The Influence of Integrin Binding RGD Domains on Notch Signaling and Angiogenesis
The Notch pathway is an important juxtacrine signaling mechanism that controls gene expression during cell development and angiogenesis. Unbalanced Notch signaling can provoke an excess of angiogenesis and capillary growth to tumors, providing nutrients and a pathway for metastasis. Therefore understanding the basic mechanism of angiogenesis will lead to therapies targeting this mechanism, aiming to combat tumors and prevent their metastatic spread. It has been demonstrated that the extracellular matrix (ECM) protein microfibril-associated glycoprotein-2 (MAGP-2) inhibits Notch signaling in endothelial cells, thereby promoting angiogenic cell sprouting. MAGP-2 contains an RGD integrin-binding domain that, when mutated, converts MAGP-2 from an inhibitor of Notch to a signaling promoter. Further experiments have demonstrated that integrin ligation in general seems to be responsible for this observed regulation of Notch signaling. Thus we hypothesize that integrin signaling suppresses Notch signaling. To test our hypothesis, we will experimentally add or remove RGD integrin-binding domains to and from other ECM molecules with various Notch activities, and compare the ability of the different mutants to control Notch signaling. A Notch responsive luciferase assay and western blot for the Notch intracellular domain were used to assess Notch activity. Our preliminary data shows that CCN-3 and MAGP-1 significantly increase Notch signaling activity, while the RGD containing EGFL-7 and FBLN-5 do not. Results from these experiments may be useful to help design new molecules to disrupt integrin-Notch signaling, and suppress inappropriate angiogenesis critical for cancer and metastasis.
DeFord, Peter and Westover, Katherine, "The Influence of Integrin Binding RGD Domains on Notch Signaling and Angiogenesis" (2014). College of Arts and Sciences Presentations. 64.