DESCRIPTION (provided by applicant): The growth of new blood capillaries from existing vessels (angiogenesis) is essential for development, tissue regeneration and remodeling. Angiogenesis also contributes to pathologic conditions including tumor growth and metastasis, diabetic retinopathy, rheumatoid arthritis, psoriasis, and cardiovascular diseases. Vascular Endothelial Growth Factor (VEGF) is a critical pro-angiogenic factor that stimulates multiple signal transduction pathways through binding to its receptor KDR. VEGF has received attention as a target for angiogenesis inhibition for several reasons, including the observations that blocking VEGF's actions by several experimental approaches inhibits the growth of tumors in animal models. Endothelial cell migration is a crucial step in angiogenesis; however, the cellular mechanisms that mediate this process remain unclear. Our preliminary data indicate that the cell signaling proteins Nck and Crk play important roles in VEGF-induced cell migration. Both proteins are recruited to KDR after VEGF treatment, although their interaction with receptor is indirect and mediated by the FRS2 scaffolding protein. The introduction of dominant negative (DN) inhibitors of Crk or Nck into endothelial cells has dramatic effects on VEGF-induced responses related to migration. The DNs inhibit focal complex turnover as they lead to a loss in the formation of new focal complexes and a significant increase in the size of existing focal complexes. This is accompanied by a loss in cell adhesion. The DNs also blocked VEGF-induced changes in F-actin dynamics. We plan to continue these studies by proposing three Specific Aims. AIM1 focuses on clarifying molecular aspects of how Nck and Crk are recruited to the cell surface after VEGF treatment. AIM 2 examines in detail the signaling pathway by which Nck regulates cell migration. AIM 3 asks how Crk functions in VEGF-induced cell migration.
|Effective start/end date||2/1/05 → 12/31/09|
- Cell Biology
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