Secreted and membrane-bound isoforms of protease ADAM9 have opposing effects on breast cancer cell migration.
Tumor cell migration is mediated by cell-autonomous signaling mechanisms as well as paracrine and autocrine factors secreted by activated stromal cells in the tumor microenvironment. Like other members of the ADAM (a disintegrin and metalloproteinase) family, the integrin-binding metalloproteinase ADAM9 modulates cell-cell and cell-matrix interactions as well as ectodomain shedding of cell surface receptors and ligands, thereby modifying intracellular and extracellular signaling. ADAM9 transcripts are alternatively spliced to express a transmembrane protein (ADAM9-L) and a secreted variant (ADAM9-S). In this study, we show that ADAM9-S promotes breast cancer cell migration in a manner requiring its metalloproteinase activity, whereas ADAM9-L suppresses cell migration independent of its metalloproteinase activity. Suppression of migration by ADAM9-L requires a functional disintegrin domain and integrin binding. Expression analysis revealed that both ADAM9 isoforms are expressed in breast cancer cell lines and tissues. Therefore, relative levels of membrane-tethered and secreted variants of ADAM9 are a key determinant in manifestation of aggressive migratory phenotypes associated with breast cancer progression.
Fry
Jessica L
JL
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Toker
Alex
A
D051722:ADAM Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology; D002465:Cell Movement / Q000502:physiology*; D003429:Cross Reactions; D017931:DNA Primers; D018450:Disease Progression; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D015151:Immunoblotting; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009154:Mutation; D034741:RNA, Small Interfering / Q000235:genetics; D017384:Sequence Deletion; D014162:Transfection
D017931:DNA Primers; D007527:Isoenzymes; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D051722:ADAM Proteins; C098339:ADAM9 protein, human