PDGF Signal Transduction- A Role for Abl Family Kinases in Cell Migration

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 role of the PDGF receptor in Abl kinase signaling. We have evidence of bidirectional phosphorylation between Abl kinases and PDGF receptors. We will determine the functional consequence of these phospt:mrylation events, and examine whether they influence cell migration. 2) Identify indirect and direct downstream targets of Abl kinases involved in PDGF-induced cell motility. We will determine whether the Abl kinases lie upstream of the Rho GTPase, Rac, a key regulator of cell motility. Additionally, we will identify proteins that are phosphorylated in response to PDGF stimulation in an Abl kinase-dependent manner. Once we identify a potential downstream target, we will: 1) determine whether it is a direct substrate of the Abl kinases, 2) determine whether it functions during Abl-dependent migration, and 3) identify whether the Abl kinases regulate target function. The longterm goals of this project are to define the mechanism by which the Abl family kinases influence cell migration. 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.