Life after proteolysis. Exploring the signaling capabilities of classical cadherin cleavage fragments

Classical cadherins are a group of Ca⁺⁺ dependent transmembrane cell adhesion molecules, mostly known for their ability to perform homophylic interactions with like-cadherin molecules on the surface of neighboring cells. Over the past decade, many studies have also established cadherins as key players of intracellular signaling events by modifying the activity of Rho GTPases, members of the Wnt signaling pathway, and receptor tyrosine kinases. Given the utility of these molecules, it is not surprising that they play multiple roles during different embryological and adult processes. Yet, these activities have been primarily tied to their fulllength molecules. And, while the activity of full-length molecules is undoubtedly an essential part of how cadherins perform in vivo, it is becoming increasingly evident that the proteolytic fragments of these molecules may also play a role. This is an exciting development because proteolysis of cadherins was previously thought to be a simple clearing-mechanism meant to regulate the levels of cadherin molecules on the cell-surface. Here, we will further discuss our recent findings by McCusker and colleagues, showing that both N-terminal and C-terminal fragments of cadherin-11 retain biological activity in Xenopus embryos. We will also review the current literature demonstrating that both the extracellular and intracellular fragments of other classical cadherins are capable of activating certain signaling events tied to Epithelial to Mesenchymal Transitions (EMTs), cell survival, cell proliferation and cell migration.