Title: Tetraspanin12 regulates ADAM10‐dependent cleavage of amyloid precursor protein
Abstract: The FASEB JournalVolume 23, Issue 11 p. 3674-3681 Research CommunicationFree to Read Tetraspanin12 regulates ADAM10-dependent cleavage of amyloid precursor protein Daosong Xu, Daosong Xu Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorChandan Sharma, Chandan Sharma Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorMartin E. Hemler, Corresponding Author Martin E. Hemler [email protected] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USACorrespondence. Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115; E-mail: [email protected]Search for more papers by this author Daosong Xu, Daosong Xu Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorChandan Sharma, Chandan Sharma Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorMartin E. Hemler, Corresponding Author Martin E. Hemler [email protected] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USACorrespondence. Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115; E-mail: [email protected]Search for more papers by this author First published: 08 July 2009 https://doi.org/10.1096/fj.09-133462Citations: 100Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat ABSTRACT Using mass spectrometry, we identified ADAM10 (a membrane-associated metalloproteinase) as a partner for TSPAN12, a tetraspanin protein. TSPAN12-ADAM10 interaction was confirmed by reciprocal coimmunoprecipitation in multiple tumor cell lines. TSPAN12, to a greater extent than other tet-raspanins (CD81, CD151, CD9, and CD82), associated with ADAM10 but not with ADAM17. Overexpression of TSPAN12 enhanced ADAM10-dependent shedding of amyloid precursor protein (APP) in MCF7 (breast cancer) and SH-SY5Y (neuroblastoma) cell lines. Conversely, siRNA ablation of endogenous TSPAN12 mark-edly diminished APP proteolysis in both cell lines. Furthermore, TSPAN12 overexpression enhanced ADAM10 prodomain maturation, whereas TSPAN12 ablation diminished ADAM10 maturation. A palmitoylation-deficient TSPAN12 mutant failed to associate with ADAM10, inhibited ADAM10-dependent proteolysis of APP, and inhibited ADAM10 maturation, most likely by interfering with endogenous wild-type TSPAN12. In conclusion, TSPAN12 serves as a novel and robust partner for ADAM10 and promotes ADAM10 maturation, thereby facilitating ADAM10-dependent proteolysis of APP. This novel mode of regulating APP cleavage is of relevance to Alzheimer's disease therapy.—Xu, D., Sharma, C., Hemler, M. E. Tetraspanin12 regulates ADAM10-dependent cleavage of amyloid precursor protein. FASEB J. 23, 3674-3681 (2009). www.fasebj.org Supporting Information Filename Description fsb2fj09133462-sup-0001.docapplication/doc, 24 KB Supplementary Material 1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. REFERENCES 1Stone, A. L., Kroeger, M., and Sang, Q. X. 1999 Structure-function analysis of the ADAM family of disintegrin-like and metalloproteinase-containing proteins (review). J. 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