E-cadherin signaling
Introduction on Cadherins
Cadherins, which is a cell surface molecules were originally identified in Chinese hamster V79 cells by Takeichi. These adhesion proteins are involved in Ca2+-dependent cell–cell adhesion as well as modulating crucial morphogenetic and differentiation processes during development. Cadherins are Ca2+ sensitive proteins and are readily degraded by proteolysis in the absence of Ca2+. It is one of the best studied classical family of cadherins which has a primary structure of 723 to 748 amino acids, similar in different cadherins [1]. When cells contact each other, Cadherins form trans- bonds at the site of contact between the opposing cells located at the site. Once the cells form trans-bonds, cadherins can regulate the formation of the cell–cell contact in three distinct ways: by reducing the local interfacial tension directly through adhesion tension and indirectly through signaling to the actomyosin cytoskeleton, and by establishing the mechanical coupling of contacting cells [2].
What is E-cadherin?
The human epithelial cadherin (E-cadherin) is a classical calcium- dependent cellular adhesion protein which is a type of cell surface transmembrane glycoprotein in epithelial tissue[3]. The protein structure consisting of five extracellular cadherin repeats, a transmembrane region, and a highly conserved cytoplasmic tail [4], which interacts with several proteins collectively termed catenins [5]. E-cadherin plays an important role in the maintenance of the cellular adhesion and adherent junction in normal tissues. It is also been reported to participates in signaling pathways and can suppress tumor metastasis. Studies have shown that loss of E-cadherin function or expression has been implicated in epithelial-mesenchymal transition (EMT), which characterizes the transition from benign lesions to invasive and metastatic cancer [6].
Role of E-cadherin
E-cadherin has a significant role in formation and maintenance of cell- cell adhesion in epithelial tissues. Expression of E-cadherin starts very early, at two-cell stage in embryonic development. E-cadherin plays an important role in providing an early embryo to compact and helps the adhesion of the blastomeres. The function of E-cadherins lies primarily in the formation of adherens junctions [6].
The most important exhibit of E-cadherin’s function in development is its role in controlled epithelial- mesenchymal conversion [6]. E-cadherin modulate various signaling pathways which is important in maintaining the epithelial phenotype and regulating homeostasis of tissues [1].
Role of E-cadherin in cancer
E-cadherin is one of a potent tumor suppressor because down-regulation of E-cadherin is often found in malignant epithelial cancers [1]. It has been found that the E-cadherin gene is highly conserved and can play a major role in malignant cell transformation, and especially in tumor development and progression. E-cadherin adhesion stabilize the normal epithelial tissues and prevent apoptosis, but the tumor cells are resistance to apoptosis. Even tumor cells when detach from their adhesions are resistant to apoptosis. It is because of down-regulation of E-cadherins. However, tumor cells may regain their sensitivity to apoptosis when treated with E-cadherin activating mAbs. Apoptosis is induced in tumor by activating mAbs is due to their effects on adhesion or on one of the signaling pathways regulated by E-cadherin, including the hippo signaling pathway, the Wnt pathway, the small GTPases, Rac and Rho, or PI3Kinase signaling [9].
Disturbance of E-cadherin expression in different cancer
The reduced expression of E-cadherin has been reported in various cancers such as esophageal cancer, head and neck squamous, non-small cell lung cancer, invasive breast carcinoma as well as cervical cancer. Studies of E-cadherins in those caners explored the prognostic value of the down-regulation of E-cadherin protein, i.e., survival time and survival probability in confirmed cancer patients. Researches have been focusing on elucidating the role of E-cadherins in cancer diagnoisis. However, identification of E-cadherin as a biomarker in the early diagnosis and screening of precancerous lesions has yet to be thoroughly evaluated [6]. E-cadherin is expressed in normal adults in luminal epithelial cells of breast [5]. Moreover, in breast cancer cells, there is partial or total loss of E-cadherin expression which correlates with loss of differentiation characteristics, acquisition of invasiveness, increased tumor grade, metastatic behavior and poor prognoses [5].
