title: sFRP-1 binds via its netrin-related motif to the N-module of thrombospondin-1 and blocks thrombospondin-1 stimulation of MDA-MB-231 breast carcinoma cell adhesion and migration.
abstract: Secreted frizzled-related protein (sFRP)-1 is a Wnt antagonist that inhibits breast carcinoma cell motility, whereas the secreted glycoprotein thrombospondin-1 stimulates adhesion and motility of the same cells. We examined whether thrombospondin-1 and sFRP-1 interact directly or indirectly to modulate cell behavior. Thrombospondin-1 bound sFRP-1 with an apparent K(d)=48nM and the related sFRP-2 with a K(d)=95nM. Thrombospondin-1 did not bind to the more distantly related sFRP-3. The association of thrombospondin-1 and sFRP-1 is primarily mediated by the amino-terminal N-module of thrombospondin-1 and the netrin domain of sFRP-1. sFRP-1 inhibited α3β1 integrin-mediated adhesion of MDA-MB-231 breast carcinoma cells to a surface coated with thrombospondin-1 or recombinant N-module, but not adhesion of the cells on immobilized fibronectin or type I collagen. sFRP-1 also inhibited thrombospondin-1-mediated migration of MDA-MB-231 and MDA-MB-468 breast carcinoma cells. Although sFRP-2 binds similarly to thrombospondin-1, it did not inhibit thrombospondin-1-stimulated adhesion. Thus, sFRP-1 binds to thrombospondin-1 and antagonizes stimulatory effects of thrombospondin-1 on breast carcinoma cell adhesion and motility. These results demonstrate that sFRP-1 can modulate breast cancer cell responses by interacting with thrombospondin-1 in addition to its known effects on Wnt signaling.
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. mansog@mail.nih.gov
authors.forename: Gema
authors.initials: G
authors.lastname: Martin-Manso
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Calzada
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Chuman
authors.forename: John M
authors.initials: JM
authors.lastname: Sipes
authors.forename: Charles P
authors.initials: CP
authors.lastname: Xavier
authors.forename: Vladimir
authors.initials: V
authors.lastname: Wolf
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Kuznetsova
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Rubin
authors.forename: David D
authors.initials: DD
authors.lastname: Roberts
mesh_terms: D020816:Amino Acid Motifs; D001940:Breast / Q000378:metabolism* / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000737:chemistry; D019700:Thrombospondin 1 / Q000737:chemistry / Q000378:metabolism*; D000099274:Frizzled-Related Proteins; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020932:Nerve Growth Factor; D019700:Thrombospondin 1; D000099274:Frizzled-Related Proteins; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C109618:SFRP2 protein, human