nach oben

Erschienen in:

14.10.2020 | Original Paper

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

verfasst von: Miho Kobayashi, Ikumi Wakabayashi, Yasuhiro Suzuki, Kashio Fujiwara, Masanori Nakayama, Tetsuro Watabe, Yasufumi Sato

Erschienen in: Angiogenesis | Ausgabe 1/2021

Einloggen, um Zugang zu erhalten

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.

Nur mit Berechtigung zugänglich

Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8:464–478. https://doi.org/10.1038/nrm2183CrossRefPubMed

Rohlenova K, Veys K, Miranda-Santos I, De Bock K, Carmeliet P (2018) Endothelial cell metabolism in health and disease. Trends Cell Biol 28:224–236. https://doi.org/10.1016/j.tcb.2017.10.010CrossRefPubMed

Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L (2006) VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol 7:359–371. https://doi.org/10.1038/nrm1911CrossRefPubMed

Lohela M, Bry M, Tammela T, Alitalo K (2009) VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol 21:154–165. https://doi.org/10.1016/j.ceb.2008.12.012CrossRefPubMed

Sun D, Liu Y, Yu Q, Zhou Y, Zhang R, Chen X et al (2013) The effects of luminescent ruthenium(II) polypyridyl functionalized selenium nanoparticles on bFGF-induced angiogenesis and AKT/ERK signaling. Biomaterials 34:171–180. https://doi.org/10.1016/j.biomaterials.2012.09.031CrossRefPubMed

Horowitz A, Tkachenko E, Simons M (2002) Fibroblast growth factor-specific modulation of cellular response by syndecan-4. J Cell Biol 157:715–725. https://doi.org/10.1083/jcb.200112145CrossRefPubMedPubMedCentral

Sorkin A, von Zastrow M (2009) Endocytosis and signalling: intertwining molecular networks. Nat Rev Mol Cell Biol 10:609–622. https://doi.org/10.1038/nrm2748CrossRefPubMedPubMedCentral

Andersson ER (2012) The role of endocytosis in activating and regulating signal transduction. Cell Mol Life Sci 69:1755–1771. https://doi.org/10.1007/s00018-011-0877-1CrossRefPubMed

Tomas A, Futter CE, Eden ER (2014) EGF receptor trafficking: consequences for signaling and cancer. Trends Cell Biol 24:26–34. https://doi.org/10.1016/j.tcb.2013.11.002CrossRefPubMedPubMedCentral

10.

Jopling HM, Odell AF, Hooper NM, Zachary IC, Walker JH, Ponnambalam S (2009) Rab GTPase regulation of VEGFR2 trafficking and signaling in endothelial cells. Arterioscler Thromb Vasc Biol 29:1119–1124. https://doi.org/10.1161/atvbaha.109.186239CrossRefPubMedPubMedCentral

11.

Elfenbein A, Lanahan A, Zhou TX, Yamasaki A, Tkachenko E, Matsuda M et al (2012) Syndecan 4 regulates FGFR1 signaling in endothelial cells by directing macropinocytosis. Sci Signal 5:ra36. https://doi.org/10.1126/scisignal.2002495CrossRefPubMed

12.

Nakayama M, Nakayama A, van Lessen M, Yamamoto H, Hoffmann S, Drexler HC et al (2013) Spatial regulation of VEGF receptor endocytosis in angiogenesis. Nat Cell Biol 15:249–260. https://doi.org/10.1038/ncb2679CrossRefPubMedPubMedCentral

13.

Yaqoob U, Jagavelu K, Shergill U, de Assuncao T, Cao S, Shah VH (2014) FGF21 promotes endothelial cell angiogenesis through a dynamin-2 and Rab5 dependent pathway. PLoS ONE 9:e98130. https://doi.org/10.1371/journal.pone.0098130CrossRefPubMedPubMedCentral

14.

Bhadada SV, Goyal BR, Patel MM (2011) Angiogenic targets for potential disorders. Fundam Clin Pharmacol 25:29–47. https://doi.org/10.1111/j.1472-8206.2010.00814.xCrossRefPubMed

15.

Herbert SP, Stainier DY (2011) Molecular control of endothelial cell behaviour during blood vessel morphogenesis. Nat Rev Mol Cell Biol 12:551–564. https://doi.org/10.1038/nrm3176CrossRefPubMedPubMedCentral

16.

