Yaqoob Usman, Jagavelu Kumaravelu, Shergill Uday, de Assuncao Thiago, Cao Sheng, Shah Vijay H
Gastroenterology Research Unit, Mayo Clinic, Rochester, Minnesota, United States of America.
PLoS One. 2014 May 21;9(5):e98130. doi: 10.1371/journal.pone.0098130. eCollection 2014.
Binding of angiogenic molecules with cognate receptor tyrosine kinases (RTK) is required for angiogenesis however the precise link between RTK binding, endocytosis, and signaling requires further investigation. Here, we use FGFR1 as a model to test the effects of the large GTPase and endocytosis regulatory molecule dynamin-2 on angiogenic signaling in context of distinct FGF ligands. In vitro, overexpression of dominant negative dynamin-2 (DynK44A) attenuates FGFR1 activation of Erk and tubulogenesis by FGF2. Furthermore, we identify FGF21, a non-classical, FGF ligand implicated in diverse human pathologies as an angiogenic molecule acting through FGFR1 and β-Klotho coreceptor. Disruption of FGFR1 activation of ERK by FGF21 is achieved by perturbation of the function of both dynamin-2 and Rab5 GTPase. In vivo, mice harboring endothelial selective overexpression of DynK44A, show impaired angiogenesis in response to FGF21. In conclusion, dynamin dependent endocytosis of FGFR1 is required for in vitro and in vivo angiogenesis in response to FGF2 and the non-classical FGF ligand, FGF21. These studies extend our understanding of the relationships between RTK binding, internalization, endosomal targeting, and angiogenic signaling.
血管生成需要血管生成分子与同源受体酪氨酸激酶（RTK）结合，然而RTK结合、内吞作用和信号传导之间的确切联系仍需进一步研究。在这里，我们以FGFR1为模型，在不同的FGF配体背景下，测试大GTP酶和内吞作用调节分子发动蛋白-2对血管生成信号传导的影响。在体外，显性负性发动蛋白-2（DynK44A）的过表达减弱了FGF2对Erk的激活以及对成管作用的影响。此外，我们确定FGF21是一种非经典的FGF配体，与多种人类疾病有关，它作为一种通过FGFR1和β-klotho共受体起作用的血管生成分子。FGF21对ERK的FGFR1激活的破坏是通过扰乱发动蛋白-2和Rab5 GTP酶的功能来实现的。在体内，内皮细胞选择性过表达DynK44A的小鼠对FGF21的血管生成反应受损。总之，FGFR1的发动蛋白依赖性内吞作用是体外和体内对FGF2和非经典FGF配体FGF21血管生成反应所必需的。这些研究扩展了我们对RTK结合、内化、内体靶向和血管生成信号传导之间关系的理解。
