HCK AND MYELOID DIFFERENTIATION AND ACTIVATION

特定蛋白质底物的酪氨酸磷酸化是一个不可分割的过程 介导细胞的信号转导通路的组成部分 分化和激活途径。的表达方式 蛋白酪氨酸激酶src家族的某些成员(在一些 病例，它们与表面受体的关联)表明，这些 在造血系统中，这些信号转导通路中都有蛋白激酶的参与。 细胞。最近的功能研究证实了这一假说。 支持两个src相关的激酶lck和fyn在T细胞中的作用 激活。Hck基因在两者的髓系细胞中均有表达。 单核/巨噬细胞和粒细胞系，表达最高 在两个谱系的成熟细胞中。这一提议的长期目标是 研究确定HCK蛋白在巨噬细胞激活中的作用 和髓系分化。这项工作的主要战略是 操纵hk1或hk1基因的“激活”或“死亡”突变体的表达 髓系细胞中的激酶，以探讨HCK在激活中的作用 和分化途径。来自该实验室的初步数据 提示HCK表达对粒细胞不是必需的 分化但不排除激酶在其中的一个重要作用 粒细胞功能成熟。小鼠巨噬细胞的初步研究 Bac 1.2F5株系显示HCK表达与 激活这些细胞以产生细胞因子，如肿瘤坏死 因子(肿瘤坏死因子)。我们假设HCK的表达是必要的，但不是 足以支持正常的单核/巨噬细胞分化和HCK 在成熟巨噬细胞的激活途径中发挥重要作用 这会导致细胞因子基因的表达。因此，这一行动的具体目标是 建议：(1)确定HCK在巨噬细胞激活和释放中的作用 细胞因子基因表达的调控；(2)功能测定 HCK在单核/巨噬细胞分化中的作用；(3)研究 人绒毛膜促性腺激素释放酶、酪氨酸激酶活性和亚细胞的调节 髓系细胞的定位。这些研究应该会有显著的改善 我们对酪氨酸激酶作为血管紧张素转换酶关键成分作用的理解 造血细胞中的信号转导途径。

The tyrosine phosphorylation of specific protein substrates is an integral component of signal transduction pathways that mediate cellular differentiation and activation pathways. The pattern of expression of certain members of the src family of protein tyrosine kinases (and, in some cases, their association with surface receptors) suggested that these kinases are involved in these signal transduction pathways in hematopoietic cells. This hypothesis has been strengthened by recent functional studies that support the role of two src-related kinases, lck and fyn, in T cell activation. The hck gene is expressed in myeloid cells of both monocyte/macrophage and granulocyte lineages and is most highly expressed in mature cells of both lineages. The long term goal of this proposed research is to define the role of the hck protein in macrophage activation and myeloid differentiation. The primary strategy of this work is to manipulate the expression of hck or "activated" or "dead" mutants of the kinase in myeloid cells in order to explore the role of hck in activation and differentiation pathways. Preliminary data from this laboratory suggest that hck expression is not essential for granulocytic differentiation but do not exclude an important role of the kinase in mature granulocyte function. Preliminary studies in the murine macrophage line, Bac 1.2F5, show a strong correlation between hck expression and the activation of these cells to produce cytokines such as tumor necrosis factor (TNF). We hypothesize that hck expression is necessary though not sufficient for normal monocyte/macrophage differentiation and that hck plays an important role in the activation pathways of mature macrophages that lead to cytokine gene expression. Thus, the specific aims of this proposal are (1) To determine the role of hck in macrophage activation and the regulation of cytokine gene expression; (2) To determine the function of hck in monocyte/macrophage differentiation; and (3) To study the regulation of hck production, tyrosine kinase activity and subcellular localization in myeloid cells. These studies should significantly improve our understanding of the role of tyrosine kinases as critical components of the signal transduction pathways in hematopoietic cells.