CDH1 (cadherin 1, type 1, E-cadherin (epithelial))

2007-10-01   Marilia de Freitas Calmon , Paula Rahal 

Laboratory of Genomics studies, So Paulo State University, Departament of Biology, So José do Rio Preto, SP, Brasil

Identity

HGNC
LOCATION
16q22.1
LOCUSID
ALIAS
Arc-1,BCDS1,CD324,CDHE,ECAD,LCAM,UVO
FUSION GENES

DNA/RNA

Atlas Image
DNA of CDH1 gene composed of 16 coding exons.

Description

DNA contains 98250 bp composed of 16 coding exons.

Transcription

4828 bp mRNA transcribed in centromeric to telomeric orientation; 2649 bp open reading frame.

Pseudogene

Yes, for example, the repeat sequence named c41-cad is a pseudogene of the cadherin family. c41-cad is localizated on 5q13

Proteins

Atlas Image
Three-dimensional structure of the beta-catenin arm repeat region in complex with the E-cadherin cytoplasmic domain (Huber and Weis, 2001). The arm repeats are formed by three helices, H1 and H2 (both gray) and H3 (blue). Residues 134-161, which include part of the alpha-catenin-binding site and a portion of the first arm repeat, form a single helix in this particular crystal structure (cyan). E-cadherin is divided into five regions of primary structure (1-5) that are indicated in distinct colors (Pokutta S and Weis WI, 2007).

Description

The cadherins are a family of calcium-dependent transmembrane linker proteins; the first three that were discovered were named according to their tissue origin (E-cadherin from epithelium, N-cadherin from neural tissue and P-cadherin from placenta). The mature E-cadherin protein consists of three major domains: a large extracellular portion (exons 4-13), which mediates homophilic cellular interactions; and smaller transmembrane (exons 13-14) and cytoplasmic domains (exons 14-16), the latter providing a link to the actin cytoskeleton through an association with various catenins, such as B-catenin. The protein E-cadherin is a calcium-dependent cell-cell adhesion molecule expressed in adherents junctions between epithelial cells. It is a transmembrane glycoprotein with five extracellular domains that mediate intercellular adhesion through homophilic binding. The cytoplasmatic domain is bound to the actin cytoskeleton via intracellular attachment proteins, the catenins. The actin cytoskeleton forms a transcellular network mediating structural integrity, cellular polarity and epithelial morphogenesis.

Expression

Present tissue specificity for non-neural epithelial tissues and there are high levels in solid tissues.

Localisation

Cell junction; single-pass type I membrane protein. Anchored to actin microfilaments through association with alpha-catenin, beta-catenin and gamma-catenin. Sequential proteolysis induced by apoptosis or calcium influx, results in translocation from sites of cell-cell contact to the cytoplasm.

Function

One of the most important and ubiquitous types of adhesive interactions required for the maintenance of solid tissues is that mediated by the classic cadherin adhesion molecules. Cadherins are transmembrane Ca2+- dependent homophilic adhesion receptors that are well known to play important roles in cell recognition and cell sorting during development. However, they continue to be expressed at high levels in virtually all solid tissues. There are many members of the classic cadherin family (which is a subset of the larger cadherin superfamily), but E-cadherin in epithelial tissues has been the most studied in the context of stable adhesions. Continued expression and functional activity of E-cadherin are required for cells to remain tightly associated in the epithelium, and in its absence the many other cell adhesion and cell junction proteins expressed in epithelial cells (see below) are not capable of supporting intercellular adhesion. In its capacity to maintain the overall state of adhesion between epithelial cells, E-cadherin is thought to act as an important suppressor of epithelial tumor cell invasiveness and metastasis.

Homology

Pan troglodytes - CDH1; Canis lupus familiaris - CDH1; Mus musculus - Cdh1; Rattus norvegicus - Cdh1; Gallus gallus - LOC415860; Danio rerio - cdh1

Mutations

Atlas Image
57 CDH1 mutations have been found to date. 50 of these are listed in Human Gene Mutation Database. Truncating (27) and splice site (7) mutations are found above the Schema (34/45, 76%), missense mutations below it (11/45, 24%). Two marked with an asterisk have been reported as somatic mutations in sporadic diffuse gastric cancer. No Polymorphisms. No Gross deletions/duplications, complex rearrangements, repeat variations been reported. They spread out all over CDH1 gene (Brooks-Wilson et al., 2004).

Germinal

30 CDH1 germline mutations have been described in hereditary diffuse gastric cancer families. 25 have been inactivating (frameshift, nonsense, and splice-site), the remainders are missense. The mutations are distributed equally throughout the gene.

