. W. Related Collections Immunobiology Oncogenes and Tumor Suppressors Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Tumor suppressor function of Bruton tyrosine kinase is independent of its catalytic activity Sabine Middendorp, A. J. Esther Zijlstra, Rogier Kersseboom, Gemma M. Dingjan, Hassan Jumaa, and Rudolf W. Hendriks From the Department of Immunology, Erasmus MC Rotterdam, Rotterdam, The Netherlands; and Institute for Biology III, Albert-Ludwigs University of Freiburg, and Max Planck Institute for Immunobiology, Freiburg, Germany. During B-cell development in the mouse, Bruton tyrosine kinase (Btk) and the adaptor protein SLP-65 (Src homology 2 [SH2] domain-containing leukocyte protein of 65 kDa) limit the expansion and promote the differentiation of pre-B cells. Btk is thought to mainly function by phosphorylating phospholipase C2, which is brought into close proximity of Btk by SLP-65. However, this model was recently challenged by the identification of a role for Btk as a tumor suppressor in the absence of SLP-65 and by the finding that Btk function is partially independent of its kinase activity. To investigate if enzymatic activity is critical for the tumor suppressor function of Btk, we crossed transgenic mice expressing the kinase-inactive K430R-Btk mutant onto a Btk/SLP-65 double-deficient background. We found that K430R-Btk expression rescued the severe developmental arrest at the pre-B-cell stage in Btk/SLP-65 double-deficient mice. Moreover, K430R-Btk could functionally replace wild-type Btk as a tumor suppressor in SLP-65- mice: at 6 months of age, the observed pre-B-cell lymphoma frequencies were approximately 15% for SLP-65- mice, 44% for Btk/SLP-65-deficient mice, and 14% for K430R-Btk transgenic mice on the Btk/SLP-65-deficient background. Therefore, we conclude that Btk exerts its tumor suppressor function in pre-B cells as an adaptor protein, independent of its catalytic activity. (Blood. 2005;105:259-265) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. Sahu, C. Mueller, A. Fischer, and A. August Differential Sensitivity to Itk Kinase Signals for T Helper 2 Cytokine Production and Chemokine-Mediated Migration J. Immunol., March 15, 2008; 180(6): 3833 - 3838. [Abstract] [Full Text] [PDF] R. Kersseboom, V. B. T. Ta, A. J. E. Zijlstra, S. Middendorp, H. Jumaa, P. Fokko van Loo, and R. W. Hendriks Bruton's Tyrosine Kinase and SLP-65 Regulate Pre-B Cell Differentiation and the Induction of Ig Light Chain Gene Rearrangement. J. Immunol., April 15, 2006; 176(8): 4543 - 4552. [Abstract] [Full Text] [PDF] R. Nakagawa, J. W. Soh, and A. M. Michie Subversion of Protein Kinase C{alpha} Signaling in Hematopoietic Progenitor Cells Results in the Generation of a B-Cell Chronic Lymphocytic Leukemia-Like Population In vivo Cancer Res., January 1, 2006; 66(1): 527 - 534. [Abstract] [Full Text] [PDF] N. Feldhahn, F. Klein, J. L. Mooster, P. Hadweh, M. Sprangers, M. Wartenberg, M. M. Bekhite, W.-K. Hofmann, S. Herzog, H. Jumaa, et al. Mimicry of a constitutively active pre-B cell receptor in acute lymphoblastic leukemia cells J. Exp. Med., June 6, 2005; 201(11): 1837 - 1852. [Abstract] [Full Text] [PDF]

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