CDH1 (gene)

Cadherin-1 (not to be confused with the APC/C activator protein CDH1) 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.[5] CDH1 has also been designated as CD324 (cluster of differentiation 324). It is a tumor suppressor gene.[6][7]

CDH1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1O6S, 2O72, 2OMT, 2OMU, 2OMV, 2OMX, 2OMY, 2OMZ, 3FF7, 3FF8, 3L6X, 3L6Y, 4ZT1, 4ZTE
Identifiers
Aliases	CDH1, Arc-1, CD324, CDHE, ECAD, LCAM, UVO, cadherin 1, BCDS1
External IDs	OMIM: 192090 MGI: 88354 HomoloGene: 20917 GeneCards: CDH1
Gene location (Human) Chr. Chromosome 16 (human)[1] Band 16q22.1 Start 68,737,292 bp[1] End 68,835,541 bp[1]
Gene location (Mouse) Chr. Chromosome 8 (mouse)[2] Band 8 D3|8 53.18 cM Start 106,603,351 bp[2] End 106,670,246 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • calcium ion binding • GO:0001948 protein binding • ankyrin binding • gamma-catenin binding • beta-catenin binding • GTPase activating protein binding • metal ion binding • cell adhesion molecule binding • cadherin binding • identical protein binding • cytoskeletal protein binding • protein homodimerization activity Cellular component • apical junction complex • trans-Golgi network • extracellular region • perinuclear region of cytoplasm • cortical actin cytoskeleton • Golgi apparatus • lamellipodium • cytoplasmic side of plasma membrane • endosome • lateral plasma membrane • catenin complex • actin cytoskeleton • flotillin complex • membrane • extracellular exosome • integral component of membrane • cell junction • cytoplasm • cell membrane • cell surface • postsynapse • glutamatergic synapse Biological process • negative regulation of cell-cell adhesion • positive regulation of transcription, DNA-templated • cellular response to lithium ion • cell adhesion • extracellular matrix organization • response to drug • cellular response to indole-3-methanol • extracellular matrix disassembly • synapse assembly • pituitary gland development • response to toxic substance • response to organic substance • neuron projection development • adherens junction organization • homophilic cell adhesion via plasma membrane adhesion molecules • entry of bacterium into host cell • protein localization to plasma membrane • cell-cell adhesion • cell morphogenesis • cell-cell junction assembly • regulation of gene expression • calcium-dependent cell-cell adhesion via plasma membrane cell adhesion molecules • negative regulation of cell migration • positive regulation of protein import into nucleus • cell-cell adhesion mediated by cadherin • regulation of protein catabolic process at postsynapse, modulating synaptic transmission Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	999	12550
Ensembl	ENSG00000039068	ENSMUSG00000000303
UniProt	P12830	P09803
RefSeq (mRNA)	NM_004360 NM_001317184 NM_001317185 NM_001317186	NM_009864
RefSeq (protein)	NP_001304113 NP_001304114 NP_001304115 NP_004351	NP_033994
Location (UCSC)	Chr 16: 68.74 – 68.84 Mb	Chr 8: 106.6 – 106.67 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[8]

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.[9]

Clinical significance

Loss of E-cadherin function or expression has been implicated in cancer progression and metastasis.[10][11] 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.[11] 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.[12]

Interactions

CDH1 (gene) has been shown to interact with

• CBLL1,[13]
• CDC27,[14]
• CDON,[15]
• CDH3,[16]
• C-Met,[17]
• CTNND1,[18][19][20][21][22][23][24][25]
• CTNNB1,[15][17][20][21][23][24][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]
• CTNNA1[20][34][35][36][41]
• FOXM1,[43]
• HDAC1,[44]
• HDAC2,[44]
• IQGAP1,[45]
• FYN,[23]
• NEDD9,[46]
• Plakoglobin,[20][21][47][48][49]
• Vinculin,[21][28]

• PTPmu(PTPRM)[50][51]
• PTPrho(PTPRT)[52]

Cancer

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.[53]

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.[53]

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.[53]

