title: Multiple FAS1 domains and the RGD motif of TGFBI act cooperatively to bind αvβ3 integrin, leading to anti-angiogenic and anti-tumor effects.
abstract: TGFBI, a transforming growth factor β-induced extracellular matrix protein, circulates at a level of ~300ng/ml in humans and modulates several integrin-mediated cellular functions. The protein contains an N-terminal EMI domain, four consecutive FAS1 domains, and the RGD motif. Each FAS1 domain and the RGD motif have been known to interact with avb3 integrin. Here, we found that the binding affinity (Kd) of TGFBI for αvβ3 integrin was approximately 3.8×10(-8)M, a value ~2300-fold higher than that of a single FAS1 domain, and demonstrated that this greater affinity was due to the cooperative action of the four FAS1 domains and the RGD motif. Moreover, TGFBI exhibited more potent anti-angiogenic and anti-tumorigenic activities, even at a 100-fold lower molar dose than the reported effective dose of the FAS1 domain. Finally, our data showed that TGFBI specifically targeted the tumor vasculature and accumulated at the tumor site. Collectively, our results support the theory that TGFBI acts as a potent endogenous anti-tumor and anti-angiogenic molecule by targeting αvβ3 integrin, and highlights the importance of physiological circulating TGFBI levels in inhibiting tumor growth.
authors.affiliation: Department of Biochemistry and Cell Biology, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Hye-Nam
authors.initials: HN
authors.lastname: Son
authors.forename: Ju-Ock
authors.initials: JO
authors.lastname: Nam
authors.forename: Soyoun
authors.initials: S
authors.lastname: Kim
authors.forename: In-San
authors.initials: IS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000917:Antibody Formation; D015153:Blotting, Western; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000737:chemistry* / Q000378:metabolism; D000099222:betaIG-H3 Protein
chemical_list: D000911:Antibodies, Monoclonal; D016326:Extracellular Matrix Proteins; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D019014:fas Receptor; D000099222:betaIG-H3 Protein; C491901:FAS protein, human; C047981:arginyl-glycyl-aspartic acid
keywords: Angiogenesis; Anti-tumor effect; FAS1 domain; TGFBI; αvβ3 integrin