INTEGRIN SIGNALING IN HCK-/-FGR-/-LYN-/-TUMOR CELLS

整合素参与肿瘤的多方面调控 细胞生物学，如增殖、凋亡、侵袭、运动和 肿瘤血管生成。然而，整合素的确切机制是 在癌症中触发这些生物过程还没有很好的定义。一 潜在的假设是，这些反应可能与整合素- 中介信号转导。粘着斑激酶(FAK)与Src家族 激酶已被证明参与了整合素介导的 发信号。为了直接解决Src家族激酶、HCK、 FGR和Lyn在整合素信号转导中的作用，我们已经产生了三个突变的小鼠 这三种激酶都是缺乏的。原代巨噬细胞 突变小鼠的酪氨酸磷酸化受损 在整合素连接后，表明有三个激酶参与 在整合素信号转导方面。为了进一步调查 HCK、FGR和Lyn在肿瘤细胞中的整合素信号转导，我们将产生 三种突变小鼠的致瘤细胞系，然后鉴定 与野生型相比，这些细胞中整合素相关的信号事件 键入单元格。目前的提案提供了最好的模式系统 研究src家族激酶在整合素中的功能重要性 肿瘤细胞的信号传导。

Integrins are involved in the regulation of multiple aspects of tumor cell biology such as proliferation, apoptosis, invasion, motility and tumor angiogenesis. However, the precise mechanism by which integrins trigger these biological processes in cancer is not well defined. One potential hypothesis is that these responses might relate to integrin- mediated signal transduction. Focal adhesion kinase (FAK) and Src-family kinases have been demonstrated to be involved in integrin-mediated signaling. To directly address the function of Src-family kinases, Hck, Fgr and Lyn in integrin signaling, we have generated triple mutant mice that are deficient for all three of these kinases. Primary macrophages derived from mutant mice show impaired tyrosine phosphorylation following integrin ligation indicating that three kinases are involved in integrin signal transduction. To further investigate the roles of Hck, Fgr and Lyn in integrin signaling in tumor cells, we will generate tumorigenic cell lines from the triple mutant mice, then characterize the integrin-related signaling events in these cells compared to wild type cells. The current proposal provides the best model system to study the functional importance of Src-family kinases in integrin signaling of tumor cells.