PDGF SIGNAL TRANSDUCTION--ABI KINASES IN CELL MIGRATION

PDGF信号转导--细胞迁移中的ABI激酶

• 批准号: 6972205
• 负责人: RINA PLATTNER
• 金额: $ 23.65万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6972205
• 关键词: RNA interference; biological signal transduction; cell migration; cell motility; enzyme activity; enzyme induction /repression; growth factor receptors; immunoprecipitation; mass spectrometry; phosphorylation; platelet derived growth factor; protein tyrosine kinase; receptor binding; receptor expression; western blottings

Growth factors induce cell proliferation, differentiation, migration, apoptosis, and angiogenesis. Regulation of these processes is extremely important as deregulation contributes to the induction and progression of malignancy. In particular, cell motility is critical for tumor invasion and metastasis, hallmarks of aggressive cancers. Growth factors control cellular events by activating proteins in a complex web of signaling pathways. Previously, we found that c-Abl, a kinase involved in the development of leukemia, is activated by platelet-derived growth factor (PDGF), and is required for mitogenesis, cytoskeletal reorganization, and migration downstream of PDGF. Signaling pathways that control cell migration are beginning to be identified, however, the pathways are not completely characterized, and cross-talk between the pathways is only beginning to be elucidated. The overall goal of this proposal is to define Abl kinase-dependent PDGF signaling pathways that control cell migration. We aim to: 1) Determine the functional significance of PDGFR-Abl kinase bidirectional signaling. 2) Identify downstream targets of Abl kinases involved in PDGF-induced cell motility. 3) Determine whether Abl kinase activity is upregulated in non-hematopoeitic cancer cell lines, and whether Abl kinases function to promote motility and/or invasion in these cells. Results from these experiments will provide us with mechanistic insight into how Abl kinase deregulation contributes to cancer formation/progression, which will aid in the discovery of new drug combinations for cancer treatment.

生长因子诱导细胞增殖、分化、迁移、凋亡和血管生成。这些过程的调节极其重要，因为放松调节会导致恶性肿瘤的诱发和进展。特别是，细胞运动对于肿瘤侵袭和转移至关重要，这是侵袭性癌症的标志。生长因子通过激活复杂的信号通路网络中的蛋白质来控制细胞事件。此前，我们发现c-Abl是一种参与白血病发展的激酶，被血小板源性生长因子（PDGF）激活，并且是有丝分裂、细胞骨架重组和PDGF下游迁移所必需的。控制细胞迁移的信号通路开始被识别， 然而，这些途径尚未完全表征，并且途径之间的串扰才刚刚开始被阐明。该提案的总体目标是定义控制细胞迁移的 Abl 激酶依赖性 PDGF 信号通路。我们的目标是： 1) 确定 PDGFR-Abl 激酶双向信号传导的功能意义。 2) 确定参与 PDGF 诱导的细胞运动的 Abl 激酶的下游靶标。 3)确定Abl激酶活性在非造血癌细胞系中是否上调，以及Abl激酶是否发挥作用以促进这些细胞的运动和/或侵袭。这些实验的结果将为我们提供有关 Abl 激酶失调如何导致癌症形成/进展的机制见解，这将有助于发现用于癌症治疗的新药物组合。