Probing fibroblast growth factor dimerization and role of heparin-like glycosaminoglycans in modulating dimerization and signaling
Probing fibroblast growth factor dimerization and role of heparin-like glycosaminoglycans in modulating dimerization and signaling
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DOI：
10.1074/jbc.m010786200
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发表时间：
2001-06-29
影响因子：
4.8
通讯作者：
Sasisekharan, R
中科院分区：
文献类型：
--
作者：
Kwan, CP;Venkataraman, G;Sasisekharan, R
对于许多生长因子和细胞因子，配体二聚化被认为是活性信号传导复合物形成的核心。在成纤维细胞生长因子-2（FGF 2）信号传导的情况下，肝素/硫酸乙酰肝素样糖胺聚糖（HLGAG）通过与FGF 2及其受体（FGFR）两者的相互作用参与组装三级复合物并调节FGF 2活性。生物化学数据表明HLGAG诱导的FGF 2二聚化的不同模式涉及特定的蛋白质-蛋白质接触。此外，最近的一些FGF（.）FGFR和FGF（.）FGFR（.）HLGAG复合物揭示了分子组装的其他模式，没有FGF-FGF接触。所有这些不同的生物化学和结构研究结果澄清了较少，实际上提出了更多的问题，即FGF 2二聚化的模式，如果有的话，是必不可少的信号。在这项研究中，我们解决的问题，FGF 2二聚化的信号使用的组合，生物化学，生物物理，和定点突变的方法。我们的研究结果提供了直接的证据，FGF 2二聚体介导的FGF 2信号。
For a number of growth factors and cytokines, ligand dimerization is believed to be central to the formation of an active signaling complex. In the case of fibroblast growth factor-2 (FGF2) signaling, heparin/heparan sulfate-like glycosaminoglycans (HLGAGs) are involved through interaction with both FGF2 and its receptors (FGFRs) in assembling a tertiary complex and modulating FGF2 activity. Biochemical data have suggested different modes of HLGAG-induced FGF2 dimerization involving specific protein-protein contacts. In addition, several recent x-ray crystallography studies of FGF(.)FGFR and FGF(.)FGFR(.)HLGAG complexes have revealed other modes of molecular assemblage, with no FGF-FGF contacts. All these different biochemical and structural findings have clarified less and in fact raised more questions as to which mode of FGF2 dimerization, if any, is essential for signaling. In this study, we address the issue of FGF2 dimerization in signaling using a combination of biochemical, biophysical, and site-directed mutagenesis approaches. Our findings presented here provide direct evidence of FGF2 dimerization in mediating FGF2 signaling.