Vasohibins encode tubulin detyrosinating activity

Nieuwenhuis, Joppe; Adamopoulos, Athanassios; Bleijerveld, Onno B.; Mazouzi, Abdelghani; Stickel, Elmer; Celie, P.H.N.; Altelaar, Maarten; Knipscheer, Puck; Perrakis, Anastassis; Blomen, Vincent A.; Brummelkamp, Thijn R.

doi:10.1126/science.aao5676

Cited by 205 publications

(219 citation statements)

References 33 publications

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“…Microtubules receive a variety of post‐translational modifications including tubulin detyrosination. VASH2 has recently been shown to have TCP activity . In accordance with this evidence, the present study showed that VASH2 stimulated metastatic activity of PDAC cells, at least in part, through its TCP activity within the cell.…”

Section: Discussionsupporting

confidence: 91%

“…Vasohibins have recently been identified to have TCP activity, which deletes a tyrosine residue from the carboxy‐terminus of α‐tubulin . We confirmed that detyrosinated tubulin was decreased in Vash2‐knockdown KPC cells and tissue of orthotopic tumors (Figure A‐C).…”

Section: Resultssupporting

confidence: 76%

“…One such modification, namely tubulin detyrosination, is reported to be accumulated in cancer cells during tumor development and is correlated with histological grade in breast cancer . VASH have recently been identified to have TCP activity, which catalyzes the C‐terminus tyrosine residue of α‐tubulin . Thus, VASH2 may influence cancer cell behavior by augmenting tubulin detyrosination.…”

Section: Introductionmentioning

confidence: 99%

“…17,18 VASH have recently been identified to have TCP activity, which catalyzes the C-terminus tyrosine residue of α-tubulin. 19,20 Thus, VASH2 may influence cancer cell behavior by augmenting tubulin detyrosination.…”

Section: Introductionmentioning

confidence: 99%

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Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma

et al. 2019

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Vasohibin‐2 (VASH2) is expressed in various cancers and promotes their progression. We recently reported that pancreatic cancer patients with higher VASH2 expression show poorer prognosis. Herein, we sought to characterize the role of VASH2 in pancreatic cancer. We used LSL‐KrasG12D; LSL‐Trp53R172H; Pdx‐1‐Cre (KPC) mice, a mouse model of pancreatic ductal adenocarcinoma (PDAC), and cells isolated from them (KPC cells). Knockdown of Vash2 from PDAC cells did not affect their proliferation, but decreased their migration. When Vash2‐knockdown PDAC cells were orthotopically inoculated, liver metastasis and peritoneal dissemination were reduced, and the survival period was significantly prolonged. When KPC mice were crossed with Vash2‐deficient mice, metastasis was significantly decreased in Vash2‐deficient KPC mice. VASH2 was recently identified to have tubulin carboxypeptidase activity. VASH2 knockdown decreased, whereas VASH2 overexpression increased tubulin detyrosination of PDAC cells, and tubulin carboxypeptidase (TCP) inhibitor parthenolide inhibited VASH2‐induced cell migration. We next clarified its role in the tumor microenvironment. Tumor angiogenesis was significantly abrogated in vivo when VASH2 was knocked down or deleted. We further examined genes downregulated by Vash2 knockdown in KPC cells, and found chemokines and cytokines that were responsible for the recruitment of myeloid derived suppressor cells (MDSC). Indeed, MDSC were accumulated in PDAC of KPC mice, and they were significantly decreased in Vash2‐deficient KPC mice. These findings suggest that VASH2 plays an essential role in the metastasis of PDAC with multiple effects on both cancer cells and the tumor microenvironment, including tubulin detyrosination, tumor angiogenesis and evasion of tumor immunity.

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Section: Discussionsupporting

confidence: 91%

Section: Resultssupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma

et al. 2019

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“…Shortly after, it was found that a cytosolic tubulin carboxypeptidase (TCP) activity, preferentially working on polymerized tubulin, was responsible for the cleavage of the C-terminal tyrosine (Gundersen, Khawaja, & Bulinski, 1987; Hallak, Rodriguez, Barra, & Caputto, 1977). However, the identity of TPC(s) mediating this cleavage remained elusive for more than three decades and only recently were identified by two different groups (Aillaud et al, 2017; Nieuwenhuis et al, 2017). Vasohibin-1 and its homologue Vasohibin-2, previously described has angiogenic factors, were shown to catalyse detyrosination when in complex with a chaperone-like peptide - small vasohibin binding protein (SVBP).…”

Section: Introductionmentioning

confidence: 99%

Dissecting the role of the tubulin code in mitosis

Ferreira

Figueiredo

Orr

et al. 2018

Mitosis and Meiosis Part A

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Mitosis is an essential process that takes place in all eukaryotes and involves the equal division of genetic material from a parental cell into two identical daughter cells. During mitosis, chromosome movement and segregation are orchestrated by a specialized structure known as the mitotic spindle, composed of a bipolar array of microtubules. The fundamental structure of microtubules comprises of α/β-tubulin heterodimers that associate head-to-tail and laterally to form hollow filaments. In vivo, microtubules are modified by abundant and evolutionarily conserved tubulin posttranslational modifications (PTMs), giving these filaments the potential for a wide chemical diversity. In recent years, the concept of a "tubulin code" has emerged as an extralayer of regulation governing microtubule function. A range of tubulin isoforms, each with a diverse set of PTMs, provides a readable code for microtubule motors and other microtubule-associated proteins. This chapter focuses on the complexity of tubulin PTMs with an emphasis on detyrosination and summarizes the methods currently used in our laboratory to experimentally manipulate these modifications and study their impact in mitosis.

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Decoding microtubule detyrosination: enzyme families, structures, and functional implications

Bak,

Brummelkamp,

Perrakis

2024

FEBS Letters

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Microtubules are a major component of the cytoskeleton and can accumulate a plethora of modifications. The microtubule detyrosination cycle is one of these modifications; it involves the enzymatic removal of the C‐terminal tyrosine of α‐tubulin on assembled microtubules and the re‐ligation of tyrosine on detyrosinated tubulin dimers. This modification cycle has been implicated in cardiac disease, neuronal development, and mitotic defects. The vasohibin and microtubule‐associated tyrosine carboxypeptidase enzyme families are responsible for microtubule detyrosination. Their long‐sought discovery allows to review and summarise differences and similarities between the two enzymes families and discuss how they interplay with other modifications and functions of the tubulin code.

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Vasohibins encode tubulin detyrosinating activity

Cited by 205 publications

References 33 publications

Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma

Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma

Dissecting the role of the tubulin code in mitosis

Decoding microtubule detyrosination: enzyme families, structures, and functional implications

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