) Anglogenesis (the formation of new blood capillaries) is an important component of several normal physiological processes including development and wound healing. Angiogenesis also contributes to the onset and spread of disease, for example in cancer angiogenesis provides tumor cells with essential nutrients and thus contributes to tumor growth. An anti-angiogenesis strategy for fighting cancer is attractive because this would target endothelial cells and potentially avoid the drug resistance observed when targeting tumor cells. Vascular Endothelial Growth Factor (VEGF) has received consideration as a target for angiogenesis inhibition for several reasons: Its expression by tumor cells is augmented by a lack of nutrients, VEGF's actions are specific to endothelial cells, and blocking VEGF's actions will inhibit the growth of tumors grown in mice. Information on the signal transduction pathways activated by VEGF is limited. Previously, our laboratory discovered the KDR gene and identified it as a receptor for VEGF. KDR is a receptor tyrosine kinase and we have identified four autophosphorylation sites. The experiments proposed in this application are directed at two goals. First, we wish to understand at a molecular level how KDR autophosphorylation recruits cell signaling proteins. Second, we have designed experiments to clarify the cellular consequence of specific receptor/signaling protein interactions.
Four Specific Aims are proposed to accomplish these goals.
Specific Aim 1 will determine whether there are autophosphorylation sites in addition to the ones reported earlier.
Specific Aim 2 will test the hypothesis that receptor autophosphorylation in the kinase domain is required for maximum catalytic activity.
Specific Aim 3 is directed at clarifying the signaling proteins which interact with receptor autophosphorylation sites.
Specific Aim 4 is directed at clarifying endothelial cellular response which are dependent upon receptor phosphorylation at specific tyrosines.
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