Alternative titles; symbols
HGNC Approved Gene Symbol: CDH5
Cytogenetic location: 16q21 Genomic coordinates (GRCh38): 16:66,366,691-66,404,784 (from NCBI)
Cadherins are calcium-dependent adhesive proteins that mediate cell-to-cell interaction. Huber et al. (1996) noted that they constitute an expanding family of receptors involved in the structural and functional organization of cells in various tissues. Members of the family include epithelial cadherin (E-cadherin; 192090), neural cadherin (N-cadherin; 114020), placental cadherin (P-cadherin; 114021), muscle cadherin (M-cadherin; 114019), and vascular endothelial cadherin (VE-cadherin, or CDH5). They share a common domain structure and primary sequence homologies. Each cadherin type has a unique tissue-distribution pattern. In most of them, expression is not restricted to 1 cell type, and more than 1 cadherin type may be found at the surface of a particular cell. The authors stated that endothelial cells have been shown to express N-cadherin, VE-cadherin, and to a lesser extent, P-cadherin. Among these, only VE-cadherin is expressed specifically in endothelial cells (Salomon et al., 1992). Furthermore, VE-cadherin is associated consistently with intercellular junctions, whereas N-cadherin remains diffuse on the cell membrane.
Tzima et al. (2005) investigated the pathway upstream of integrin (see 192975) activation leading to fluid shear stress response in vascular endothelial cells. They found that PECAM1 (173445), which directly transmits mechanical force, VE-cadherin, which functions as an adaptor, and VEGFR2 (191306), which activates phosphatidylinositol-3-OH kinase, comprise a mechanosensory complex. Together, these receptors were sufficient to confer responsiveness to flow in heterologous cells. In support of the relevance of this pathway in vivo, Pecam1 knockout mice did not activate NF-kappa-B (see 164011) and downstream inflammatory genes in regions of disturbed flow. Therefore, Tzima et al. (2005) concluded that this mechanosensing pathway is required for the earliest known events in atherogenesis.
Huber et al. (1996) isolated and characterized the genomic clones spanning 36 kb and encompassing the mouse VE-cadherin gene. The gene is composed of 12 exons; the first exon is entirely untranslated, and both exons 2 and 12 contain untranslated regions. A single major transcriptional start site is located 75 bp upstream of the translation initiation codon in the cDNA sequence. The proximal 5-prime flanking domain lacks consensus TATA and CAAT boxes at the usual positions. Exon/intron boundaries are similar to those of other cadherin genes, with some exceptions that may have functional significance.
Bussemakers et al. (1994) found that the E-cadherin (CDH1) and P-cadherin genes (CDH3) are molecularly linked in humans, being located within 32 kb of each other on 16q22.1. Thus, the location of the human VE-cadherin gene was predicted to be 16q22.1, as well.
Huber et al. (1996) mapped the Cdh5 gene to mouse chromosome 8 by interspecific backcross analysis. It colocalizes with Cdh1, Cdh3, and Cdh14, suggesting that it may be part of a larger cluster of cadherin genes. In human, the CDH1, CDH3, and CDH14 genes are all located on chromosome 16q.
Kremmidiotis et al. (1998) mapped the human CDH5 gene to 16q22.1 using somatic cell hybrid panels. They demonstrated that 5 cadherin genes (CDH1; CDH3; CDH5; CDH8, 603008; and CDH11, 600023) are clustered in the 16q21-q22.1 region.
In order to define the role of CDH5 and of its binding to beta-catenin (see 116806) in intracellular signaling, Carmeliet et al. (1999) generated mice that lacked a functional Cdh5 gene, that expressed a mutant Cdh5 gene lacking the beta-catenin-binding cytoplasmic tail, or that did not express detectable Cdh5 levels because of an intronic neomycin phosphotransferase (neo) gene. They found in all of these mice that deletion or truncation of the Cdh5 gene did not affect assembly of endothelial cells in vascular plexuses, but did impair their subsequent remodeling and maturation, causing lethality at 9.5 days of gestation. Deficiency or truncation of Cdh5 induced endothelial apoptosis and abolished transmission of the endothelial survival signal by vascular endothelial growth factor A (VEGF; 192240) to AKT kinase (164730) and BCL2 (151430) via reduced complex formation with VEGF receptor-2 (191306), beta-catenin, and phosphoinositide-3 kinase (see 171833). Thus, Carmeliet et al. (1999) concluded that CDH5/beta-catenin signaling controls endothelial survival.
Bussemakers, M. J. G., van Bokhoven, A., Voller, M., Smit, F. P., Schalken, J. A. The genes for the calcium-dependent cell adhesion molecules P- and E-cadherin are tandemly arranged in the human genome. Biochem. Biophys. Res. Commun. 203: 1291-1294, 1994. [PubMed: 8093046] [Full Text: https://doi.org/10.1006/bbrc.1994.2322]
Carmeliet, P., Lampugnani, M.-G., Moons, L., Breviario, F., Compernolle, V., Bono, F., Balconi, G., Spagnuolo, R., Oosthuyse, B., Dewerchin, M., Zanetti, A., Angellilo, A., and 11 others. Targeted deficiency of cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 98: 147-157, 1999. [PubMed: 10428027] [Full Text: https://doi.org/10.1016/s0092-8674(00)81010-7]
Huber, P., Dalmon, J., Engiles, J., Breviario, F., Gory, S., Siracusa, L. D., Buchberg, A. M., Dejana, E. Genomic structure and chromosomal mapping of the mouse VE-cadherin gene (Cdh5). Genomics 32: 21-28, 1996. [PubMed: 8786117] [Full Text: https://doi.org/10.1006/geno.1996.0072]
Kremmidiotis, G., Baker, E., Crawford, J., Eyre, H. J., Nahmias, J., Callen, D. F. Localization of human cadherin genes to chromosome regions exhibiting cancer-related loss of heterozygosity. Genomics 49: 467-471, 1998. [PubMed: 9615235] [Full Text: https://doi.org/10.1006/geno.1998.5281]
Salomon, D., Ayalon, O., Patel-King, R., Hynes, R. O., Geiger, B. Extrajunctional distribution of N-cadherin in cultured human endothelial cells. J. Cell Sci. 102: 7-17, 1992. [PubMed: 1500442] [Full Text: https://doi.org/10.1242/jcs.102.1.7]
Tzima, E., Irani-Tehrani, M., Kiosses, W. B., Dejana, E., Schultz, D. A., Engelhardt, B., Cao, G., DeLisser, H., Schwartz, M. A. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437: 426-431, 2005. [PubMed: 16163360] [Full Text: https://doi.org/10.1038/nature03952]