Somatic

Somatically acquired mutations in CDH1 were found in about 56% of lobular breast tumors, generally (>90%) in combination with loss of the wild-type allele, while no mutations were found in ductal primary breast carcinomas. Most of these somatic mutations result in premature stop codons as a consequence of insertions, deletions and nonsense mutations. As the majority of these frameshift and nonsense mutations is predicted to generate secreted E-cadherin fragments, the functionality of this major cell-cell adhesion protein is lost. Other cancer-confined E-cadherin mutations also result in crippled proteins. The distinctive invasive growth pattern, which is typical for lobular breast cancers, is fully compatible with this functional inactivation.

Implicated in

Entity name
Non-small cell lung cancer
Prognosis
Reduced E-cadherin correlates with lymph node metastasis. The rate of vascular invasion was statistically high in cases with the reduced expression of E-cadherin. Reduction of E-cadherin is associated with the degree of differentiation. Bohm et al. found a correlation between differentiation and E-cadherin expression in lung squamous cell carcinoma, and Bongiorno et al. found that well-differentiated lung cancers express E-cadherin, in a preserved fashion, and that poorly differentiated tumors exhibited a reduced or disorganized staining pattern. Sulzer et al. also found that E-cadherin expression significantly correlated with increasing tumor differentiation. In general, undifferentiated or poorly differentiated cancer cells tend to have a strong potential to invade tissues. These results suggest that reduction of E-cadherin correlates with tumor invasion.
Oncogenesis
Reduced E-cadherin expression weakens cell-to-cell attachment, and tumor cells detach from the primary tumor, invade vessels, and migrate to lymph nodes. Once tumor cells reattach to lymph nodes, E-cadherin is strongly expressed, and lymph nodes are subject to metastases.
Entity name
Melanoma
Oncogenesis
The major adhesion mediator between keratinocytes and normal melanocytes is E-cadherin, which disappears during melanoma progression. While normal melanocytes express E-cadherin, this molecule is not found on nevus or melanoma cells. The loss of E-cadherin likely plays a crucial role in tumor progression. Cells that have lost epithelial differentiation, as manifested by the loss of functional E-cadherin, show increased mobility and invasiveness. Keratinocytes can no longer control melanoma cells that have lost E-cadherin. When melanoma cells are forced to express E-cadherin and are cocultured with keratinocytes, they dramatically change: melanomas adhere to keratinocytes, no longer express invasion-related molecules, and lose their invasive capacities
Entity name
Oesophageal adenocarcinoma
Prognosis
Reduction in the expression of E-cadherin in patients with OSCC was shown to be strongly associated with postoperative blood borne recurrence, resulting in a poorer prognosis than in those patients with tumours showing normal expression before surgery. This finding suggested that in patients with reduced E-cadherin immunoreactivity, the metastatic potential of the oesophageal cancer cells may be increased. Therefore, the evaluation of E-cadherin immunoreactivity may be useful in predicting haematogenous spread and hence recurrence, thus serving as an aid for planning adjuvant treatment after surgery in patients with OSCC. It has also been reported that E-cadherin might be an independent predictor of micrometastasis in lymph nodes that are classified as N0 by routine histopathological analysis.

Bibliography

Pubmed IDLast YearTitleAuthors
82876211994Differences of E-cadherin expression levels and patterns in primary and metastatic human lung cancer.Böhm M et al
97444721998Mutations of the human E-cadherin (CDH1) gene.Berx G et al
89345381996E-cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain.Berx G et al
91952321997An efficient and reliable multiplex PCR-SSCP mutation analysis test applied to the human E-cadherin gene.Berx G et al
76014541995Cloning and characterization of the human invasion suppressor gene E-cadherin (CDH1).Berx G et al
115973162001The E-cadherin/catenin complex: an important gatekeeper in breast cancer tumorigenesis and malignant progression.Berx G et al
78190341995E-cadherin expression in primary and metastatic thoracic neoplasms and in Barrett's oesophagus.Bongiorno PF et al
152350212004Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria.Brooks-Wilson AR et al
118795522002E-cadherin and loss of heterozygosity at chromosome 16 in breast carcinogenesis: different genetic pathways in ductal and lobular breast cancer?Cleton-Jansen AM et al
86085881996Cell adhesion: the molecular basis of tissue architecture and morphogenesis.Gumbiner BM et al
111562362000Expression of E-cadherin and beta-catenin in human non-small cell lung cancer and the clinical significance.Kase S et al
157906952005Expression of cell adhesion molecules in oesophageal carcinoma and its prognostic value.Nair KS et al
150479222004Recent advances in melanoma biology.Perlis C et al
175397522007Structure and mechanism of cadherins and catenins in cell-cell contacts.Pokutta S et al
77319681995Expressed cadherin pseudogenes are localized to the critical region of the spinal muscular atrophy gene.Selig S et al
95637561998Reduced E-cadherin expression is associated with increased lymph node metastasis and unfavorable prognosis in non-small cell lung cancer.Sulzer MA et al
152350182004Genetic aetiology of diffuse gastric cancer: so near, yet so far.Sweet KM et al

