CDH1 (gene)

Cadherin 1, type 1
PDB rendering based on 1i7w.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1O6S​, 2O72​, 2OMT​, 2OMU​, 2OMV​, 2OMX​, 2OMY​, 2OMZ​, 3FF7​, 3FF8​, 3L6X​, 3L6Y​
Identifiers
Symbols	CDH1 ; Arc-1; CD324; CDHE; ECAD; LCAM; UVO
External IDs	OMIM: 192090 MGI: 88354 HomoloGene: 20917 GeneCards: CDH1 Gene
Gene ontology Molecular function • glycoprotein binding • calcium ion binding • protein binding • beta-catenin binding • ankyrin binding • GTPase activating protein binding • gamma-catenin binding • cell adhesion molecule binding Cellular component • extracellular region • cytoplasm • endosome • trans-Golgi network • plasma membrane • cell-cell adherens junction • focal adhesion • cytoplasmic side of plasma membrane • actin cytoskeleton • integral component of membrane • aggresome • lateral plasma membrane • catenin complex • flotillin complex • lamellipodium • cell junction • cortical actin cytoskeleton • apical junction complex • perinuclear region of cytoplasm • extracellular exosome Biological process • apoptotic process • cellular component disassembly involved in execution phase of apoptosis • homophilic cell adhesion via plasma membrane adhesion molecules • small GTPase mediated signal transduction • synapse assembly • response to toxic substance • programmed cell death • single organismal cell-cell adhesion • pituitary gland development • negative regulation of cell-cell adhesion • extracellular matrix disassembly • extracellular matrix organization • neuron projection development • cell junction assembly • adherens junction organization • response to drug • positive regulation of transcription factor import into nucleus • cell-cell junction organization • positive regulation of transcription, DNA-templated • regulation of epithelial cell proliferation • regulation of immune response • cellular response to lithium ion • cellular response to indole-3-methanol • protein localization to plasma membrane • establishment of protein localization to plasma membrane Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	999	12550
Ensembl	ENSG00000039068	ENSMUSG00000000303
UniProt	P12830	P09803
RefSeq (mRNA)	NM_004360	NM_009864
RefSeq (protein)	NP_004351	NP_033994
Location (UCSC)	Chr 16: 68.74 – 68.84 Mb	Chr 8: 106.6 – 106.67 Mb
PubMed search

Cadherin-1 also known as CAM 120/80 or epithelial cadherin (E-cadherin) or uvomorulin is a protein that in humans is encoded by the CDH1 gene.^[1] CDH1 has also been designated as CD324 (cluster of differentiation 324). It is a tumor suppressor gene.^[2][3]

Function

Cadherin-1 is a classical member of the cadherin superfamily. The encoded protein is a calcium-dependent cell-cell adhesion glycoprotein composed of five extracellular cadherin repeats, a transmembrane region, and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid, and ovarian cancers. Loss of function is thought to contribute to progression in cancer by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells, and the cytoplasmic domain is required for internalization. Identified transcript variants arise from mutation at consensus splice sites.^[4]

E-cadherin (epithelial) is the most well-studied member of the cadherin family. It consists of 5 cadherin repeats (EC1 ~ EC5) in the extracellular domain, one transmembrane domain, and an intracellular domain that binds p120-catenin and beta-catenin. The intracellular domain contains a highly-phosphorylated region vital to beta-catenin binding and, therefore, to E-cadherin function. Beta-catenin can also bind to alpha-catenin. Alpha-catenin participates in regulation of actin-containing cytoskeletal filaments. In epithelial cells, E-cadherin-containing cell-to-cell junctions are often adjacent to actin-containing filaments of the cytoskeleton.

E-cadherin is first expressed in the 2-cell stage of mammalian development, and becomes phosphorylated by the 8-cell stage, where it causes compaction. In adult tissues, E-cadherin is expressed in epithelial tissues, where it is constantly regenerated with a 5-hour half-life on the cell surface. Cell-cell interactions mediated by E-cadherin are crucial to blastula formation in many animals.^[5]

Clinical significance

Loss of E-cadherin function or expression has been implicated in cancer progression and metastasis.^[6][7] E-cadherin downregulation decreases the strength of cellular adhesion within a tissue, resulting in an increase in cellular motility. This in turn may allow cancer cells to cross the basement membrane and invade surrounding tissues.^[7] E-cadherin is also used by pathologists to diagnose different kinds of breast cancer. When compared with invasive ductal carcinoma, E-cadherin expression is markedly reduced or absent in the great majority of invasive lobular carcinomas when studied by immunohistochemistry.^[8]

Interactions

CDH1 (gene) has been shown to interact with

• CBLL1,^[9]
• CDC27,^[10]
• CDON,^[11]
• CDH3,^[12]
• C-Met,^{[13][14][15][16][17][18][19][20]}
• CTNNB1,^{[11][15][16][18][19][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]}
• CTNNA1^{[15][30][31][32][37]}
• FOXM1,^[39]
• HDAC1,^[40]
• HDAC2,^[40]
• IQGAP1,^[41]
• FYN,^[18]
• NEDD9,^[42]
• Plakoglobin,^{[15][16][43][44][45]}
• Vinculin,^[16][24]

• PTPmu(PTPRM)^[46][47]
• PTPrho(PTPRT)^[48]

Cadherin-1 and cancer

Cadherin-1 in metastasis

Transitions between epithelial and mesenchymal states play important roles in embryonic development and cancer metastasis. E-cadherin level changes in EMT (epithelial-mesenchymal transition) and MET (mesenchymal-epithelial transition). E-cadherin acts as an invasion suppressor and a classical tumor suppressor gene in pre-invasive lobular breast carcinoma.^[49]

