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.
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