ADAM-ephrin interactions in cell signaling and adhesion

About This Grant

PROJECT SUMMARY The interactions between cell-surface ephrin proteins and their cognate Eph receptors play diverse roles in cell signaling and adhesion in nearly every tissue and organ. Disruption of these interactions may lead to various diseases, including developmental defects, autoimmunity, tumors and neurological disorders. One of the key mechanisms that regulate the ephrin-Eph interactions is the proteolysis (“shedding”) of ephrin ligands by cell-surface proteases, which is well documented for class A ephrins but understudied for class B ephrins. In this application, we present unpublished data showing that members of the disintegrin metalloproteinase (ADAM) family shed ephrinBs by responding to Eph receptor binding. We have determined the ADAM cleavage sites and generated uncleavable ephrinB mutants. Leveraging these new tools, we will assess the effects of ephrinB shedding on downstream signaling and cell adhesion in Aim 1. We have also uncovered an unexpected connection between the ADAM-ephrinB interactions and the activation of a unique branch of the beta-catenin signaling pathway, which is required for normal neuronal function. We will continue to understand this novel ADAM-ephrin-beta-catenin signaling crosstalk in Aim 2. If successful, the proposed work will not only address several fundamental questions in ephrinB signaling but also open the door to new directions of research on this ubiquitous signaling pathway.