E-CADHERIN

Official Full Name

cadherin 1

Organism

Homo sapiens

GeneID

999

Background

This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised 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 cancer. Loss of function of this gene is thought to contribute to cancer progression 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. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]

Synonyms

CDH1; UVO; CDHE; ECAD; LCAM; Arc-1; BCDS1; CD324;

Clones

Cat.No.	Product Name	Price

Detailed Information

Human-derived E-cadherin is encoded by the CDH1 gene and is currently the most studied member of the cadherin family. Its extracellular domain contains five cadherin repeats (EC1-EC5), one transmembrane domain, and one intracellular domain. Van et al found that the intracellular domain of E-cadherin contains a hyperphosphorylated region that is closely related to the binding of β-catenin, which in turn affects the function of E-cadherin. β-catenin is also able to bind to α-catenin, which is involved in the regulation of cytoskeletal formation including actin. In epithelial cells, the intercellular junction containing E-cadherin is usually adjacent to the cytoskeleton containing actin. Bhatt et al found that E-cadherin is involved in regulating the epithelial formation and maintaining homeostasis, and its primary function is to form adhesive junctions. This effect is critical for the intercellular spaces in different cells of different tissues and the homeostasis of cell interactions.

If E-cadherin expression is decreased, epithelial cells lose their normal polarity and adhesion loss occurs, which changes from epithelial phenotype to interstitial phenotype, ie EMT occurs. The EMT of tumor cells is the basis for their ability to invade and metastasize. If E-cadherin is re-transformed in a cell line lacking E-cadherin, the poorly differentiated state of the cell line can be reversed to regain high adhesion between cells and return to a highly differentiated epithelioid phenotype.

E-cadherin Related Signaling Pathway

E-cadherin plays an important role in the regulation of Wnt signaling pathway, mainly by affecting the activity of β-catenin. The level of β-catenin in the cytoplasm is affected by the binding of E-cadherin to the surface of the cell membrane, which interferes with the adhesion of β-catenin to E-cadherin, and it can affect the level of β-catenin in the cytoplasm and affect the Wnt pathway. E-cadherin-β-catenin-related signaling also affects the regulation of the cellular scaffold signaling network by regulating the activity of small GTPase Rho family members. The Rho small GTPase superfamily includes three members, Rho, Rac, and Cdc42. Among them, Rho helps to maintain the stability of the cell microfilament skeleton or promote cytoskeletal polymerization, increase cell contractility and promote cell migration. Rac is involved in the formation of lamellipodia during cell migration. Cdc42 induces the formation of filopodia, thereby clarifying the direction of cell movement.

Canel et al. found that deletion of the E-cadherin exon 8 reading frame resulted in attenuated Rac1 activation and inhibited Rho activity. In addition to β-catenin, another important molecule of the catenin family, p120, is also closely related to E-cadherin. When p120 binds to the intracellular domain of E-cadherin, it blocks its ubiquitination site, thereby blocking its endocytosis and maintaining tight adhesion between cells and cells. In addition, Leckband et al. found that p120 can also regulate the activity of Rho GTPase by binding to E-cadherin, thereby affecting the structure and motility of the cytoskeleton.

Figure 1. Mediation of cross-talk between signalling pathways by E-cadherin and p120. (Du, et al. 2014)

On the other hand, E-cadherins interact with receptor tyrosine kinases (RTKs), which inhibit the activation of RTKs, which in turn affects RTKs-mediated signaling pathways that are closely related to cellular homeostasis. In particular, studies have reported a two-way interaction between EGFR and E-cadherin: E-cadherin-associated cell adhesion inhibits EGF-dependent EGFR activation; whereas E-cadherin transiently activates EGFR when intercellular junctions are formed. E-cadherin interferes with the EGFR, c-Met, and IGF-1R signaling pathways, primarily uses the interaction of homologous receptors between them to affect the affinity between the ligand and the receptor. E-cadherin binds to EGFR and blocks its downstream signaling pathway, which in turn causes RhoA activation and promotes cell movement.

