Multiple FAS1 domains and the RGD motif of TGFBI act cooperatively to bind αvβ3 integrin, leading to anti-angiogenic and anti-tumor effects

Hye Nam Son, Ju Ock Nam, Soyoun Kim, In-San Kim

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 (K d ) 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.

Original languageEnglish
Pages (from-to)2378-2388
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1833
Issue number10
DOIs
Publication statusPublished - 2013 Oct 1
Externally publishedYes

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Integrins
Neoplasms
Extracellular Matrix Proteins
Transforming Growth Factors
Growth
Proteins

Keywords

  • αvβ3 integrin
  • Angiogenesis
  • Anti-tumor effect
  • FAS1 domain
  • TGFBI

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Multiple FAS1 domains and the RGD motif of TGFBI act cooperatively to bind αvβ3 integrin, leading to anti-angiogenic and anti-tumor effects. / Son, Hye Nam; Nam, Ju Ock; Kim, Soyoun; Kim, In-San.

In: Biochimica et Biophysica Acta - Molecular Cell Research, Vol. 1833, No. 10, 01.10.2013, p. 2378-2388.

Research output: Contribution to journalArticle

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