Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan.
Biochemistry. 2010 Dec 21;49(50):10756-64. doi: 10.1021/bi101318m. Epub 2010 Nov 23.
Acidic fibroblast growth factor (FGF1) regulates a wide array of important biological phenomena such as angiogenesis, cell differentiation, tumor growth, and neurogenesis. Generally, FGFs are known for their strong affinity for the glycosaminoglycan heparin, as a prerequisite for recognition of a specific tyrosine kinase on the cell surface and are responsible for the cell signal transduction cascade. Inositol hexaphosphate (IP6) is a natural antioxidant and is known for its antiangiogenic role, in addition to its ability to control tumor growth. In the present study, we investigated the interaction of IP6 with the acidic fibroblast growth factor (FGF1) using various biophysical techniques including isothermal calorimetry, circular dichroism, and multidimensional NMR spectroscopy. Herein, we have reported the three-dimensional solution structure of the FGF1-IP6 complex. These data show that IP6 binds FGF1 and enhances its thermal stability. In addition, we also demonstrate that IP6 acts as an antagonist to acidic fibroblast growth factor by inhibiting its receptor binding and subsequently decreasing the mitogenic activity. The inhibition likely results in the ability of IP6 to antagonize the angiogenic and mitogenic activity of FGF1.
酸性成纤维细胞生长因子 (FGF1) 调节着广泛的重要生物学现象，如血管生成、细胞分化、肿瘤生长和神经发生。一般来说，FGFs 以其与糖胺聚糖肝素的强亲和力而闻名，这是识别细胞表面特定酪氨酸激酶的前提条件，并负责细胞信号转导级联。肌醇六磷酸 (IP6) 是一种天然抗氧化剂，除了能够控制肿瘤生长外，还具有抗血管生成作用。在本研究中，我们使用各种生物物理技术，包括等温量热法、圆二色性和多维 NMR 光谱法，研究了 IP6 与酸性成纤维细胞生长因子 (FGF1) 的相互作用。在此，我们报告了 FGF1-IP6 复合物的三维溶液结构。这些数据表明，IP6 结合 FGF1 并增强其热稳定性。此外，我们还证明 IP6 通过抑制其受体结合并随后降低有丝分裂活性来充当酸性成纤维细胞生长因子的拮抗剂。这种抑制可能导致 IP6 拮抗 FGF1 的血管生成和有丝分裂活性的能力。
