Author : Binod G C
E-cadherin is one of the members of cadherin superfamily. Classical cadherins are transmembrane glycoproteins that mediate cell-cell adhesion in a calcium dependent manner. Cadherin plays a central role in cell patterning during development and maintaining tissue architecture in mature organism. E-cadherin is a type I cadherin molecule that is involved in maintenance of stable cell-cell adhesion in epithelial tissues and is found at adheren junction. It is one of the best characterized classical cadherins that plays important roles in the formation of tissues during gastrulation, neurulation and organogenesis(Barth, Näthke, & Nelson, 1997). It’s importance in epithelial development and maintenance of epithelial polarity was first identified in chicken(Gallin, Sorkin, Edelman, & Cunningham, 1987). The loss of e-cadherin is one of the molecular events in metastasis that leads to disruption adheren junction making the tumor cell more invasive.
The human epithelial (E) cadherin gene, CDH1, is located on chromosome 16q22.1 and encodes the 120 kDa glycoprotein. The mature e-cadherin consists of highly conserved carboxy terminal domain, a single pass transmembrane domain and an extracellular domain(Berx et al., 1995).
The extracellular domain consists of five tandem sub domain repeats(EC1-EC5) that bind calcium. The distal subdomain(EC1) contains a histidine-alanine-valine sequence(HAV). Binding of calcium causes a conformational change in the HAV structure that allows E-cadherin to form a ‘zipper’ between neighbouring cells(Van Roy & Berx, 2008). The cytoplasmic domain of the E-cadherin interacts with actin via protein complex made up of alpha catenin and either beta or gama catenins. The cytoplasmic domain has two sub-domains: the juxtramembrane region and the catenin binding region. These regions are functionally active and supports cadherin clustering and adhesive strength(Van Roy & Berx, 2008). In short N terminal of the extracellular domains of dimer interacts with similar E-cadherin dimers from the neighboring cell and the c-terminal ends of cytoplasmic domains are linked with catenin and the actin cytoskeleton. Now a days, it has been suggested that E-cadherin interacts with other components of the complex cell adhesion system and the dynamic interaction of E-cadherin with the cytoskeleton proteins allows it to regulate the signaling pathways that controls the epithelial cell behavior (Weber, Bjerke, & DeSimone, 2011).
E-cadherin expression is highly regulated in both physiological and pathological processes such as tumorigenesis and embryonic morphogenesis. It is expressed early in embryonic development. E-cadherin is primarily involved in the formation of adheren junction. Adhesive contacts between cells is necessary for forming a highly organized tissues. These contacts ensure effective intracellular communication by facilitating the cross-talks between molecular components of the cell membrane and intracellular pathways. Apart from forming adheren junction, it maintains the tissue plasticity during development by regulating epithelial-mesenchymal transition (Thiery, 2002).Beside this E-cadherin also maintains the homeostasis and the integrity of adult epithelial tissue. There are several evidence that cadherins are not only targets for signaling pathways that controls adhesion, but may themselves act as a signaling center that regulates cellular processes like proliferation, apoptosis and cell differentiation(Van Roy & Berx, 2008).
Recent studies have shown that it is tightly linked to key signaling transduction networks such a s Wnt/β catenin, NF-κB, GTPase and receptor tyrosine kinase(RTK). E-cadherin and Wnt/β catenin signaling pathway both share a key component catenin. In response to WNT signaling, cytoplasmic beta-catenin is stabilized in the cytoplasm and translocated to the nucleus, where it interacts with a transcription factor LEF/TCF (T cell factor-lymphoid enhancer factor). Wnt signaling activation represses the expression of E-cadherin in a TCF/β catenin dependent manner and e-cadherin gene promoter contains TCF/β catenin binding sites suggesting feedback circuit between these two signaling pathways(Jamora, DasGupta, Kocieniewski, & Fuchs, 2003). In addition to E-cadherin also regulate the activity of various RTKs. It has been found that generally E-cadherin interacts with EGFR and either activates or inhibits the EGFR mediated downstream signaling pathways like MAPK and PI3/AKt pathway. For example, it activates the EGFR mediated MAPK signaling in mammary cells whilst it inhibits the MPAK signaling in normal human urothelial cell (Fedor-Chaiken et al. 2003) . Also in most cases, E-cadherin negatively regulates NF-κB activation. Studies showed that the overexpression of E-cadherin suppresses the NF-κB signaling while the loss of E-cadherin and the loss of cadherin mediated cell–cell contacts activates it (Cowell et al., 2009; Kuphal, Poser, Jobin, Hellerbrand, & Bosserhoff, 2004).Studies have also shown that E-cadherin regulates transcription by regulating GTPase signaling activity(Kim, Li, & Sacks, 2000). Thus, e-cadherin also acts as a gene transcriptional regulator.
E-cadherin expression is highly regulated in the normal cells. Conversely, E-cadherin is deregulated in the cancer. Loss of E-cadherin is associated with the malignant transformation and tumor progression. Malignant carcinoma cells are characterized by poor intercellular adhesion, aberrant adhesion mediated signaling, loss of differentiated epithelial morphology and increased cellular motility. In tumor cells, disruption of adheren junction enhances the ability of the tumor cell to migrate and proliferate making it more invasive. E-cadherin plays an important role in regulating the invasion and metastasis by promoting homotypic cell-cell adhesion. Thus, E-cadherin acts as a tumor suppressor gene. Studies have shown that there is downregulation of E-cadherin in several tumors including stomach, colon, pancreas, liver and prostate(Guilford, 1999). E-cadherin expression or its cell surface localization is often lost in advanced tumors and has been linked to a higher incidence of metastasis(Van Roy & Berx, 2008).Numerous mechanism effects the adheren junctions in tumor cells. Studies have shown that the disruption of junction mainly happens due to reduction of E-cadherin expression, reduced transcription of genes encoding catenin proteins, redistribution of E-cadherin to different sites within the cell, shedding of E-cadherin, cleavage of E-cadherin and competition of proteins for binding sites on E-cadherin(Cavallaro & Christofori, 2004). Mutations in CDH1 has been found in numerous cancers including breast, stomach, endometrium, ovary and thyroid. However, the exact mechanism of downregulation of E-cadherin in the tumor is still under investigation. There are several reports that has shown that e-cadherin loss is mainly subjected to methylation of its promoter, or upregulation of the transcriptional repressors such as Snail, SLUG, Zeb1 that targets the e-cadherin promoter(Van Roy & Berx, 2008) .
In summary, E-cadherin is involved in multiple aspects of tissue morphogenesis which includes cell-cell adhesion, maintenance of structural and functional cell and tissue polarity. During development E-cadherin plays an important role in sustaining tissue plasticity by regulating the epithelial mesenchymal conversion. The Loss of E-cadherin is one of the key molecular event in the epithelial-mesenchymal transition(EMT) during tumorigenesis.
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