Watanabe K, Hasegawa Y, Yamashita H, Shimizu K, Ding Y, Abe M et al (2004) Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis. J Clin Invest 114:898–907. https://doi.org/10.1172/JCI21152CrossRefPubMedPubMedCentral

17.

Hosaka T, Kimura H, Heishi T, Suzuki Y, Miyashita H, Ohta H et al (2009) Vasohibin-1 expression in endothelium of tumor blood vessels regulates angiogenesis. Am J Pathol 175:430–439. https://doi.org/10.2353/ajpath.2009.080788CrossRefPubMedPubMedCentral

18.

Heishi T, Hosaka T, Suzuki Y, Miyashita H, Oike Y, Takahashi T et al (2010) Endogenous angiogenesis inhibitor vasohibin1 exhibits broad-spectrum antilymphangiogenic activity and suppresses lymph node metastasis. Am J Pathol 176:1950–1958. https://doi.org/10.2353/ajpath.2010.090829CrossRefPubMedPubMedCentral

19.

Miyashita H, Watanabe T, Hayashi H, Suzuki Y, Nakamura T, Ito S et al (2012) Angiogenesis inhibitor vasohibin-1 enhances stress resistance of endothelial cells via induction of SOD2 and SIRT1. PLoS ONE 7:e46459. https://doi.org/10.1371/journal.pone.0046459CrossRefPubMedPubMedCentral

20.

Aillaud C, Bosc C, Peris L, Bosson A, Heemeryck P, Van Dijk J et al (2017) Vasohibins/SVBP are tubulin carboxypeptidases (TCPs) that regulate neuron differentiation. Science 358:1448–1453. https://doi.org/10.1126/science.aao4165CrossRefPubMed

21.

Janke C, Bulinski JC (2011) Post-translational regulation of the microtubule cytoskeleton: mechanisms and functions. Nat Rev Mol Cell Biol 12:773–786. https://doi.org/10.1038/nrm3227CrossRefPubMed

22.

Gadadhar S, Bodakuntla S, Natarajan K, Janke C (2017) The tubulin code at a glance. J Cell Sci 130:1347–1353. https://doi.org/10.1242/jcs.199471CrossRefPubMed

23.

Zink S, Grosse L, Freikamp A, Banfer S, Muksch F, Jacob R (2012) Tubulin detyrosination promotes monolayer formation and apical trafficking in epithelial cells. J Cell Sci 125:5998–6008. https://doi.org/10.1242/jcs.109470CrossRefPubMed

24.

Herms A, Bosch M, Reddy BJ, Schieber NL, Fajardo A, Ruperez C et al (2015) AMPK activation promotes lipid droplet dispersion on detyrosinated microtubules to increase mitochondrial fatty acid oxidation. Nat Commun 6:7176. https://doi.org/10.1038/ncomms8176CrossRefPubMedPubMedCentral

25.

Barisic M, Maiato H (2016) The tubulin code: a navigation system for chromosomes during mitosis. Trends Cell Biol 26:766–75. https://doi.org/10.1016/j.tcb.2016.06.001CrossRefPubMedPubMedCentral

26.

Chen CY, Caporizzo MA, Bedi K, Vite A, Bogush AI, Robison P et al (2018) Suppression of detyrosinated microtubules improves cardiomyocyte function in human heart failure. Nat Med 24:1225–1233. https://doi.org/10.1038/s41591-018-0046-2CrossRefPubMed

27.

Steinmetz MO, Akhmanova A (2008) Capturing protein tails by CAP-Gly domains. Trends Biochem Sci 33:535–545. https://doi.org/10.1016/j.tibs.2008.08.006CrossRefPubMed

28.

Peris L, Thery M, Faure J, Saoudi Y, Lafanechere L, Chilton JK et al (2006) Tubulin tyrosination is a major factor affecting the recruitment of CAP-Gly proteins at microtubule plus ends. J Cell Biol 174:839–849. https://doi.org/10.1083/jcb.200512058CrossRefPubMedPubMedCentral

29.

Raybin D, Flavin M (1977) Modification of tubulin by tyrosylation in cells and extracts and its effect on assembly in vitro. J Cell Biol 73:492–504CrossRef

30.

