Multiple FAS1 domains and the RGD motif ofTGFBI act cooperatively to bind αvβ3 integrin, leading to anti-angiogenic and anti-tumor effects
- Multiple FAS1 domains and the RGD motif ofTGFBI act cooperatively to bind αvβ3 integrin, leading to anti-angiogenic and anti-tumor effects
- Hye-Nam Son; Ju-Ock Nam; Soyoun Kim; 김인산
- TGFBI; Angiogenesis; αvβ3 integrin; Anti-tumor effec; FAS1 domain
- Issue Date
- Biochimica et biophysica acta, Biomembranes
- VOL 1833, NO 10, 2378-2388
- TGFBI, a transforming growth factor β-induced extracellularmatrix protein, circulates at a level of ~300 ng/ml in humans andmodulates 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 RGDmotif.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.
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