Tubulin carboxypeptidase activity of vasohibin-1 inhibits angiogenesis by interfering with endocytosis and trafficking of pro-angiogenic factor receptors.
Receptor endocytosis is crucial for integrating extracellular stimuli of pro-angiogenic factors, including vascular endothelial growth factor (VEGF), into the cell via signal transduction. VEGF not only triggers various angiogenic events including endothelial cell (EC) migration, but also induces the expression of negative regulators of angiogenesis, including vasohibin-1 (VASH1). While we have previously reported that VASH1 inhibits angiogenesis in vitro and in vivo, its mode of action on EC behavior remains elusive. Recently VASH1 was shown to have tubulin carboxypeptidase (TCP) activity, mediating the post-translational modification of microtubules (MTs) by detyrosination of α-tubulin within cells. However, the role of VASH1 TCP activity in angiogenesis has not yet been clarified. Here, we showed that VASH1 detyrosinated α-tubulin in ECs and suppressed in vitro and in vivo angiogenesis. In cultured ECs, VASH1 impaired endocytosis and trafficking of VEGF receptor 2 (VEGFR2), which resulted in the decreased signal transduction and EC migration. These effects of VASH1 could be restored by tubulin tyrosine ligase (TTL) in ECs, suggesting that detyrosination of α-tubulin negatively regulates angiogenesis. Furthermore, we found that detyrosinated tubulin-rich MTs were not adequate as trafficking rails for VEGFR2 endocytosis. Consistent with these results, inhibition of TCP activity of VASH1 led to the inhibition of VASH1-mediated suppression of VEGF-induced signals, EC migration, and in vivo angiogenesis. Our results indicate a novel mechanism of VASH1-mediated inhibition of pro-angiogenic factor receptor trafficking via modification of MTs.
['Kobayashi|Miho|M|0000-0003-2548-4120', 'Wakabayashi|Ikumi|I|', 'Suzuki|Yasuhiro|Y|', 'Fujiwara|Kashio|K|', 'Nakayama|Masanori|M|', 'Watabe|Tetsuro|T|', 'Sato|Yasufumi|Y|']
D043925:Angiogenesis Inducing Agents D020533:Angiogenesis Inhibitors D000818:Animals D002268:Carboxypeptidases D018797:Cell Cycle Proteins D002465:Cell Movement D004705:Endocytosis D061307:Human Umbilical Vein Endothelial Cells D006801:Humans D007700:Kinetics D051379:Mice D008870:Microtubules D008954:Models, Biological D050505:Mutant Proteins D009389:Neovascularization, Pathologic D010766:Phosphorylation D015398:Signal Transduction D014404:Tubulin D014443:Tyrosine D040301:Vascular Endothelial Growth Factor Receptor-2
Angiogenesis Signal transduction Post-translational modification of microtubules Intracellular trafficking