Webster DR, Wehland J, Weber K, Borisy GG (1990) Detyrosination of alpha tubulin does not stabilize microtubules in vivo. J Cell Biol 111:113–122CrossRef

31.

Nieuwenhuis J, Adamopoulos A, Bleijerveld OB, Mazouzi A, Stickel E, Celie P et al (2017) Vasohibins encode tubulin detyrosinating activity. Science 358:1453–1456. https://doi.org/10.1126/science.aao5676CrossRefPubMed

32.

Idriss HT (2000) Phosphorylation of tubulin tyrosine ligase: a potential mechanism for regulation of alpha-tubulin tyrosination. Cell Motil Cytoskelet 46:1–5CrossRef

33.

Lamalice L, Le Boeuf F, Huot J (2007) Endothelial cell migration during angiogenesis. Circ Res 100:782–794. https://doi.org/10.1161/01.RES.0000259593.07661.1eCrossRefPubMed

34.

Rodriguez OC, Schaefer AW, Mandato CA, Forscher P, Bement WM, Waterman-Storer CM (2003) Conserved microtubule-actin interactions in cell movement and morphogenesis. Nat Cell Biol 5:599–609. https://doi.org/10.1038/ncb0703-599CrossRefPubMed

35.

Lee HN, Bosompra OA, Coller HA (2019) RECK isoforms differentially regulate fibroblast migration by modulating tubulin post-translational modifications. Biochem Biophys Res Commun 510:211–218. https://doi.org/10.1016/j.bbrc.2019.01.063CrossRefPubMedPubMedCentral

36.

Seetharaman S, Etienne-Manneville S (2020) Cytoskeletal crosstalk in cell migration. Trends Cell Biol. https://doi.org/10.1016/j.tcb.2020.06.004CrossRefPubMed

37.

Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657. https://doi.org/10.1126/science.296.5573.1655CrossRefPubMed

38.

Sai J, Fan GH, Wang D, Richmond A (2004) The C-terminal domain LLKIL motif of CXCR2 is required for ligand-mediated polarization of early signals during chemotaxis. J Cell Sci 117:5489–5496. https://doi.org/10.1242/jcs.01398CrossRefPubMedPubMedCentral

39.

Vilalta PM, Zhang L, Hamm-Alvarez SF (1998) A novel taxol-induced vimentin phosphorylation and stabilization revealed by studies on stable microtubules and vimentin intermediate filaments. J Cell Sci 111(Pt 13):1841–1852PubMed

40.

Koch S, Claesson-Welsh L (2012) Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med 2:a006502. https://doi.org/10.1101/cshperspect.a006502CrossRefPubMedPubMedCentral

41.

Pang Y, Wang K, Wang Y, Chenlin Z, Lei W, Zhang Y (2018) Tumor-promoting and pro-angiogenic effects of roxarsone via VEGFR2/PLCγ/PKC signaling. Chem Biol Interact 292:110–120. https://doi.org/10.1016/j.cbi.2018.07.012CrossRefPubMed

42.

Lampugnani MG, Orsenigo F, Gagliani MC, Tacchetti C, Dejana E (2006) Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments. J Cell Biol 174:593–604. https://doi.org/10.1083/jcb.200602080CrossRefPubMedPubMedCentral

43.

Ewan LC, Jopling HM, Jia H, Mittar S, Bagherzadeh A, Howell GJ et al (2006) Intrinsic tyrosine kinase activity is required for vascular endothelial growth factor receptor 2 ubiquitination, sorting and degradation in endothelial cells. Traffic 7:1270–1282CrossRef

44.

Gampel A, Moss L, Jones MC, Brunton V, Norman JC, Mellor H (2006) VEGF regulates the mobilization of VEGFR2/KDR from an intracellular endothelial storage compartment. Blood 108:2624–2631. https://doi.org/10.1182/blood-2005-12-007484CrossRefPubMed

45.

Bruns AF, Herbert SP, Odell AF, Jopling HM, Hooper NM, Zachary IC et al (2010) Ligand-stimulated VEGFR2 signaling is regulated by co-ordinated trafficking and proteolysis. Traffic 11:161–174. https://doi.org/10.1111/j.1600-0854.2009.01001.xCrossRefPubMed

46.