Role of E-cadherin in signaling
Various catenins (α, β, and p120) are associated with cytoplasmic tail of E-cadherins to the cytoskeleton and mediate down-stream signaling effects. Some of the identified signaling pathways that linked to E-cadherins include the Hippo, Wnt, TGFβ, NF-κB, and other growth factor signaling pathways [7]. E-cadherin mediated cell signaling pathways is a considered as dynamic process which is regulated by several other signal transduction pathways. It is worth noted that E-cadherins are not only targets for signaling pathways that regulate adhesion, but may themselves transduce signals that regulate basic cellular processes, such as migration, proliferation, apoptosis and cell differentiation [6]. β-catenin encoded by CTNNB1 gene which is considered as a proto-oncogene. Mutations in CTNNB1 gene resulted in cancer due to damage in N-terminal region of β-catenin, β:TrCP binding motif. Damage to this binding motif disables ubiquitination and degradation of β-catenin [8].
Role of E-cadherin in Wnt signaling
E-cadherin/β-catenin complex mediateted signaling plays a central role in the Wnt signaling pathway. β-catenin is inactive in the cytoplasm by binding to the APC/GSK3β/Axin/CK1 degradation complex unless Wnt signal is activated. For Wnt pathway, β-catenin is considered the prime signal transducer. Wnt signaling phosphorylates the GSK3β which inhibits the E-cadherin/β-catenin complex and prevent the degradation process [3]. Activation of Wnt pathway causes translocation of intact β-catenin to the nucleus, where, together with the lymphoid enhancer factor (LEF)/T-cell factor (TCF), it activates a variety of transcription factors, resulting in positive or negative regulation by TCF/β-catenin. Therefore, tyrosine phosphorylation of β-catenin leads to beta-catenin signaling activation (and transcriptional impact), whereas β-catenin degradation inhibition in the presence of Wnt signaling is an inactivating mechanism [8].
Conclusion:
E-cadherin is an important cellular adhesion protein which can regulate cellular response generated by external signals the cell receives. It can regulate migration, proliferation, apoptosis and cell differentiation. E-cadherin is also regarded as a tumor suppressor gene. Reduced expression of E-cadherins can cause dysfunction of the cell- cell adhesion system, triggering cancer invasion and metastasis. Therefore, E-cadherin has elucidated insights into both embryogenesis and oncogenesis.
References
[1] C. Y. Loh et al., The e-cadherin and n-cadherin switch in epithelial-to-mesenchymal transition: Signaling, therapeutic implications, and challenges, vol. 8, no. 10. 2019.
[2] J. L. Maître and C. P. Heisenberg, “Three functions of cadherins in cell adhesion,” Curr. Biol., vol. 23, no. 14, pp. 626–633, 2013.
[3] H. Zhao et al., “Overview on the Role of E-Cadherin in Gastric Cancer: Dysregulation and Clinical Implications,” Front. Mol. Biosci., vol. 8, no. July, pp. 1–11, 2021.
[4] X. Ma et al., “Meta-analysis of downregulated E-cadherin as a diagnostic biomarker for cervical cancer,” Arch. Gynecol. Obstet., no. 99, 2022.
[5] G. Berx and F. Van Roy, “The E-cadherin/catenin complex: An important gatekeeper in breast cancer tumorigenesis and malignant progression,” Breast Cancer Res., vol. 3, no. 5, pp. 289–293, 2001.
[6] N. Pećina-Šlaus, “Tumor suppressor gene E-cadherin and its role in normal and malignant cells,” Cancer Cell Int., vol. 3, pp. 1–7, 2003.
[7] A. M. Mendonsa, T. Y. Na, and B. M. Gumbiner, “E-cadherin in contact inhibition and cancer,” Oncogene, vol. 37, no. 35, pp. 4769–4780, 2018.
[8] I. Kaszak, O. Witkowska-piłaszewicz, Z. Niewiadomska, F. N. Toka, and P. Jurka, “Role of Cadherins in Cancer — A Review,” pp. 1–17.