Epithelial cadherin precursor - Homo sapiens (Human)

Names and origin

Protein names

Recommended name:
    Epithelial cadherin
      Short name=E-cadherin
Alternative name(s):
    Cadherin-1
    Uvomorulin
    CAM 120/80
    CD_antigen=CD324
Cleaved into the following 3 chains:
    1- Recommended name:
            E-Cad/CTF1
    2- Recommended name:
            E-Cad/CTF2
    3- Recommended name:
            E-Cad/CTF3

Gene names

Name:	CDH1
Synonyms:	CDHE, UVO

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Hide | Top

Protein attributes

Sequence length	882 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

Hide | Top

General annotation (Comments)

Function	Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. CDH1 is involved in mechanisms regulating cell-cell adhesions, mobility and proliferation of epithelial cells. Has a potent invasive suppressor role. It is a ligand for integrin alpha-E/beta-7. E-Cad/CTF2 promotes non-amyloidogenic degradation of Abeta precursors. Has a strong inhibitory effect on APP C99 and C83 production.
Subunit structure	Homodimer; disulfide-linked. Interacts directly, via the cytoplasmic domain, with CTNNB1 or JUP to form the PSEN1/cadherin/catenin adhesion complex which connects to the actin skeleton through the actin binding of alpha-catenin. Interaction with PSEN1, cleaves CDH1 resulting in the disassociation of cadherin-based adherens junctions (CAJs). Interacts with AJAP1, CTNND1 and DLGAP5.
Subcellular location	Cell junction. Cell membrane; Single-pass type I membrane protein. Note= Colocalizes with DLGAP5 at sites of cell-cell contact in intestinal epithelial cells. Anchored to actin microfilaments through association with alpha-, beta- and gamma-catenin. Sequential proteolysis induced by apoptosis or calcium influx, results in translocation from sites of cell-cell contact to the cytoplasm.
Tissue specificity	Non-neural epithelial tissues.
Post-translational modification	During apoptosis or with calcium influx, cleaved by a membrane-bound metalloproteinase (ADAM10), PS1/gamma-secretase and caspase-3 to produce fragments of about 38 kDa (E-CAD/CTF1), 33 kDa (E-CAD/CTF2) and 29 kDa (E-CAD/CTF3), respectively. Processing by the metalloproteinase, induced by calcium influx, causes disruption of cell-cell adhesion and the subsequent release of beta-catenin into the cytoplasm. The residual membrane-tethered cleavage product is rapidly degraded via an intracellular proteolytic pathway. Cleavage by caspase-3 releases the cytoplasmic tail resulting in disintegration of the actin microfilament system. The gamma-secretase-mediated cleavage promotes disaaaembly of adherens junctions.
Involvement in disease	Defects in CDH1 are involved in dysfunction of the cell-cell adhesion system, triggering cancer invasion (gastric, breast, ovary, endometrium and thyroid) and metastasis. Defects in CDH1 are a cause of hereditary diffuse gastric cancer (HDGC) [MIM:137215]. Defects in CDH1 are a cause of susceptibility to endometrial cancer [MIM:608089].
Sequence similarities	Contains 5 cadherin domains.
Sequence caution	The sequence AAA61259.1 differs from that shown. Reason: Frameshift at positions 16, 22, 25, 28, 31, 34, 52, 67, 73, 76, 94, 102, 633 and 636.

Hide | Top

Ontologies

Keywords
Biological process	Cell adhesion
Cellular component	Cell junction Cell membrane Membrane
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Repeat Signal Transmembrane
Ligand	Calcium
PTM	Cleavage on pair of basic residues Glycoprotein Phosphoprotein
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	homophilic cell adhesion Ref.11 Non-traceable author statement. Source: UniProtKB positive regulation of transcription factor import into nucleus Inferred from direct assay. Source: UniProtKB
Cellular component	Golgi apparatus Inferred from direct assay. Source: HPA actin cytoskeleton Inferred from direct assay. Source: UniProtKB cell-cell adherens junction Inferred from direct assay. Source: UniProtKB focal adhesion Inferred from direct assay. Source: HPA integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW lateral plasma membrane Inferred from direct assay. Source: UniProtKB perinuclear region of cytoplasm Inferred from direct assay. Source: UniProtKB
Molecular function	calcium ion binding Inferred from electronic annotation. Source: InterPro cell adhesion molecule binding Non-traceable author statement. Source: UniProtKB transcription activator activity Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Hide | Top