Feng L, Liao WX, Luo Q, Zhang HH, Wang W, Zheng J et al (2012) Caveolin-1 orchestrates fibroblast growth factor 2 signaling control of angiogenesis in placental artery endothelial cell caveolae. J Cell Physiol 227:2480–2491. https://doi.org/10.1002/jcp.22984CrossRefPubMedPubMedCentral

47.

Gaengel K, Betsholtz C (2013) Endocytosis regulates VEGF signalling during angiogenesis. Nat Cell Biol 15:233–235. https://doi.org/10.1038/ncb2705CrossRefPubMed

48.

Czeisler C, Mikawa T (2013) Microtubules coordinate VEGFR2 signaling and sorting. PLoS ONE. https://doi.org/10.1371/journal.pone.0075833CrossRefPubMedPubMedCentral

49.

Ballmer-Hofer K, Andersson AE, Ratcliffe LE, Berger P (2011) Neuropilin-1 promotes VEGFR-2 trafficking through Rab11 vesicles thereby specifying signal output. Blood 118:816–826. https://doi.org/10.1182/blood-2011-01-328773CrossRefPubMed

50.

Herkenne S, Paques C, Nivelles O, Lion M, Bajou K, Pollenus T et al (2015) The interaction of uPAR with VEGFR2 promotes VEGF-induced angiogenesis. Sci Signal 8:ra117. https://doi.org/10.1126/scisignal.aaa2403CrossRefPubMed

51.

Tessneer KL, Pasula S, Cai X, Dong Y, McManus J, Liu X et al (2014) Genetic reduction of vascular endothelial growth factor receptor 2 rescues aberrant angiogenesis caused by epsin deficiency. Arterioscler Thromb Vasc Biol 34:331–337. https://doi.org/10.1161/atvbaha.113.302586CrossRefPubMed

52.

McKenney RJ, Huynh W, Vale RD, Sirajuddin M (2016) Tyrosination of alpha-tubulin controls the initiation of processive dynein-dynactin motility. EMBO J 35:1175–1185. https://doi.org/10.15252/embj.201593071CrossRefPubMedPubMedCentral

53.

Driskell OJ, Mironov A, Allan VJ, Woodman PG (2007) Dynein is required for receptor sorting and the morphogenesis of early endosomes. Nat Cell Biol 9:113–120. https://doi.org/10.1038/ncb1525CrossRefPubMed

54.

Scott-Solomon E, Kuruvilla R (2018) Mechanisms of neurotrophin trafficking via Trk receptors. Mol Cell Neurosci 91:25–33. https://doi.org/10.1016/j.mcn.2018.03.013CrossRefPubMedPubMedCentral

55.

Li F, Hu Y, Qi S, Luo X, Yu H (2019) Structural basis of tubulin detyrosination by vasohibins. Nat Struct Mol Biol 26:583–591. https://doi.org/10.1038/s41594-019-0242-xCrossRefPubMedPubMedCentral

56.

Zhang X, Simons M (2014) Receptor tyrosine kinases endocytosis in endothelium: biology and signaling. Arterioscler Thromb Vasc Biol 34:1831–1837. https://doi.org/10.1161/atvbaha.114.303217CrossRefPubMedPubMedCentral

57.

Iniguez A, Allard J (2017) Spatial pattern formation in microtubule post-translational modifications and the tight localization of motor-driven cargo. J Math Biol 74:1059–1080. https://doi.org/10.1007/s00285-016-1053-xCrossRefPubMed

58.

Ebos JM, Kerbel RS (2011) Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat Rev Clin Oncol 8:210–221. https://doi.org/10.1038/nrclinonc.2011.21CrossRefPubMedPubMedCentral

59.

Kamba T, McDonald DM (2007) Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer 96:1788–1795. https://doi.org/10.1038/sj.bjc.6603813CrossRefPubMedPubMedCentral

60.

Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592–603. https://doi.org/10.1038/nrc2442CrossRefPubMedPubMedCentral

61.

Chen HX, Cleck JN (2009) Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin Oncol 6:465–477. https://doi.org/10.1038/nrclinonc.2009.94CrossRefPubMed

62.

Cao Y (2014) VEGF-targeted cancer therapeutics-paradoxical effects in endocrine organs. Nat Rev Endocrinol 10:530–539. https://doi.org/10.1038/nrendo.2014.114CrossRefPubMed

63.

