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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.
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Submitted July 15, 2004
Accepted August 14, 2004
Tumor suppressor function of Bruton's tyrosine kinase is independent of its catalytic activity
Sabine Middendorp, A J Zijlstra, Rogier Kersseboom, Gemma M Dingjan, Hassan Jumaa, and Rudolf W Hendriks*
Department of Immunology, Erasmus MC Rotterdam, Rotterdam, The Netherlands
Institute for Biology III, Albert-Ludwigs University of Freiburg and Max Planck Institute for Immunobiology, Freiburg, Germany
* Corresponding author; email: r.hendriks{at}erasmusmc.nl.
During B cell development in the mouse, Bruton's tyrosine kinase (Btk) and the adaptor protein SLP-65 limit the expansion and promote the differentiation of pre-B cells. Btk is thought to mainly function by phosphorylating phospholipase C 2, 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 ~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.
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