Abstract
Abstract Abstract: Vascular endothelial growth factor receptor 1 (VEGFR1) is a receptor tyrosine kinase (RTK) predominantly expressed in endothelial cells. Recent studies have shown that VEGFR1 is also expressed in several types of human cancer cells, and its expression correlates with cancer progression. Moreover, higher VEGFR1 expression worsened the outcome of lung cancers, breast cancer, and pancreatic cancer patients following cancer treatment. A new mode of signal transduction mediated by RTK is through internationalization of ligand-bound receptor rather than through activation of intracellular signaling cascades by the interaction of ligand and receptor on the cell surface. Epidermal growth factor receptor is the prototype for such new mode of action. One previous study has shown that VEGFR1 was colocalized with nuclear STAT1 in chronic lymphocytic leukemia B cells treated with VEGF-A, indicating a possible role for VEGFR-1 in the nucleus. Consistent with the notion, we found that the intracellular domain of VEGFR1 behaved as a transcriptional activator in yeast two-hybrid system. Second, VEGFR1 could shuttle between cytosol and nucleus following VEGF-A treatment in endothelial cells. Third, nuclear and cytosolic fractionation indicated the presence of VEGFR1 in the nuclear compartment of oral cancer and human endothelial cells. We thus hypothesized that VEGFR1 might harbor a nuclear localization signal (NLS) in the protein. Using a cytosolic protein pyruvate kinase fused with green fluorescent protein (GFP) and the putative NLS derived from VEGFR1 together with serial deletions and fluorescence microscopy, we were able to alter the subcellular location of pyruvate kinase fusion protein. Moreover, mutations of crucial arginine or lysine residues in the putative NLS significantly reduced the nuclear presence of VEGFR1 in the transfected cells. More studies are needed to address the molecules involved in nuclear transport of VEGFR1 and the target DNA sequence recognized by nuclear VEGFR1. The functional consequence of VEGFR1 localization in different subcellular compartments will be also studied by the use of oral cancer cells as a model. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2385.
Published Version
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