KY COBRE: PDGF SIGNAL TRANSDUCTION ROLE FOR ABI FAMILY KINASES IN CELL MIGRATIO

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 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，因为失调有助于恶性肿瘤的诱导和进展。特别地，细胞运动性对于肿瘤侵袭和转移（侵袭性癌症的标志）至关重要。生长因子通过激活信号通路复杂网络中的蛋白质来控制细胞事件。以前，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识别，然而，这些通路还没有完全表征，并且通路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)鉴定参与PDGF诱导的细胞运动性的Abl激酶的下游靶标。3)确定Abl激酶活性是否在非造血癌细胞系中上调，以及Abl激酶是否在这些细胞中起促进运动性和/或侵袭的作用。这些实验的结果将为我们提供Abl激酶失调如何促进癌症形成/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。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 PDGFinduced 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 ce_ls. 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.