血管内皮生长因子受体-2所介导信号通路的研究进展

Progress in The Study of VEGFR-2 Signaling Pathway

血管新生是许多生理和病理进程发生的重要机理.在生物体内,血管新生需经过多步精细调控历程,现有研究表明,血管内皮生长因子(VEGF)及其受体蛋白酪氨酸激酶,尤其是血管内皮生长因子受体-2(VEGFR-2)所介导的信号级联通路是其中关键性的调节途径.VEGF/VEGFR-2所介导的信号级联通路可以调控血管内皮细胞的增殖、迁移、存活和通透性的改变,促进血管的新生.VEGF与VEGFR-2的胞外区特异性结合后,引起受体的二聚化和自身的交互磷酸化,使胞内特定的酪氨酸残基磷酸化.下游信号蛋白可以通过其Src同源结构域-2(SH2)与VEGFR-2结合,随后激活下游的效应蛋白,调控内皮细胞的生物学活性.此外,VEGF/VEGFR-2信号通路还可以下调树突细胞(DC)的活性.对VEGF/VEGFR-2信号通路作用的深入了解,将有助于新药的研发.

Angiogenesis is of great importance to a variety of normal physiological processes and pathological disorders. It is tightly regulated by many mechanisms, among which vascular endothelial growth factor （VEGF） is one of the most potent promoters. VEGF binds and activates its specific receptor tyrosine kinases, especially vascular endothelial growth factor receptor-2 （VEGFR-2）. VEGFR-2 mediates the key functional and biochemical effects of VEGF in endothelial cells including proliferation, migration, survival, and permeability. Following its binding to VEGF, VEGFR-2 dimerizes and undergoes autophosphorylation on tyrosine residues within its cytoplasmic portion. This creates docking sites for adapter molecules to be recruited through their Src homology domain-2 （SH2）. These adapter molecules can then initiate the activation of downstream signaling cascades. Further down-stream effector molecules are activated, and regulate the biological effects of endothelial cells. It is also foound that VEGF/VEGFR-2 signaling pathway may negatively regulate the function of human monocyte-derived mature dendritic cells （DCs） as well as the maturation of immature-DCs. Advances in the understanding of the VEGF/VEGFR-2 signaling pathway may contribute to the discovery of kinds of pharmaceutical agents.