Background: ADAM10 is a transmembrane metalloprotease that regulates development, inflammation, cancer, and Alzheimer disease. Results: The TspanC8 subgroup of tetraspanin membrane proteins interacts with and promotes ADAM10 maturation and cell surface localization. Conclusion: This study defines the TspanC8 tetraspanins as essential regulators of ADAM10. Significance: Focusing on specific TspanC8-ADAM10 complexes may allow ADAM10 therapeutic targeting in a cell typeand/or substrate-specific manner.

Tetraspanins function as organizers of the cell surface by recruiting specific partner proteins into tetraspanin-enriched microdomains, which regulate processes such as cell adhesion, signalling and intracellular trafficking. Endothelial cells appear to express at least 23 of the 33 human tetraspanins, and a number of recent studies have demonstrated their importance in endothelial cell biology. Tetraspanin CD151 is essential for pathological angiogenesis, which may in part be due to regulation of its main partner proteins, the laminin-binding integrins α3β1, α6β1 and α6β4. CD9 and CD151 are essential for leucocyte recruitment during an inflammatory response, through the formation of pre-assembled nano-platforms containing the adhesion molecules ICAM-1 (intercellular adhesion molecule 1) and VCAM-1 (vascular cell adhesion molecule 1), which ultimately coalesce to form docking structures around captured leucocytes. Tetraspanin CD63 also facilitates leucocyte capture by promoting clustering of the adhesion molecule P-selectin. Finally, Tspan12 is required for blood vessel development in the eye, through regulation of Norrin-induced Frizzled-4 signalling, such that Tspan12 mutations can lead to human disease. Future studies on these and other endothelial tetraspanins are likely to provide further novel insights into angiogenesis and inflammation.