Identification of an antiangiogenic FGF2-binding site in the N terminus of the soluble pattern recognition receptor PTX3
Identification of an antiangiogenic FGF2-binding site in the N terminus of the soluble pattern recognition receptor PTX3
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DOI：
10.1074/jbc.m601023200
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发表时间：
2006-08-11
影响因子：
4.8
通讯作者：
Presta, Marco
中科院分区：
文献类型：
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作者：
Camozzi, Maura;Rusnati, Marco;Presta, Marco
长正五聚蛋白3（Long-pentraxin 3，PTX 3）是一种可溶性模式识别受体，在炎症和先天免疫中具有非冗余功能。PTX 3包含通过C1 q相互作用参与补体激活的五聚蛋白样C末端结构域和具有未知功能的N末端延伸。PTX 3结合成纤维细胞生长因子-2（FGF 2），抑制其促血管生成和促再狭窄活性。在此，过表达N-末端片段PTX 3-（1-178）的逆转录病毒转导的内皮细胞（EC）显示出对FGF 2应答的促有丝分裂活性降低。因此，纯化的重组PTX 3-（1-178）结合FGF 2，阻止PTX 3/FGF 2相互作用，并抑制EC中的FGF 2促有丝分裂活性。此外，识别PTX 3-（87-99）表位的单克隆抗体mAb-MNB 4阻止FGF 2/PTX 3相互作用并消除PTX 3的FGF 2拮抗剂活性。一致地，合成肽PTX 3-（82-110）和PTX 3-（97-110）结合FGF 2并抑制FGF 2与固定于BIAcore传感器芯片的PTX 3的相互作用、FGF 2依赖性EC增殖和体内血管生成。因此，这些数据鉴定了PTX 3的N-末端延伸中跨越PTX 3-（97-110）区域的FGF 2结合结构域，指出了PTX 3的N-末端延伸的新功能，并强调了PTX 3分子用于模块化体液模式识别的复杂性。
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.