Cadherin-1 (cadherin-E) is a specific calcium ion-dependent cell adhesion molecule. E-cadherin is simultaneously a major cell-adhesion molecule, a tumour suppressor protein, a determinant of cell polarity and a partner to the potent catenin signalling molecules.

During E-cadherin intracellular trafficking, E-cadherin is trafficked to and from the cell surface by exocytic and multiple endocytic pathways. A complex vesicle-trafficking machinery is responsible for the sorting, transport, actin association and vesicle targeting of E-cadherin to regulate its movement and function during growth and development and, possibly, in cancer.

Function

 cell-cell adhesion

Epithelial-cadherin molecules (CDH1) that are expressed on the plasma membranes of adjacent cells probably interact in a zipper-like fashion. The most amino-terminal cadherin (CAD) domain on each E-cadherin molecule contains the histidine-alanine-valine (HAV) motif that is thought to interact with E-cadherin molecules of adjacent cells.

Cadherin molecules interact through their tips in cis and in trans in a highly flexible manner. The cytoplasmic cell-adhesion complex (CCC), consisting of -catenin, -catenin, -catenin (plakoglobin) and p120-catenin, links E-cadherin homodimers to the actin cytoskeleton.

Neural cell-adhesion molecule (NCAM), a member of the immunoglobulin (Ig)-like CAM superfamily, interacts through its first two Ig-like domains in a homophilic manner with NCAM molecules on neighbouring cells.

Different NCAM isoforms exist, which are either linked to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor (NCAM120) or have transmembrane and cytoplasmic domains (NCAM140 and NCAM180).

NCAM140 can associate through its cytoplasmic domain with the SRC family kinase FYN. NCAM also interacts with components of the extracellular matrix (ECM). The various isoforms of NCAM are differentially polysialylated, a post-translational modification that modulates their adhesive functions.

Pathology

 reduced expression of E-cadherin in cancer invasion and metastasis trigger. E-cadherin-mediated cell-cell adhesion is lost during the development of most epithelial cancers.

 somatic mutations in

• endometrial carcinoma
• ovarian carcinoma
• mammary lobular carcinoma

 constitutional mutations in autosomal dominant familial gastric cancer (MIM.137215)

• with cleft palate (#15831593#)

 constitutional mutations in susceptibility to Listeria monocytogenes

Pathogeny

 Loss of E-cadherin in tumorigenesis

Most human cancers originate from epithelial tissue. E-cadherin (CDH1) is the prototype member of the classical cadherin family. CDH1 is the key player in inducing cell polarity and organizing an epithelium. In most cancers of epithelial origin, E-cadherin-mediated cell-cell adhesion is lost concomitantly with progression towards tumour malignancy. Although E-cadherin expression can still be found in differentiated tumours in patients, there is an inverse correlation between E-cadherin levels, tumour grade and patient mortality rates.

The loss of E-cadherin function during tumour progression can be caused by various genetic or epigenetic mechanisms.

 CDH1 mutations

In patients with diffuse gastric cancer and lobular breast cancer, and at a lower incidence in thyroid, bladder and gynaecological cancers, the E-cadherin gene is mutated, leading to the expression of a non-functional protein. Such mutations have also been found in families that are predisposed to the development of diffuse gastric cancer.

 downregulation of CDH1 expression

E-cadherin expression can be downregulated at the transcriptional level. The zinc-finger-containing proteins Snail, Slug and SIP1, and the helix-loop-helix transcription factor E12/E47 are important transcriptional repressors that bind to E2 boxes in the promoter of the E-cadherin gene and actively repress its expression.

Interestingly, MTA3, a recently identified component of the Mi-2/NuRD transcriptional co-represssor complex, links Snail expression to oestrogen-receptor (ER) activity: ER signalling upregulates MTA3 to repress Snail expression.

In turn, the lack of Snail allows unimpeded E-cadherin expression, so preventing tumour invasion. This connection might be one of the several mechanisms linking positive ER status with good prognosis in patients with breast cancer.

As a direct consequence of transcriptional inactivation, the E-cadherin gene locus is epigenetically silenced by hypermethylation, leading to further downregulation of E-cadherin expression. For example, the E-cadherin promoter is hypermethylated in 83% of thyroid carcinomas and at comparably high levels in many other cancer types.

Proteolytic degradation of E-cadherin by matrix metalloproteases (MMPs)

Proteolytic degradation of E-cadherin by matrix metalloproteases (MMPs) is another mechanism by which E-cadherin-mediated cell-cell adhesion can be ablated.

A soluble 80-kDa form of E-cadherin, produced by the degradation of the full-length protein, is frequently found in cultured tumour cell lines and in tumour biopsy samples.

This soluble form of E-cadherin promotes tumour-cell invasion by upregulating MMPs, such as MMP2, MMP9 and MMP. Such ectodomain shedding of E-cadherin might have an active part in the invasive process during tumour progression.

A novel transmembrane protein, dysadherin, interferes with E-cadherin function by downregulating its protein levels, without affecting messenger RNA levels, and it induces the metastatic spread of tumour cells in xenograft transplantation experiments.

 tyrosine phosphorylation

Tyrosine phosphorylation has been previously implicated in the regulation of cadherin function: receptor tyrosine kinases (RTKs), which are frequently activated in cancer cells), such as epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (MET) and fibroblast growth-factor receptor (FGFR), and the non-RTK SRC, phosphorylate E-cadherin, neuronal (N)-cadherin, beta-catenin (CTTN1), gamma-catenin (JUP) and p120-catenin (CTNND1), resulting in the disassembly of the CCC and, with it, the disruption of cadherin-mediated cell-cell adhesion.

References

 Cavallaro U, Christofori G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer. 2004 Feb;4(2):118-32. PMID: #14964308#

 Bryant DM, Stow JL. The ins and outs of E-cadherin trafficking. Trends Cell Biol. 2004 Aug;14(8):427-34. PMID: #15308209#

 Furukawa F, Fujii K, Horiguchi Y, Matsuyoshi N, Fujita M, Toda K, Imamura S, Wakita H, Shirahama S, Takigawa M. Roles of E- and P-cadherin in the human skin. Microsc Res Tech. 1997 Aug 15;38(4):343-52. PMID: #9297684#