A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2
A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2
复制标题
DOI：
10.1007/s00018-006-6254-9
复制
发表时间：
2006-09-01
影响因子：
8
通讯作者：
Ballmer-Hofer, K.
中科院分区：
文献类型：
--
作者：
Suarez, S. Cebe;Pieren, M.;Ballmer-Hofer, K.
功能性血管和淋巴管的发育需要生长因子如血管内皮生长因子（VEGF）的产生和释放的时空协调。VEGF家族蛋白以具有不同生物学特性的多种同种型产生，并结合三种类型的VEGF受体。VEGF-A剪接变体VEGF-A（165）B最近已从肾上皮细胞中分离出来。该变体与VEGF-A（165）相同，除了由选择性外显子编码的最后6个氨基酸。VEGF-A（165）B和VEGF-A（165）以相似的亲和力结合VEGF受体1和2。VEGF-A（165）B在血管生成测定中显著降低活性，甚至抵消VEGF-A（165）的信号传导。VEGF-A（165）B与硫酸乙酰肝素弱结合，不与VEGF受体2的辅助受体神经纤毛蛋白-1相互作用。为了确定VEGF-A（165）B改变信号传导的分子基础，我们测量了培养的内皮细胞中VEGF受体2和ERK激酶的活性。VEGF-A（165）诱导VEGF受体2和ERK-1和-2的强烈和持续激活，而VEGF-A（165）B的激活仅是微弱和短暂的。总之，这些数据表明VEGF-A（165）B通过VEGF受体2具有减弱的信号传导潜力，将VEGF家族的这个新成员定义为部分受体激动剂。
The development of functional blood and lymphatic vessels requires spatio-temporal coordination of the production and release of growth factors such as vascular endothelial growth factors (VEGFs). VEGF family proteins are produced in multiple isoforms with distinct biological properties and bind to three types of VEGF receptors. A VEGF-A splice variant, VEGF-A(165)b, has recently been isolated from kidney epithelial cells. This variant is identical to VEGF-A(165) except for the last six amino acids encoded by an alternative exon. VEGF-A(165)b and VEGF-A(165) bind VEGF receptors 1 and 2 with similar affinity. VEGF-A(165)b elicits drastically reduced activity in angiogenesis assays and even counteracts signaling by VEGF-A(165). VEGF-A(165)b weakly binds to heparan sulfate and does not interact with neuropilin-1, a coreceptor for VEGF receptor 2. To determine the molecular basis for altered signaling by VEGF-A(165)b we measured VEGF receptor 2 and ERK kinase activity in endothelial cells in culture. VEGF-A(165) induced strong and sustained activation of VEGF receptor 2 and ERK-1 and -2, while activation by VEGF-A(165)b was only weak and transient. Taken together these data show that VEGF-A(165)b has attenuated signaling potential through VEGF receptor 2 defining this new member of the VEGF family as a partial receptor agonist.