Grant: $224,569 - National Institutes of Health - Jun. 5, 2009
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Award Description: The goal of this project is to define the mechanisms by which crosstalk between the insulin-like growth factor 1 receptor (IGF1R) and vascular endothelial growth factor (VEGF) receptors leads oral squamous cell carcinoma (OSCC) cells to metastatic progression. The IGF1R is an essential regulator of cell growth and transformation, that promotes tumor cell proliferation, motility and protection from apoptosis. We have shown that in OSCC cells IGF1R activation increases vascular endothelial growth factor (VEGF) synthesis and secretion, initiating an autocrine VEGF:VEGFR2 signaling loop. Our overall hypothesis stipulates that VEGF signaling via VEGFR2, leads to enhanced OSCC tumorigenicity and invasive cell behavior. In strong support of this hypothesis we have used a phosphotyrosine proteomics screen and identified a cluster of proteins involved in cell motility that is activated by VEGF stimulation. These proteins include human enhancer of filamentation1 (HEF1), cortactin, paxillin, and focal adhesion kinase. Of significance, HEF1 has been identified as a signature protein required for metastasis in melanoma, glioblastoma and breast cancer. The goal of AIM 1 is to define the mechanism through which HEF1 mediates VEGF induced OSCC cell migration and invasion. To this end, we will define the specific tyrosine residues in HEF1 that are phosphorylated in response to VEGFR2 activation using complementary biochemical techniques and site-directed mutagenesis. In AIM 2 we will define VEGF regulation of invadopodia formation and the structural and functional contributions of HEF1 to this process. As a subset of this aim we will examine HEF1 localization to invadopodia and what domains on HEF1 enable its association with invadopodia. These studies should provide important evidence demonstrating a role for HEF1 in OSCC metastatic signaling downstream of crosstalk to VEGFR2. They will lead to the development of novel strategies and therapeutic agents aimed at reducing the tumorigenic and metastatic effects of the IGF and VEGF pathways in OSCC.
Project Description: As defined in the Award Description field.
Jobs Summary: Research Specialist II (Total jobs reported: 0)
Project Status: Less Than 50% Completed
This award's data was last updated on Jun. 5, 2009. Help expand these official descriptions using the wiki below.