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CTNNB1	P35222	1	EBI-727477,EBI-491549
FGFR1	P11362	1	EBI-727477,EBI-1028277
inlA	P25146	1	EBI-727477,EBI-1035388	From a different organism.
PPP1CA	P62136	2	EBI-727477,EBI-357253
PRKD1	Q15139	3	EBI-727477,EBI-1181072

Hide | Top

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 22

22

Potential

Propeptide

23 – 154

132

Potential

PRO_0000003715

Chain

155 – 882

728

Epithelial cadherin

PRO_0000003716

Chain

701 – 882

182

E-Cad/CTF1

PRO_0000236067

Chain

732 – 882

151

E-Cad/CTF2

PRO_0000236068

Chain

751 – 882

132

E-Cad/CTF3

PRO_0000236069

Regions

Topological domain

155 – 709

555

Extracellular Potential

Transmembrane

710 – 730

21

Potential

Topological domain

731 – 882

152

Cytoplasmic Potential

Domain

155 – 262

108

Cadherin 1

Domain

263 – 375

113

Cadherin 2

Domain

376 – 486

111

Cadherin 3

Domain

487 – 593

107

Cadherin 4

Domain

594 – 697

104

Cadherin 5

Region

758 – 769

12

Required for binding CTNND1 and PSEN1

Region

811 – 882

72

Required for binding alpha, beta and gamma catenins

Compositional bias

838 – 851

14

Ser-rich

Sites

Site

700 – 701

2

Cleavage; by a metalloproteinase

Site

731 – 732

2

Cleavage; by gamma-secretase/PS1

Site

750 – 751

2

Cleavage; by caspase-3

Amino acid modifications

Modified residue

838

1

Phosphoserine By similarity

Modified residue

840

1

Phosphoserine By similarity

Modified residue

846

1

Phosphoserine By similarity

Glycosylation

558

1

N-linked (GlcNAc...) Potential

Glycosylation

637

1

N-linked (GlcNAc...) Potential

Disulfide bond

163

Interchain

Natural variations

Natural variant

123

1

H → Y in diffuse gastric cancer.

VAR_001306

Natural variant

193

1

T → P in diffuse gastric cancer.

VAR_001307

Natural variant

244

1

D → G in HDGC.

VAR_008712

Natural variant

270

1

S → A May contribute to prostate cancer.

VAR_013970

Natural variant

274 – 277

4

Missing in gastric adenocarcinoma.

VAR_001308

Natural variant

282

1

M → I in a breast cancer sample; somatic mutation.

VAR_033026

Natural variant

315

1

N → S in lobular breast carcinoma.

VAR_001309

Natural variant

336

1

E → D

VAR_001310

Natural variant

340

1

T → A in HDGC and colorectal cancer.

VAR_013971

Natural variant

370

1

D → A in diffuse gastric cancer.

VAR_001311

Natural variant

400

1

Missing in gastric carcinoma; loss of heterozygosity.

VAR_001312

Natural variant

418 – 423

6

Missing in gastric carcinoma.

VAR_001313

Natural variant

463

1

E → Q in diffuse gastric cancer.

VAR_001314

Natural variant

470

1

T → I

VAR_001315

Natural variant

473

1

V → D in diffuse gastric cancer.

VAR_001317

Natural variant

478

1

L → P

VAR_023357

Natural variant

487

1

V → A in HDGC.

VAR_008713

Natural variant

592

1

A → T in thyroid cancer; may play a role in colorectal carcinogenesis.

VAR_001318

Natural variant

598

1

R → Q in diffuse gastric cancer.

VAR_001319

Natural variant

617

1

A → T in endometrial cancer; loss of heterozygosity; also found as a polymorphism.

VAR_001320

Natural variant

630

1

L → V: dbSNP rs2276331.

VAR_021868

Natural variant

695

1

C → R: dbSNP rs9282655.

VAR_021869

Natural variant

711

1

L → V in endometrial cancer.

VAR_001321

Natural variant

777

1

D → N in a breast cancer sample; somatic mutation.

VAR_033027

Natural variant

832

1

V → M

VAR_023358

Natural variant

838

1

S → G in ovarian cancer; loss of heterozygosity.

VAR_001322

Natural variant

880

1

E → K

VAR_023359

Experimental info

Mutagenesis

759 – 761

3

GGG → AAA: Binds to CTNNB1 but abolishes formation of the PSEN1/CTNNB1 complex; when associated with CTNNB1 D-431. Abolishes binding PSEN1. Abolishes gamma-secretase cleavage

Sequence conflict

10

1

A → G in AAA61259. Ref.3

Sequence conflict

29

1

H → L in AAA61259. Ref.3

Sequence conflict

47

1

E → R in AAA61259. Ref.3