Genetic and Biochemical Approaches to Tyrosine Kinase Function

本实验室研究非受体酪氨酸激酶的功能，酪氨酸激酶是参与正常细胞生长和分化的细胞内信号通路所需的分子，也是参与癌症形成和进展的异常生长和发育的分子。我们将小鼠遗传学、细胞生物学和蛋白质生物化学结合起来研究这些分子。我们的工作集中在这些分子如何促进免疫系统和骨骼系统细胞的正常功能，以及我们如何从这些系统中学到的经验教训可以扩展到这些分子起作用的其他细胞类型。我们最近的工作集中在Btk家族激酶的研究上。Btk先前已被证明是B细胞正常功能所必需的，并且Btk的突变是导致人类遗传疾病x连锁无淋巴细胞贫血症的原因。我们最近发现，其他Btk家族激酶的突变可严重损害小鼠T淋巴细胞功能，从而首次确立了这些激酶在T细胞介导的免疫应答中的作用。特别是，我们已经证明了两个Btk家族激酶，Rlk和Itk的突变导致T细胞对培养刺激和动物感染因子的反应显着缺陷。我们还继续研究Src家族激酶在骨细胞功能中的作用。我们最近的研究表明，Src的一个截短突变体的表达可以作为一个显性负分子，导致程序性细胞死亡或凋亡。我们已经扩展了这项工作，以表明这种突变可以改变血管生成和肿瘤生长所需的细胞存活途径。最近的研究表明，SH2 （Src同源性2）结构域对这些细胞存活途径很重要。这项工作为使用Src功能抑制剂治疗某些肿瘤提供了一个模型。-遗传学，免疫学，传染病，热带病，骨质疏松症

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, cellular biology 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. In particular, we have demonstrated that mutation of two Btk family kinases, Rlk and Itk leads to marked defects in T cell responses to stimulation in culture and to infectious agents in the animal. 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 required for angiogenesis and tumor growth. Recent work has demonstrated that the SH2 (Src homology 2) domain is important for these cell survival pathways. This work provides a model for the use of inhibitors of Src function in the treatment of certain tumors. - Genetics, Immunology, Infectious Diseases, Tropical Diseases, Osteoporosis