Project Summary Extracellular matrix, integrins, and Notch collectively regulate a host of normal and pathological cellular activities. Evidence emerging from our preliminary studies shows that these cellular entities are coordinated into a signaling mechanism that has not been previously observed. The implications of our observation are broad and likely to have deep impacts on our understanding of cell interactions within cellular microenvironments as well as cellular behaviors in a range of normal and pathological scenarios. In this renewal application, we investigate the hypothesis that Notch tyrosine phosphorylation regulates angiogenesis. To address this hypothesis, we have proposed two aims that dig deeper into the molecular regulation of Notch activity through tyrosine phosphorylation by Src kinase, and to understand how Notch tyrosine phosphorylation impacts angiogenesis and vascular function. Throughout these studies and in the spirit of the AREA program, we will engage high school, undergraduate, and graduate students to build scientific confidence and teach skills these students will require in order to pursue careers in science. At the conclusion of our studies, we will have accomplished two important milestones towards understanding this novel regulatory mechanism. Specifically, we will have unraveled many molecular details describing how Src controls Notch, and we will have defined the importance of this signaling cascade to vascular biology. Since both Notch and vascular biology operate in a wide variety of normal and disease states, our work is highly relevant to the promotion of human health.

Narrative: The Notch signaling mechanism is emerging as a central control point through which cellular microenvironment regulates cell behavior in both healthy and diseased tissues. Our data has uncovered a novel collaboration between integrins, Src kinase, and Notch that we hypothesize regulates Notch response to several microenvironmental stimuli. The main goal of this proposal is to understand microenvironmental regulation of Notch by integrins and Src kinase, and how this impacts vascular health.