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Tubulin carboxypeptidase activity of vasohibin-1 inhibits angiogenesis by interfering with endocytosis and trafficking of pro-angiogenic factor receptors

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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.

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Acknowledgements

We would like to acknowledge Yuriko Fujinoya, Masanori Ikeda, and Kozo Tanaka (IDAC, Tohoku University, Japan) for help with experiments and providing materials or expertise, and Katarzyna A Podyma-Inoue for critical comments. We also appreciate scientific and technical assistance from the staff at Lonza, Leica Microsystems, and Bitplane. This work was supported by grants from the Japan Society for the Promotion of Science (Grant-in-Aid for Young Scientists (B): 15K20874, 16KK0177) and the Project for Promoting Leading edge Research in Oral Science at Tokyo Medical and Dental University (TMDU).

Funding

This work was supported by grants from the Japan Society for the Promotion of Science (Grant-in-Aid for Young Scientists (B): 15K20874, 16KK0177) and the Project for Promoting Leading edge Research in Oral Science at Tokyo Medical and Dental University (TMDU).

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Authors and Affiliations

  1. Department of Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan

    Miho Kobayashi, Ikumi Wakabayashi, Kashio Fujiwara & Tetsuro Watabe

  2. Department of Vascular Biology, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, 980-8575, Japan

    Miho Kobayashi, Yasuhiro Suzuki & Yasufumi Sato

  3. Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, 192-0392, Japan

    Ikumi Wakabayashi

  4. New Industry Creation Hatchery Center (NICHe), Tohoku University, Sendai, 980-8579, Japan

    Yasuhiro Suzuki & Yasufumi Sato

  5. Laboratory for Cell Polarity and Organogenesis, Max Planck Institute for Heart and Lung Research, 61231, Bad Nauheim, Germany

    Masanori Nakayama

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Contributions

MK, MN, TW and YS conceived and designed the study. MK and YS carried out the first identification of ∆Y-tubulin increase in ECs. IW constructed the expression vector of VASH1 C169A mutant. All other experiments were carried out by MK and KF; MK and TW wrote the manuscript.

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Correspondence to Miho Kobayashi or Yasufumi Sato.

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All the experiments were approved by “the Safety Control Committee for Experiments Using Genetically Modified Organisms, Etc.” and done according to the guideline of “Safety Control Regulations for Experiments Using Genetically Modified Organisms, Etc., Tohoku University and Tokyo Medical and Dental University”.

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Kobayashi, M., Wakabayashi, I., Suzuki, Y. et al. Tubulin carboxypeptidase activity of vasohibin-1 inhibits angiogenesis by interfering with endocytosis and trafficking of pro-angiogenic factor receptors. Angiogenesis 24, 159–176 (2021). https://doi.org/10.1007/s10456-020-09754-6

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