Genetic and Biochemical Approaches to Tyrosine Kinase Function

我们实验室研究了非受体的功能 酪氨酸激酶，细胞内信号传递所需的分子 参与正常细胞生长和分化的途径，如 以及涉及的异常生长和发育 癌症的形成和发展。我们将组合应用于 小鼠遗传学和蛋白质生物化学对这些的研究 分子。我们的工作集中在这些分子是如何 有助于免疫系统细胞的正常功能和 以及我们从这些系统中学到的教训可以是什么 延伸到这些分子发挥作用的其他细胞类型。我们的 最近的工作集中在对BTK家族的研究上 激活剂。此前已证明，正常情况下需要BTK B细胞功能和BTK基因突变与人类 遗传性疾病X连锁无丙种球蛋白血症。我们有 最近发现，其他BTK家族激酶的突变可以 严重损害小鼠的T淋巴细胞功能，从而建立 这些激酶首次在T细胞介导的免疫中发挥作用 回应。我们还继续开展对Src家族的研究工作 骨细胞功能中的蛋白激酶。我们最近已经证明， Src基因截短突变体的表达可作为 显性负性分子并导致程序性细胞死亡或 细胞凋亡。我们已经扩展了这项工作，以表明这个突变体 可以改变其他细胞中的细胞存活途径，尤其是 有效地抑制血管生成所需的细胞存活和 肿瘤生长。因此，这种分子提供了一种使用的模型 某些肿瘤治疗中的Src功能抑制物。

Our laboratory studies the functions of non-receptor tyrosine kinases, molecules required for intracellular signaling pathways involved in normal cellular growth and differentiation as well as abnormal growth and development involved in the formation and progression of cancer. We apply a combination of mouse genetics and protein biochemistry to the study of these molecules. Our work has concentrated on how these molecules contribute to normal function of cells of the immune system and the skeletal system and how lessons we learn from these systems can be extended to other celltypes in which these molecules function. Our recent work has concentrated on studies of the Btk family of kinases. Btk has previously been shown to be required for normal function of B cells and mutation of Btk is responsible for the human genetic disorder X-linked agammmaglobulimemia. We have recently shown that mutation of other Btk family kinases can severely impair T lymphocyte function in mice, thereby establishing for the first time a role for these kinases in T cell mediated immune responses. We have also continued work on the study of Src family kinases in bone cell function. We have recently shown that expression of a truncated mutant of Src can act as a dominant-negative molecule and lead to programmed cell death or apoptosis. We have extended this work to show that this mutant can alter cell survival pathways in other cells and is particularly potent in inhibiting cell survival required for angiogenesis and tumor growth. Thus, this molecule provides a model for the use of inhibitors of Src function in the treatment of certain tumors.