The Role of Integrins in the Regulation of Angiogenesis by the Notch Signalling Pathway in Endothelial Cells
The Notch pathway is an important juxtacrine signaling mechanism that controls gene expression during cell development and angiogenesis. An excess of pro-angiogenic activity promotes the outgrowth of capillaries to tumors, providing nutrients and providing a pathway for metastasis. It has been demonstrated that microfibril-associated glycoprotein-2 (MAGP-2) inhibits Notch signaling in endothelial cells thereby promoting angiogenic cell sprouting. MAGP-2 contains and RGD domain which has been shown to associate with integrins. When the RGD domain is mutated to an RGE there was an increase in Notch activity subsequently decreasing angiogenic cell sprouting. Several other extra cellular matrix proteins have been identified which also associate with the Notch pathway, not all of which have apparent integrin binding activity. We have selected four to characterize, both with and without RGD domains. The key to better understanding the relationships between these proteins and their effect on angiogenesis via the notch signaling pathway is to distort or encourage their binding affinity to integrins via RGD domains similar to the one in MAGP-2.