CAREER: Proteolytic cleavage in contact-dependent signaling

About This Grant

Cells communicate with each other to share information on when and where to divide, die, or develop into a certain type. The way that cells communicate is through direct contact where a protein on the surface of one cell binds a specific interacting protein bound to the surface of a neighboring cell forming a physical 'bridge'. This bridge can be pulled at either end, in a 'tug-of-war' between the two cells, and can also be cut by enzymes, destroying the bridge. However, the relationship between these two factors is little understood but is important in whether a message is sent from one cell to another. This project aims to uncover how the enzymes that can sever signaling bridges are regulated. This is critical to understand communication between neurons, a process that controls the wiring of the brain. At the same time an integrated education plan and outreach activities at a local nature reserve will engage undergraduate students and the wider public in the scientific research. The insight gained in this project will further our understanding of organismal development, brain physiology and neurodegenerative states. This project uses an in vivo platform to examine contact-dependent cell signaling where surface receptors bind to ligands on neighboring cells, forming bridges that influence cell behavior. These ligand/receptor bridges have complex dynamics beyond simple activation - their fate depends on whether the bridge remains at the cell surface, gets severed and internalized, or is completely engulfed by one cell. The planned work will test the hypothesis that force-dependent proteolytic cleavage by ADAM family proteases is a crucial regulatory mechanism across multiple contact-dependent signal transduction pathways. ADAM proteases are remarkably promiscuous, cleaving hundreds of substrates, yet key knowledge gaps remain regarding how ADAM proteases recognize substrates and regulate bridge cleavage based on contextual factors. The project aims to characterize ADAM protease cleavage requirements, examine its functional role in neural systems, and develop synthetic biology approaches to study ADAM activity. The latter will be part of a course-based undergraduate research experience and will allow classes of students to contribute to genuine research. Overall, this project seeks to decipher the general principles governing ligand/receptor bridge fate in cell communication which will define one of the Rules of Life relevant to multiple signal transduction pathways and biological processes. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.