PDGF SIGNAL TRANSDUCTION--ABI KINASES IN CELL MIGRATION

生长因子诱导细胞增殖、分化、迁移、凋亡和血管生成。这些过程的调节是极其重要的，因为放松管制有助于恶性肿瘤的诱导和进展。特别是，细胞运动是肿瘤侵袭和转移的关键，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。先前，我们发现c-Abl，一种参与白血病发展的激酶，被血小板衍生生长因子（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发现，

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.