Yang Y, Zhang Y, Cao Z, Ji H, Yang X, Iwamoto H et al (2013) Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues. Proc Natl Acad Sci USA 110:12018–12023. https://doi.org/10.1073/pnas.1301331110CrossRefPubMed

64.

Yang Y, Zhang Y, Iwamoto H, Hosaka K, Seki T, Andersson P et al (2016) Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism. Nat Commun 7:12680. https://doi.org/10.1038/ncomms12680CrossRefPubMedPubMedCentral

65.

Grant BD, Donaldson JG (2009) Pathways and mechanisms of endocytic recycling. Nat Rev Mol Cell Biol 10:597–608. https://doi.org/10.1038/nrm2755CrossRefPubMedPubMedCentral

66.

Ito S, Miyashita H, Suzuki Y, Kobayashi M, Satomi S, Sato Y (2013) Enhanced cancer metastasis in mice deficient in vasohibin-1 gene. PLoS ONE 8:e73931. https://doi.org/10.1371/journal.pone.0073931CrossRefPubMedPubMedCentral

67.

Noiges R, Eichinger R, Kutschera W, Fischer I, Nemeth Z, Wiche G et al (2002) Microtubule-associated protein 1A (MAP1A) and MAP1B: light chains determine distinct functional properties. J Neurosci 22:2106–2114. https://doi.org/10.1523/JNEUROSCI.22-06-02106.2002CrossRefPubMedPubMedCentral

Titel: Tubulin carboxypeptidase activity of vasohibin-1 inhibits angiogenesis by interfering with endocytosis and trafficking of pro-angiogenic factor receptors
verfasst von: Miho Kobayashi
Ikumi Wakabayashi
Yasuhiro Suzuki
Kashio Fujiwara
Masanori Nakayama
Tetsuro Watabe
Yasufumi Sato
Publikationsdatum: 14.10.2020
Verlag: Springer Netherlands
Erschienen in: Angiogenesis / Ausgabe 1/2021
Print ISSN: 0969-6970
Elektronische ISSN: 1573-7209
DOI: https://doi.org/10.1007/s10456-020-09754-6

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

„Jeder Fall von plötzlichem Tod muss obduziert werden!“

17.05.2024 Plötzlicher Herztod Nachrichten

Ein signifikanter Anteil der Fälle von plötzlichem Herztod ist genetisch bedingt. Um ihre Verwandten vor diesem Schicksal zu bewahren, sollten jüngere Personen, die plötzlich unerwartet versterben, ausnahmslos einer Autopsie unterzogen werden.

Hirnblutung unter DOAK und VKA ähnlich bedrohlich

17.05.2024 Direkte orale Antikoagulanzien Nachrichten

Kommt es zu einer nichttraumatischen Hirnblutung, spielt es keine große Rolle, ob die Betroffenen zuvor direkt wirksame orale Antikoagulanzien oder Marcumar bekommen haben: Die Prognose ist ähnlich schlecht.

Schlechtere Vorhofflimmern-Prognose bei kleinem linken Ventrikel

17.05.2024 Vorhofflimmern Nachrichten

Nicht nur ein vergrößerter, sondern auch ein kleiner linker Ventrikel ist bei Vorhofflimmern mit einer erhöhten Komplikationsrate assoziiert. Der Zusammenhang besteht nach Daten aus China unabhängig von anderen Risikofaktoren.

Semaglutid bei Herzinsuffizienz: Wie erklärt sich die Wirksamkeit?

17.05.2024 Herzinsuffizienz Nachrichten

Bei adipösen Patienten mit Herzinsuffizienz des HFpEF-Phänotyps ist Semaglutid von symptomatischem Nutzen. Resultiert dieser Benefit allein aus der Gewichtsreduktion oder auch aus spezifischen Effekten auf die Herzinsuffizienz-Pathogenese? Eine neue Analyse gibt Aufschluss.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 1/2021

Angiogenesis, hereditary hemorrhagic telangiectasia and COVID-19

Protection of capillaries may be critical in delaying aging around the eyes and prevention of facial plastic surgery

Epigenetic regulation of the lineage specificity of primary human dermal lymphatic and blood vascular endothelial cells

3D analysis of microvasculature in murine liver fibrosis models using synchrotron radiation-based microtomography

AgeR deletion decreases soluble fms-like tyrosine kinase 1 production and improves post-ischemic angiogenesis in uremic mice