Other Information

Locus ID:

NCBI: 999
MIM: 192090
HGNC: 1748
Ensembl: ENSG00000039068

Variants:

dbSNP: 999
ClinVar: 999
TCGA: ENSG00000039068
COSMIC: CDH1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000039068ENST00000261769P12830
ENSG00000039068ENST00000261769A0A0U2ZQU7
ENSG00000039068ENST00000422392P12830
ENSG00000039068ENST00000561751J3QKP1
ENSG00000039068ENST00000566510H3BVI7
ENSG00000039068ENST00000566612H3BNC6
ENSG00000039068ENST00000611625A0A087WXI5
ENSG00000039068ENST00000612417A0A087WU43
ENSG00000039068ENST00000621016A0A087WX17

Expression (GTEx)

0
50
100
150

Pathways

PathwaySourceExternal ID
Cell adhesion molecules (CAMs)KEGGko04514
Adherens junctionKEGGko04520
Pathogenic Escherichia coli infectionKEGGko05130
Endometrial cancerKEGGko05213
Thyroid cancerKEGGko05216
MelanomaKEGGko05218
Bladder cancerKEGGko05219
Cell adhesion molecules (CAMs)KEGGhsa04514
Adherens junctionKEGGhsa04520
Pathogenic Escherichia coli infectionKEGGhsa05130
Pathways in cancerKEGGhsa05200
Endometrial cancerKEGGhsa05213
Thyroid cancerKEGGhsa05216
MelanomaKEGGhsa05218
Bladder cancerKEGGhsa05219
Bacterial invasion of epithelial cellsKEGGko05100
Bacterial invasion of epithelial cellsKEGGhsa05100
Hippo signaling pathwayKEGGhsa04390
Hippo signaling pathwayKEGGko04390
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
DiseaseREACTOMER-HSA-1643685
Infectious diseaseREACTOMER-HSA-5663205
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cellREACTOMER-HSA-198933
Signal TransductionREACTOMER-HSA-162582
Signaling by Rho GTPasesREACTOMER-HSA-194315
RHO GTPase EffectorsREACTOMER-HSA-195258
RHO GTPases activate IQGAPsREACTOMER-HSA-5626467
Cell-Cell communicationREACTOMER-HSA-1500931
Cell junction organizationREACTOMER-HSA-446728
Cell-cell junction organizationREACTOMER-HSA-421270
Adherens junctions interactionsREACTOMER-HSA-418990
Extracellular matrix organizationREACTOMER-HSA-1474244
Degradation of the extracellular matrixREACTOMER-HSA-1474228
Integrin cell surface interactionsREACTOMER-HSA-216083
Programmed Cell DeathREACTOMER-HSA-5357801
ApoptosisREACTOMER-HSA-109581
Apoptotic execution phaseREACTOMER-HSA-75153
Apoptotic cleavage of cellular proteinsREACTOMER-HSA-111465
Apoptotic cleavage of cell adhesion proteinsREACTOMER-HSA-351906
Listeria monocytogenes entry into host cellsREACTOMER-HSA-8876384
InlA-mediated entry of Listeria monocytogenes into host cellsREACTOMER-HSA-8876493
Apelin signaling pathwayKEGGhsa04371

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
184112772008The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2.658
184832462008Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways.540
201737402010miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis.489
119121302002The SLUG zinc-finger protein represses E-cadherin in breast cancer.337
195842962009Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer.323
191536692009E-cadherin, beta-catenin, and ZEB1 in malignant progression of cancer.296
190116312008Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer.258
217301312011E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components.230
159585332005ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation.217
126687232003Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail.216

Citation

Marilia de Freitas Calmon ; Paula Rahal

CDH1 (cadherin 1, type 1, E-cadherin (epithelial))

Atlas Genet Cytogenet Oncol Haematol. 2007-10-01

Online version: http://atlasgeneticsoncology.org/gene/166/cdh1id166ch16q22