Identification of an antiangiogenic FGF2-binding site in the N terminus of the soluble pattern recognition receptor PTX3

被引:100
作者
Camozzi, Maura
Rusnati, Marco
Bugatti, Antonella
Bottazzi, Barbara
Mantovani, Alberto
Bastone, Antonio
Inforzato, Antonio
Vincenti, Silvia
Bracci, Luisa
Mastroianni, Domenico
Presta, Marco
机构
[1] Univ Brescia, Dept Biomed Sci & Biotechnol, Sch Med, Unit Gen Pathol & Immunol, I-25123 Brescia, Italy
[2] Univ Milan, Inst Gen Pathol, I-20133 Milan, Italy
[3] Ist Clin Humanitas, I-20089 Milan, Italy
[4] Mario Negri Inst Pharmacol Res, I-20157 Milan, Italy
[5] Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy
[6] Sigma Tau Res Dept, I-0040 Rome, Italy
[7] Univ Siena, Dept Mol Biol, I-53100 Siena, Italy
[8] Tecnogen SCpA, I-81015 Piana Di Monte Verna, Caserta, Italy
关键词
D O I
10.1074/jbc.M601023200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Long-pentraxin 3 (PTX3) is a soluble pattern recognition receptor with non-redundant functions in inflammation and innate immunity. PTX3 comprises a pentraxin-like C-terminal domain involved in complement activation via C1q interaction and an N-terminal extension with unknown functions. PTX3 binds fibroblast growth factor-2 (FGF2), inhibiting its pro-angiogenic and pro-restenotic activity. Here, retroviral transduced endothelial cells (ECs) overexpressing the N-terminal fragment PTX3-(1-178) showed reduced mitogenic activity in response to FGF2. Accordingly, purified recombinant PTX3-(1-178) binds FGF2, prevents PTX3/FGF2 interaction, and inhibits FGF2 mitogenic activity in ECs. Also, the monoclonal antibody mAb-MNB4, which recognizes the PTX3-(87-99) epitope, prevents FGF2/PTX3 interaction and abolishes the FGF2 antagonist activity of PTX3. Consistently, the synthetic peptides PTX3-(82-110) and PTX3-(97-110) bind FGF2 and inhibit the interaction of FGF2 with PTX3 immobilized to a BIAcore sensor chip, FGF2-dependent EC proliferation, and angiogenesis in vivo. Thus, the data identify a FGF2-binding domain in the N-terminal extension of PTX3 spanning the PTX3-(97-110) region, pointing to a novel function for the N-terminal extension of PTX3 and underlining the complexity of the PTX3 molecule for modular humoral pattern recognition.
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页码:22605 / 22613
页数:9
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