Tumor suppressor function of Bruton tyrosine kinase is independent of its catalytic activity.

Blood
Sabine MiddendorpRudolf W Hendriks

Abstract

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 Cgamma2, 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 backg...Continue Reading

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Citations

Jun 9, 2005·The Journal of Experimental Medicine·Niklas FeldhahnMarkus Müschen
Jun 11, 2011·Blood·Tereza OrmsbyAdelheid Cerwenka
Mar 25, 2014·Nature Reviews. Cancer·Rudi W HendriksLaurens P Kil
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Oct 15, 2021·Life Science Alliance·Sofian Al ShboulPaul M Brennan

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