Alternative titles; symbols
HGNC Approved Gene Symbol: VASH1
Cytogenetic location: 14q24.3 Genomic coordinates (GRCh38) : 14:76,761,468-76,783,015 (from NCBI)
VASH1 is an angiogenesis inhibitor that is produced and secreted by vascular endothelial cells (ECs) upon stimulation with VEGF (VEGFA; 192240) and FGF2 (134920) (Suzuki et al., 2010).
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Kikuno et al. (1999) cloned VASH1, which they called KIAA1036. The deduced protein contains 365 amino acids. RT-PCR ELISA detected intermediate expression in adult heart, brain, lung, liver, kidney, ovary, and spinal cord, as well as in fetal brain. Lower expression was detected in skeletal muscle, testis, pancreas, and fetal liver, and little to no expression was detected in spleen. All specific adult brain regions examined showed low to moderate expression.
By microarray analysis, Watanabe et al. (2004) found that the KIAA1036 gene was upregulated in ECs by VEGF, and they renamed the gene vasohibin. The deduced vasohibin protein contains a cluster of basic amino acids in its C terminus and no classic secretion signal sequence. Northern blot analysis revealed prominent expression in brain and placenta, and lower expression in heart and kidney. Vasohibin expression was robust between embryonic weeks 6 to 12 in heart, brain, kidney, lung, skeletal muscle, and whole embryo. Immunohistochemical analysis detected vasohibin at the endothelial layer of placenta and brain. Western blot analysis detected vasohibin at an apparent molecular mass of 42 kD in intact human umbilical vein ECs and at 30 kD in the medium, indicating proteolytic processing during secretion.
Following expression in insect cells, Watanabe et al. (2004) found that recombinant vasohibin inhibited the migration, proliferation, and network formation by ECs as well as angiogenesis in vivo. The inhibitory effect was selective to ECs, as the protein did not affect the migration of smooth muscle cells or fibroblasts. Eliminating the expression of vasohibin in ECs restored their responsiveness to higher concentrations of VEGF. Expression of vasohibin was selective to ECs, and hypoxia or TNFA (191160) abrogated its inducible expression. Transfection of Lewis lung carcinoma cells with the vasohibin gene did not affect the proliferation of the cancer cells in vitro, but did inhibit tumor growth and tumor angiogenesis in vivo in mice. Watanabe et al. (2004) concluded that vasohibin is an endothelium-derived negative feedback regulator of angiogenesis.
By yeast 2-hybrid screening of a human placenta cDNA library with full-length human VASH1 as bait, Suzuki et al. (2010) identified SVBP (617853) as a VASH1 interactor. Using recombinant human proteins, they found that SVBP interacted strongly with VASH1 and VASH2 (610471). Coimmunoprecipitation analysis showed interaction of SVBP with full-length intracellular and extracellular VASH1, as well as with all proteolytically processed forms of VASH1. SVBP enhanced secretion of cotransfected VASH1 and VASH2 from MS1 mouse ECs and protected VASH1 from ubiquitination and proteasomal degradation. Knockdown of SVBP significantly impaired VASH1 secretion. Conditioned medium containing SVBP inhibited VEGF-inducible migration of human dermal microvascular ECs. Suzuki et al. (2010) concluded that SVBP interacts with VASH1 and VASH2 and participates in their antiangiogenic activities.
Aillaud et al. (2017) used chemical proteomics with a potent irreversible inhibitor to show that the major brain tyrosine carboxypeptidase (TCP) is a complex of VASH1 with SVBP. VASH1 and its homolog VASH2, when complexed with SVBP, exhibited robust and specific tyrosine/phenylalanine carboxypeptidase activity on microtubules. Knockdown of vasohibins or SVBP and/or inhibitor addition in cultured neurons reduced detyrosinated alpha-tubulin (see 602529) levels and caused severe differentiation defects. Furthermore, knockdown of vasohibins disrupted neuronal migration in developing mouse neocortex. Thus, Aillaud et al. (2017) concluded that vasohibin/SVBP complexes represent long-sought TCP enzymes.
Nieuwenhuis et al. (2017) applied a genetic screen in haploid human cells to find regulators of tubulin detyrosination. They identified SVBP, a peptide that regulates the abundance of vasohibins VASH1 and VASH2. Vasohibins, but not SVBP alone, increased detyrosination of alpha-tubulin, and purified vasohibins removed the C-terminal tyrosine of alpha-tubulin. Nieuwenhuis et al. (2017) found that vasohibins play a cell type-dependent role in detyrosination, although cells also contain an additional detyrosinating activity. Nieuwenhuis et al. (2017) concluded that vasohibins, hitherto studied as secreted angiogenesis regulators, constitute a long-sought missing link in the tubulin tyrosination cycle.
Gross (2018) mapped the VASH1 gene to chromosome 14q24.3 based on an alignment of the VASH1 sequence (GenBank BC009031) with the genomic sequence (GRCh38).
Aillaud, C., Bosc, C., Peris, L., Bosson, A., Heemeryck, P., Van Dijk, J., Le Friec, J., Boulan, B., Vossier, F., Sanman, L. E., Syed, S., Amara, N., and 10 others. Vasohibins/SVBP are tubulin carboxypeptidases (TCPs) that regulate neuron differentiation. Science 358: 1448-1453, 2017. [PubMed: 29146868] [Full Text: https://doi.org/10.1126/science.aao4165]
Gross, M. B. Personal Communication. Baltimore, Md. 1/26/2018.
Kikuno, R., Nagase, T., Ishikawa, K., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 197-205, 1999. [PubMed: 10470851] [Full Text: https://doi.org/10.1093/dnares/6.3.197]
Nieuwenhuis, J., Adamopoulos, A., Bleijerveld, O. B., Mazouzi, A., Stickel, E., Celie, P., Altelaar, M., Knipscheer, P., Perrakis, A., Blomen, V. A., Brummelkamp, T. R. Vasohibins encode tubulin detyrosinating activity. Science 358: 1453-1456, 2017. [PubMed: 29146869] [Full Text: https://doi.org/10.1126/science.aao5676]
Suzuki, Y., Kobayashi, M., Miyashita, H., Ohta, H., Sonoda, H., Sato, Y. Isolation of a small vasohibin-binding protein (SVBP) and its role in vasohibin secretion. J. Cell Sci. 123: 3094-3101, 2010. [PubMed: 20736312] [Full Text: https://doi.org/10.1242/jcs.067538]
Watanabe, K., Hasegawa, Y., Yamashita, H., Shimizu, K., Ding, Y., Abe, M., Ohta, H., Imagawa, K., Hojo, K., Maki, H., Sonoda, H., Sato, Y. Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis. J. Clin. Invest. 114: 898-907, 2004. [PubMed: 15467828] [Full Text: https://doi.org/10.1172/JCI21152]