Examples

• Inherited inactivating mutations in CDH1 are associated with Hereditary Diffuse Gastric Cancer. Individuals with this condition have up to a 70% lifetime risk of developing diffuse gastric carcinoma, and females with CDH1 mutations have up to a 60% lifetime risk of developing lobular breast cancer.[54]
• Inactivation of CDH1 (accompany with loss of the wild-type allele) in 56% of lobular breast carcinomas.[55][56]
• Inactivation of CDH1 in 50% of diffuse gastric carcinomas.[57]
• Complete loss of E-cadherin protein expression in 84% of lobular breast carcinomas.[58]

Genetic and epigenetic control

Several proteins such as SNAI1/SNAIL,[59][60] ZFHX1B/SIP1,[61] SNAI2/SLUG,[62][63] TWIST1[64] and DeltaEF1[65] 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.[59][60][61][62][64][65] Another group of genes, such as AML1, p300 and HNF3,[66] can upregulate the expression of E-cadherin.[67]

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”.[67]

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.[68]

See also

• Cluster of differentiation

References

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68. Graff JR, Gabrielson E, Fujii H, Baylin SB, Herman JG (January 2000). "Methylation patterns of the E-cadherin 5' CpG island are unstable and reflect the dynamic, heterogeneous loss of E-cadherin expression during metastatic progression". The Journal of Biological Chemistry. 275 (4): 2727–32. doi:10.1074/jbc.275.4.2727. PMID 10644736.

Further reading

• Berx G, Becker KF, Höfler H, van Roy F (1998). "Mutations of the human E-cadherin (CDH1) gene". Human Mutation. 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 (August 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. hdl:1765/56571. PMID 10931041.
• Beavon IR (August 2000). "The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation". European Journal of Cancer. 36 (13 Spec No): 1607–20. doi:10.1016/S0959-8049(00)00158-1. PMID 10959047.
• Wilson PD (April 2001). "Polycystin: new aspects of structure, function, and regulation". Journal of the American Society of Nephrology. 12 (4): 834–45. PMID 11274246.
• Chun YS, Lindor NM, Smyrk TC, Petersen BT, Burgart LJ, Guilford PJ, Donohue JH (July 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, Badano I, Suyama K (April 2004). "Cadherin switch in tumor progression". Annals of the New York Academy of Sciences. 1014 (1): 155–63. Bibcode:2004NYASA1014..155H. doi:10.1196/annals.1294.016. PMID 15153430.
• Bryant DM, Stow JL (August 2004). "The ins and outs of E-cadherin trafficking". Trends in Cell Biology. 14 (8): 427–34. doi:10.1016/j.tcb.2004.07.007. PMID 15308209.
• Wang HD, Ren J, Zhang L (November 2004). "CDH1 germline mutation in hereditary gastric carcinoma". World Journal of Gastroenterology. 10 (21): 3088–93. doi:10.3748/wjg.v10.i21.3088. PMC 4611247. PMID 15457549.
• Reynolds AB, Carnahan RH (December 2004). "Regulation of cadherin stability and turnover by p120ctn: implications in disease and cancer". Seminars in Cell & Developmental Biology. 15 (6): 657–63. doi:10.1016/j.semcdb.2004.09.003. PMID 15561585.
• Moran CJ, Joyce M, McAnena OJ (April 2005). "CDH1 associated gastric cancer: a report of a family and review of the literature". European Journal of Surgical Oncology. 31 (3): 259–64. doi:10.1016/j.ejso.2004.12.010. PMID 15780560.
• Georgolios A, Batistatou A, Manolopoulos L, Charalabopoulos K (March 2006). "Role and expression patterns of E-cadherin in head and neck squamous cell carcinoma (HNSCC)". Journal of Experimental & Clinical Cancer Research. 25 (1): 5–14. PMID 16761612.
• Renaud-Young M, Gallin WJ (October 2002). "In the first extracellular domain of E-cadherin, heterophilic interactions, but not the conserved His-Ala-Val motif, are required for adhesion". The Journal of Biological Chemistry. 277 (42): 39609–16. doi:10.1074/jbc.M201256200. PMID 12154084.

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
• Human CDH1 genome location and CDH1 gene details page in the UCSC Genome Browser.

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