Tumor suppressor function of Bruton tyrosine kinase is independent of its catalytic activity
Tumor suppressor function of Bruton tyrosine kinase is independent of its catalytic activity
复制标题
DOI：
10.1182/blood-2004-07-2708
复制
发表时间：
2005-01-01
期刊：
影响因子：
20.3
通讯作者：
Hendriks, RW
中科院分区：
文献类型：
--
作者：
Middendorp, S;Zijlstra, AJE;Hendriks, RW
在小鼠b细胞发育过程中，布鲁顿酪氨酸激酶（Btk）和衔接蛋白SLP-65（含Src同源2 [SH2]结构域的白细胞蛋白65 kDa）限制了前b细胞的扩增并促进其分化。Btk被认为主要通过磷酸化磷脂酶Cgamma2发挥作用，该酶通过SLP-65与Btk接近。然而，这一模型最近受到了挑战，因为在缺乏SLP-65的情况下，Btk作为肿瘤抑制因子的作用被确定，并且发现Btk的功能部分独立于其激酶活性。为了研究酶活性是否对Btk的肿瘤抑制功能至关重要，我们将表达激酶失活的K430R-Btk突变体的转基因小鼠与Btk/ SLP-65双缺陷背景杂交。我们发现K430R-Btk的表达挽救了Btk/SLP-65双缺陷小鼠在b细胞前阶段严重的发育停滞。此外，在SLP-65小鼠中，K430R-Btk可以在功能上取代野生型Btk作为肿瘤抑制因子：在6个月大时，在Btk/SLP-65缺陷背景下，观察到的前b细胞淋巴瘤发生率在SLP-65小鼠中约为15%，在Btk/SLP-65缺陷小鼠中为44%，在K430R-Btk转基因小鼠中为14%。因此，我们得出结论，Btk在前b细胞中作为一种适应蛋白发挥其肿瘤抑制功能，独立于其催化活性。(C) 2005年由美国血液病学会出版。
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 background. Therefore, we conclude that Btk exerts its tumor suppressor function in pre-B cells as an adaptor protein, independent of its catalytic activity. (C) 2005 by The American Society of Hematology.