Tubulin carboxypeptidase activity of vasohibin-1 inhibits angiogenesis by interfering with endocytosis and trafficking o
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ORIGINAL PAPER
Tubulin carboxypeptidase activity of vasohibin-1 inhibits angiogenesis by interfering with endocytosis and trafficking of proangiogenic factor receptors Miho Kobayashi1,2 · Ikumi Wakabayashi1,3 · Yasuhiro Suzuki2,4 · Kashio Fujiwara1 · Masanori Nakayama5 · Tetsuro Watabe1 · Yasufumi Sato2,4 Received: 26 April 2020 / Revised: 24 September 2020 / Accepted: 29 September 2020 © Springer Nature B.V. 2020
Abstract 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. Keywords Angiogenesis · Signal transduction · Post-translational modification of microtubules · Intracellular trafficking
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10456-020-09754-6) contains supplementary material, which is available to authorized users.
Vascular systems do not only maintain body homeostasis by delivering oxygen and nutrients throughout body tissues, but also play important roles in the progression of various diseases, including cancer [1, 2]. Therefore, understanding the molecular and biochemical mechanisms underlying
* Miho Kobayashi miho‑[email protected]
3
Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo 192‑0392, Japan
* Yasufumi Sato [email protected]
4
New Industry Creation Hatchery Center (NICHe), Tohoku University, Sendai 980‑8579, Japan
5
Laboratory for Cell Polarity and Organogenesis, Ma
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