E-cadherin and Tumor

Numerous studies have shown that E-cadherin is a tumor suppressor, and inhibition of E-cadherin function or expression will lead to cell-to-mesenchymal transition, promoting cell migration, invasion and metastasis. Down-regulation of E-cadherin causes the translocation and spread of the cell basement membrane, promoting early invasive behavior of certain epithelial-derived tumors. Conversely, re-transformation of E-cadherin in cells deficient in E-cadherin reverses the poorly differentiated tumor phenotype of the cell, allowing the cell to return to a low-invasive epithelial-like phenotype and a highly differentiated state of intercellular adhesion. Brouxhon et al. found that the reduction of E-cadherin can activate multiple tumorigenic signaling pathways, including MAPK, PI3K, and NF-κB pathways. These signaling pathways are closely related to multiple physiological processes of cells. The expression or function of E-cadherin can also affect the sensitivity of tumor cells to anti-tumor therapy.

In breast cancer stem cells, E-cadherin is significantly down-regulated, and this change in E-cadherin promotes tumorigenesis and participates in the production of hypoxic resistance. In lung cancer cases, EGFR inhibitor resistance caused by downregulation of E-cadherin is also associated with tumor stem cell-like properties. However, the mechanism by which E-cadherin causes anti-tumor drug resistance remains unclear. The study found that the knockdown of E-cadherin by tumor cells increased the proliferation of cells, which may explain the effect of E-cadherin down-regulation on drug resistance to some extent. In addition, down-regulation of E-cadherin can indirectly activate the PI3K pathway and the NF-κB pathway, which are closely related to tumorigenesis, development, and drug resistance, which may be part of the cause of E-cadherin-induced resistance. More notably, the down-regulation of E-cadherin causes tumor cells to exhibit many tumor stem-like properties, and cancer stem cells tend to be more susceptible to drug resistance.

It is noteworthy that HDAC inhibitors can promote the transcription of E-cadherin, thereby increasing the expression of intracellular E-cadherin. The use of HDAC inhibitors in combination with other anti-tumor drugs is highly feasible for overcoming E-cadherin-induced resistance.

References:

Van, R. F. (2014). Beyond e-cadherin: roles of other cadherin superfamily members in cancer. Nature Reviews Cancer, 14(2), 121.
Bhatt, T., Rizvi, A., Batta, S. P., Kataria, S., & Jamora, C. (2013). Signaling and mechanical roles of e-cadherin. Cell Communication & Adhesion, 20(6), 189-199.
Canel, M., Serrels, A., Frame, M. C., & Brunton, V. G. (2013). E-cadherin–integrin crosstalk in cancer invasion and metastasis. Journal of Cell Science, 126(2), 393-401.
Leckband, D. E., & De, R. J. (2014). Cadherin adhesion and mechanotransduction. Annu Rev Cell Dev Biol, 30(1), 291-315.
Brouxhon, S. M., Kyrkanides, S., Teng, X., Athar, M., Ghazizadeh, S., & Simon, M., et al. (2014). Soluble e-cadherin: a critical oncogene modulating receptor tyrosine kinases, mapk and pi3k/akt/mtor signaling. Oncogene, 33(2), 225.
Shien, K., Toyooka, S., Yamamoto, H., Soh, J., Jida, M., & Thu, K. L., et al. (2013). Acquired resistance to egfr inhibitors is associated with a manifestation of stem cell-like properties in cancer cells. Cancer Research, 73(10), 3051-3061.
Du, W., Liu, X., Fan, G., Zhao, X., Sun, Y., & Wang, T., et al. (2014). From cell membrane to the nucleus: an emerging role of e-cadherin in gene transcriptional regulation. Journal of Cellular & Molecular Medicine, 18(9), 1712-9.

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