title: The TspanC8 subgroup of tetraspanins interacts with A disintegrin and metalloprotease 10 (ADAM10) and regulates its maturation and cell surface expression.
abstract: A disintegrin and metalloprotease 10 (ADAM10) is a ubiquitous transmembrane metalloprotease that cleaves the extracellular regions from over 40 different transmembrane target proteins, including Notch and amyloid precursor protein. ADAM10 is essential for embryonic development and is also important in inflammation, cancer, and Alzheimer disease. However, ADAM10 regulation remains poorly understood. ADAM10 is compartmentalized into membrane microdomains formed by tetraspanins, which are a superfamily of 33 transmembrane proteins in humans that regulate clustering and trafficking of certain other transmembrane "partner" proteins. This is achieved by specific tetraspanin-partner interactions, but it is not clear which tetraspanins specifically interact with ADAM10. The aims of this study were to identify which tetraspanins interact with ADAM10 and how they regulate this metalloprotease. Co-immunoprecipitation identified specific ADAM10 interactions with Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33/Penumbra. These are members of the largely unstudied TspanC8 subgroup of tetraspanins, all six of which promoted ADAM10 maturation. Different cell types express distinct repertoires of TspanC8 tetraspanins. Human umbilical vein endothelial cells express relatively high levels of Tspan14, the knockdown of which reduced ADAM10 surface expression and activity. Mouse erythrocytes express predominantly Tspan33, and ADAM10 expression was substantially reduced in the absence of this tetraspanin. In contrast, ADAM10 expression was normal on Tspan33-deficient mouse platelets in which Tspan14 is the major TspanC8 tetraspanin. These results define TspanC8 tetraspanins as essential regulators of ADAM10 maturation and trafficking to the cell surface. This finding has therapeutic implications because focusing on specific TspanC8-ADAM10 complexes may allow cell type- and/or substrate-specific ADAM10 targeting.
authors.affiliation: School of Biosciences, College of Life and Environmental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Haining
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Bailey
authors.forename: Kabir
authors.initials: K
authors.lastname: Khan
authors.forename: Richard
authors.initials: R
authors.lastname: Collier
authors.forename: Schickwann
authors.initials: S
authors.lastname: Tsai
authors.forename: Steve P
authors.initials: SP
authors.lastname: Watson
authors.forename: Jon
authors.initials: J
authors.lastname: Frampton
authors.forename: Paloma
authors.initials: P
authors.lastname: Garcia
authors.forename: Michael G
authors.initials: MG
authors.lastname: Tomlinson
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis* / Q000235:genetics; D000072197:ADAM10 Protein; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000201:enzymology; D002460:Cell Line; D004912:Erythrocytes / Q000166:cytology / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D021962:Membrane Microdomains / Q000201:enzymology* / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011485:Protein Binding; D021381:Protein Transport / Q000502:physiology; D059470:Tetraspanins / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D059470:Tetraspanins; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; C491234:Adam10 protein, mouse