Sorting nexin 9 (SNX9) regulates levels of the transmembrane ADAM9 at the cell surface

ADAM9 is an active member of the family of transmembrane ADAMs (a disintegrin and metalloproteases). It plays a role in processes such as bone formation and retinal neovascularization, and importantly, its expression in human cancers correlates with disease stage and poor prognosis. Functionally, AD...

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Published in:	The Journal of biological chemistry Vol. 293; no. 21; pp. 8077 - 8088
Main Authors:	Mygind, Kasper J., Störiko, Theresa, Freiberg, Marie L., Samsøe-Petersen, Jacob, Schwarz, Jeanette, Andersen, Olav M., Kveiborg, Marie
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 25-05-2018 American Society for Biochemistry and Molecular Biology
Subjects:	ADAM ADAM Proteins - genetics ADAM Proteins - metabolism Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Cell Biology Cell Membrane - metabolism Endocytosis Female Gene Expression Regulation, Neoplastic Humans Membrane Proteins - genetics Membrane Proteins - metabolism Protein Binding Protein Transport shedding sorting nexin (SNX) Sorting Nexins - genetics Sorting Nexins - metabolism trafficking Tumor Cells, Cultured ADAM endocytosis shedding trafficking sorting nexin (SNX)
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Summary:	ADAM9 is an active member of the family of transmembrane ADAMs (a disintegrin and metalloproteases). It plays a role in processes such as bone formation and retinal neovascularization, and importantly, its expression in human cancers correlates with disease stage and poor prognosis. Functionally, ADAM9 can cleave several transmembrane proteins, thereby shedding their ectodomains from the cell surface. Moreover, ADAM9 regulates cell behavior by binding cell-surface receptors such as integrin and membrane-type matrix metalloproteases. Because these functions are mainly restricted to the cell surface, understanding the mechanisms regulating ADAM9 localization and activity at this site is highly important. To this end, we here investigated how intracellular trafficking regulates ADAM9 availability at the cell surface. We found that ADAM9 undergoes constitutive clathrin-dependent internalization and subsequent degradation or recycling to the plasma membrane. We confirmed previous findings of an interaction between ADAM9 and the intracellular sorting protein, sorting nexin 9 (SNX9), as well as its close homolog SNX18. Knockdown of either SNX9 or SNX18 had no apparent effects on ADAM9 internalization or recycling. However, double knockdown of SNX9 and SNX18 decreased ADAM9 internalization significantly, demonstrating a redundant role in this process. Moreover, SNX9 knockdown revealed a nonredundant effect on overall ADAM9 protein levels, resulting in increased ADAM9 levels at the cell surface, and a corresponding increase in the shedding of Ephrin receptor B4, a well-known ADAM9 substrate. Together, our findings demonstrate that intracellular SNX9-mediated trafficking constitutes an important ADAM9 regulatory pathway.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Dept. of Biology, Molecular Parasitology, Humboldt-Universität zu Berlin, Faculty of Life Sciences, Philippstr. 13, Haus 14, 10115 Berlin, Germany. Present address: Institut Curie, PSL Research University, CNRS, UMR144, 26 rue d'Ulm, F-75005, Paris, France. Edited by Amanda J. Fosang Present addresses: Institute for Clinical Chemistry and Institute for Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller Str. 3, 24105 Kiel, Germany.
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.RA117.001077