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 3.8×10-8M, 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.
|Number of pages||11|
|Journal||Biochimica et Biophysica Acta - Molecular Cell Research|
|Publication status||Published - 2013 Oct|
Bibliographical noteFunding Information:
This study was supported by grants from the National R&D Program for Cancer Control, funded by the Ministry of Health & Welfare, Republic of Korea ( 0720550-2 ), the National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) ( 2010-0029206 ), and the Basic Science Research Program through the National Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology ( 2008-0061863 ).
- Anti-tumor effect
- FAS1 domain
- αvβ3 integrin
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology