Grants and Contracts Details
Description
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.
Status | Finished |
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Effective start/end date | 1/1/04 → 6/30/04 |
Funding
- American Cancer Society
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