1. E-cadherin in EMT:

E-cadherin is a crucial type of cell-cell adhesion to hold the epithelial cells tight together. E-cadherin can sequester β-catenin on the cell membrane by the cytoplasmic tail of E-cadherin. Loss of E-cadherin expression results in releasing β-catenin into the cytoplasm. Liberated β-catenin molecules may migrate into the nucleus and trigger the expression of EMT-inducing transcription factors. Together with other mechanisms, such as constitutive RTK activation, E-cadherin loss can lead cancer cells to the mesenchymal state and undergo metastasis. E-cadherin is an important switch in EMT.^[49]

2. E-cadherin in MET:

The mesenchymal state cancer cells migrate to new sites and may undergo METs in certain favorable microenvironment. For example, the cancer cells can recognize differentiated epithelial cell features in the new sites and upregulate E-cadherin expression. Those cancer cells can form cell-cell adhesions again and return to an epithelial state.^[49]

Cancer examples

• Inactivation of CDH1 (accompany with loss of the wild-type allele) in 56% of lobular breast carcinomas.^[50][51]
• Inactivation of CDH1 in 50% of diffuse gastric carcinomas.^[52]
• Complete loss of E-cadherin protein expression in 84% of lobular breast carcinomas.^[53]

Genetic and epigenetic control of CDH1

Several proteins such as SNAI1/SNAIL,^[54][55] ZFHX1B/SIP1,^[56] SNAI2/SLUG,^[57][58] TWIST1^[59] and DeltaEF1^[60] have been found to downregulate E-cadherin expression. When expression of those transcription factors is altered, transcriptional repressors of E-cadherin were overexpressed in tumor cells.^{[54][55][56][57][59][60]} Another group of genes, such as AML1, p300 and HNF3,^[61] can upregulate the expression of E-cadherin.^[62]

In order to study the epigenetic regulation of E-cadherin, M Lombaerts et al. performed a genome wide expression study on 27 human mammary cell lines. Their results revealed two main clusters that have the fibroblastic or epithelial phenotype, respectively. In close examination, the clusters showing fibroblast phenotypes only have either partial or complete CDH1 promoter methylation, while the clusters with epithelial phenotypes have both wild-type cell lines and cell lines with mutant CDH1 status. The authors also found that EMT can happen in breast cancer cell lines with hypermethylation of CDH1 promoter, but in breast cancer cell lines with a CDH1 mutational inactivation EMT cannot happen. It contradicts the hypothesis that E-cadherin loss is the initial or primary cause for EMT. In conclusion, the results suggest that “E-cadherin transcriptional inactivation is an epi-phenomenon and part of an entire program, with much more severe effects than loss of E-cadherin expression alone”.^[62]

Other studies also show that epigenetic regulation of E-cadherin expression occurs during metastasis. The methylation patterns of the E-cadherin 5’ CpG island are not stable. During metastatic progression of many cases of epithelial tumors, a transient loss of E-cadherin is seen and the heterogeneous loss of E-cadherin expression results from a heterogeneous pattern of promoter region methylation of E-cadherin.^[63]

See also

• Cluster of differentiation

References

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Further reading

• Berx G, Becker KF, Höfler H, van Roy F (1998). "Mutations of the human E-cadherin (CDH1) gene.". Hum. Mutat. 12 (4): 226–37. doi:10.1002/(SICI)1098-1004(1998)12:4<226::AID-HUMU2>3.0.CO;2-D. PMID 9744472.
• Wijnhoven BP, Dinjens WN, Pignatelli M (2000). "E-cadherin-catenin cell-cell adhesion complex and human cancer.". The British journal of surgery 87 (8): 992–1005. doi:10.1046/j.1365-2168.2000.01513.x. PMID 10931041.
• Beavon IR (2000). "The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation.". Eur. J. Cancer 36 (13 Spec No): 1607–20. doi:10.1016/S0959-8049(00)00158-1. PMID 10959047.
• Wilson PD (2001). "Polycystin: new aspects of structure, function, and regulation.". J. Am. Soc. Nephrol. 12 (4): 834–45. PMID 11274246.
• Chun YS, Lindor NM, Smyrk TC; et al. (2001). "Germline E-cadherin gene mutations: is prophylactic total gastrectomy indicated?". Cancer 92 (1): 181–7. doi:10.1002/1097-0142(20010701)92:1<181::AID-CNCR1307>3.0.CO;2-J. PMID 11443625.
• Hazan RB, Qiao R, Keren R; et al. (2004). "Cadherin switch in tumor progression.". Ann. N. Y. Acad. Sci. 1014 (1): 155–63. doi:10.1196/annals.1294.016. PMID 15153430.
• Bryant DM, Stow JL (2005). "The ins and outs of E-cadherin trafficking.". Trends Cell Biol. 14 (8): 427–34. doi:10.1016/j.tcb.2004.07.007. PMID 15308209.
• Wang HD, Ren J, Zhang L (2004). "CDH1 germline mutation in hereditary gastric carcinoma.". World J. Gastroenterol. 10 (21): 3088–93. PMID 15457549.
• Reynolds AB, Carnahan RH (2005). "Regulation of cadherin stability and turnover by p120ctn: implications in disease and cancer.". Semin. Cell Dev. Biol. 15 (6): 657–63. doi:10.1016/j.semcdb.2004.09.003. PMID 15561585.
• Moran CJ, Joyce M, McAnena OJ (2005). "CDH1 associated gastric cancer: a report of a family and review of the literature.". Eur J Surg Oncol 31 (3): 259–64. doi:10.1016/j.ejso.2004.12.010. PMID 15780560.
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External links

• CDH1 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
• GeneReviews/NCBI/NIH/UW entry on Hereditary Diffuse Gastric Cancer

This article incorporates text from the United States National Library of Medicine, which is in the public domain.