Adherens Junctions: Keeping us all together under tension

The adherens junction (AJ), with the core cadherin-catenin complex, is an integral system of cell-cell adhesion.

The AJ works to anchor the actin cytoskeleton intracellularly to the plasma membrane while simultaneously linking individual cells through extracellular interactions. The stereotypical epithelial AJ is made of E-cadherin, β-catenin, and αE-catenin¹.

Across different tissues, the types of cadherins and α-catenins which are expressed changes. In cardiac muscle and neurons, you will find N (neuronal)-cadherin. In the placenta, P (placental)-cadherin; in vasculature, VE (vascular endothelium)-cadherin; and in the retina, R (retinal)-cadherin². For α-catenins, again you will find αN (neuronal)-catenin in neurons, and αT (testes)-catenin in the heart and testes^3,4. However, there are multiple cadherin and catenin expression patterns across tissue types, with protein levels at varying degrees.

It has been long suggested that the AJ is the primary way in which cells collectively sense and respond to mechanical stimuli. Work in the last decade has highlighted the mechano-sensing abilities of core AJ components and subsequent cellular and morphological changes ¹. α-catenin is most notable – when under tension the protein undergoes conformational changes that result in the exposure of multiple binding sites. Through this, the AJ can promote reinforcement to the actin cytoskeleton through the recruitment of additional binding partners (e.g., vinculin, α-actinin, afadin), or actin nucleation through the recruitment of Arp2/3 and Ena/VASP) ^3,5. This ability to link cells and respond to mechanical cues is essential for morphogenesis in development and tissue repair after damage.

The core cadherin-catenin complex is essential for development, so therefore any disease-causing mutations must allow for some functionality. In endothelial cells, mutations in ancillary intracellular components of AJs result in cerebral cavernous malformations ⁶. In the intestines, mutations in AJ components are linked to inflammatory bowel disease.

The most notable connections between the AJ and disease and cancer. p120-catenin, which is essential for stabilization and proper trafficking of the cadherin molecule, has been identified as mutated in several cancers including invasive breast cancer, pancreatic cancer, and colorectal cancer. The loss of E-cadherin in carcinoma cells is a hallmark for the onset of invasive and metastatic tumors as the core component holding cells together is down-regulated. Additionally, a transition from E-cadherin to N-cadherin, which is expressed in migratory mesenchymal tissue, is seen in highly invasive cancers as it promotes tumor cell migration ⁹.

Using Kegg Pathway Assessment, we were able to compare known AJ genes against our catalogue of HAP1 and Cancer cell lines. Out of the known 73 genes listed in the Kegg Pathway Assessment (including essential genes), our catalogue of HAP1s + Cancer cell lines has 32 cell lines available. Check out the table below for a list of all genes covered.

References

1. Mège, R. M., & Ishiyama, N. (2017). Integration of cadherin adhesion and cytoskeleton at adherens junctions. Cold Spring Harbor Perspectives in Biology, 9(5). https://doi.org/10.1101/cshperspect.a028738
2. Colman DR, Filbin MT. The Cadherin Family. In: Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.
3. Merkel, C. D., Li, Y., Raza, Q., Stolz, D. B., & Kwiatkowski, A. V. (2019). Vinculin anchors contractile actin to the cardiomyocyte adherens junction. Molecular Biology of the Cell, 30(21), 2639–2650. https://doi.org/10.1091/mbc.e19-04-0216
4. Adam M. Stocker, Anjen Chenn, Differential expression of alpha-E-catenin and alpha-N-catenin in the developing cerebral cortex, Brain Research, Volumes 1073–1074, 2006, Pages 151-158, ISSN 0006-8993, https://doi.org/10.1016/j.brainres.2005.12.057.
5. Diana Pinheiro, Yohanns Bellaïche, Mechanical Force-Driven Adherens Junction Remodeling and Epithelial Dynamics, Developmental Cell, Volume 47, Issue 1, 2018, Pages 3-19, ISSN 1534-5807, https://doi.org/10.1016/j.devcel.2018.09.014.
6. Lampugnani, M. G., Dejana, E., & Giampietro, C. (2017). Vascular endothelial (ve)-cadherin, endothelial adherens junctions, and vascular disease. Cold Spring Harbor Perspectives in Biology, 10(10). https://doi.org/10.1101/cshperspect.a029322
7. Mehta, S., Nijhuis, A., Kumagai, T. et al. Defects in the adherens junction complex (E-cadherin/ β-catenin) in inflammatory bowel disease. Cell Tissue Res 360, 749–760 (2015). https://doi.org/10.1007/s00441-014-1994-6
8. Schackmann, R. C., Tenhagen, M., van de Ven, R. A. H., & Derksen, P. W. B. (2013). P120-catenin in cancer – mechanisms, models and opportunities for intervention. Journal of Cell Science, 126(16), 3515–3525. https://doi.org/10.1242/jcs.134411
9. Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: The next generation. Cell, 144(5), 646–674. https://doi.org/10.1016/j.cell.2011.02.013