Adherens Junctions

Abstract

Adherens junctions (AJs) are dynamic structures found in between cells that couple intercellular adhesion to the cytoskeleton thereby creating a transcellular network that coordinates the behaviour of a population of cells. Regulation of AJ formation and maintenance is crucial for cell shape, migration, morphogenesis and tissue homeostasis and repair. AJs not only regulate cell adhesion and cell shape but also form spatial landmarks for a variety of signalling complexes, thereby regulating other cellular functions next to adhesion.

Key concept:

  • AJs are essential for tissue integrity by coupling intercellular adhesion to the cytoskeleton.

  • AJ formation and maintenance requires the cooperative activity of two types of intercellular adhesive receptor complexes, the classical cadherin/catenin and nectin/afadin complexes.

  • Catenins provide cadherin‐mediated adhesion with a dynamic link to the cytoskeleton, regulate cadherin cell surface stability and couple AJs with signal pathways that regulate gene expression.

  • Cadherin‐mediated adhesion and the AJs proteins β‐catenin and p120ctn regulate the Wnt pathway important for cell fate and differentiation decisions.

  • AJs serve as spatially defined signal platforms by recruiting a range of signal transduction proteins. This is not only important for regulation of intercellular adhesive interactions and AJ stability but also allows for communication of cell surface changes to the nucleus.

  • The formation, maintenance and disassembly of AJs are regulated at different levels that involve rapid changes as well as indirect mechanisms that regulate gene expression.

  • The establishment of polarity is closely coupled to the formation of AJs.

  • Classical cadherins are essential for the formation of not only AJs but also desmosomes and tight junctions.

  • Alterations in AJ components directly contribute to human diseases, such as cancer and developmentally related syndromes.

  • AJs and human disease.

Keywords: intercellular junctions; adhesion; cadherins; nectins; Wnt signalling

Figure 1.

Schematic representation of the AJ. AJs consist of two distinct adhesive units: the calcium‐dependent classical cadherin/catenin complex and the calcium‐independent nectin/afadin complexes that both can interact with the actin cytoskeleton.

Figure 2.

Domain structure of the AJ core components. Bars indicate sites of protein interaction. IG, immunoglobulin‐like domain; Dil, dilute domain; EC, cadherin extracellular repeat; PDZ, PSD95/Dlg/ZO‐1 domain; RA, Ras association domain; FHA, Forkhead associated domain; VH, vinculin homology domain and PR, proline‐rich domain.

Figure 3.

Textbook model versus newer model for how the cadherin complex interacts with actin. In the text book model (old) the cadherin complex was directly bound to actin via α‐catenin. Recent data indicate that binding of α‐catenin to either β‐catenin or actin is mutually exclusive, resulting in a much more dynamic view on actin regulation by classical cadherins (new). In this model, actin binding either takes place in the vicinity of AJs through dynamic exchange of α‐catenin and binding is through other actin‐binding proteins that link α‐catenin to actin.

Figure 4.

Different mechanisms regulating AJ formation and maintenance. AJs are regulated on multiple levels ranging from regulation of gene expression, trafficking to posttranslational modification and proteolytic cleavage.

Figure 5.

Cadherins and catenins in the regulation of Wnt signalling. In the absence of Wnt β‐catenin is degraded on phosphorylation by the destruction complex (DC). Wnt binding to its receptors Frizzled inhibits the DC, resulting in accumulation and nuclear translocation of β‐catenin where it binds TCF/LEF transcription factors to activate Wnt‐dependent target genes. The interaction of p120ctn with the transcriptional repressor Kaiso, either in the cytoplasm or nucleus, relieves Kaiso repression of Wnt responsive genes, resulting in enhanced activation. Increased cadherin expression binds more β‐catenin and p120 resulting in a higher threshold for Wnt signalling, whereas loss of E‐cadherin may lower the threshold for Wnt/β‐catenin signalling. Reducing cadherin levels also releases p120 into the cytosol thereby further activating Wnt target genes. In addition, enhanced cadherin‐mediated adhesion promotes the activity of the membrane bound DC complex, reducing β‐catenin signal activity.

close

References

Abe K and Takeichi M (2008) EPLIN mediates linkage of the cadherin catenin complex to F‐actin and stabilizes the circumferential actin belt. Proceedings of the National Academy of Sciences of the USA 105: 13–19.

Alema S and Salvatore AM (2007) p120 catenin and phosphorylation: mechanisms and traits of an unresolved issue. Biochimica et Biophysica Acta 1773: 47–58.

Bertet C, Sulak L and Lecuit T (2004) Myosin‐dependent junction remodelling controls planar cell intercalation and axis elongation. Nature 429: 667–671.

Berx G, Nollet F and van Roy F (1998) Dysregulation of the E‐cadherin/catenin complex by irreversible mutations in human carcinomas. Cell Adhesion and Communication 6: 171–184.

Braga VM and Yap AS (2005) The challenges of abundance: epithelial junctions and small GTPase signalling. Current Opinion in Cell Biology 17: 466–474.

Daniel JM (2007) Dancing in and out of the nucleus: p120(ctn) and the transcription factor Kaiso. Biochimica et Biophysica Acta 1773: 59–68.

Daugherty RL and Gottardi CJ (2007) Phospho‐regulation of beta‐catenin adhesion and signaling functions. Physiology (Bethesda) 22: 303–309.

Dejana E, Tournier‐Lasserve E and Weinstein BM (2009) The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. Developmental Cell 16: 209–221.

Delva E and Kowalczyk AP (2009) Regulation of cadherin trafficking. Traffic 10: 259–267.

Drees F, Pokutta S, Yamada S, Nelson WJ and Weis WI (2005) Alpha‐catenin is a molecular switch that binds E‐cadherin‐beta‐catenin and regulates actin‐filament assembly. Cell 123: 903–915.

Duguay D, Foty RA and Steinberg MS (2003) Cadherin‐mediated cell adhesion and tissue segregation: qualitative and quantitative determinants. Developmental Biology 253: 309–323.

Farquhar MG and Palade GE (1963) Junctional complexes in various epithelia. Journal of Cell Biology 17: 375–412.

Gates J and Peifer M (2005) Can 1000 reviews be wrong? Actin, alpha‐catenin, and adherens junctions. Cell 123: 769–772.

Gumbiner BM (2005) Regulation of cadherin‐mediated adhesion in morphogenesis. Nature Review of Molecular Cell Biology 6: 622–634.

Halbleib JM and Nelson WJ (2006) Cadherins in development: cell adhesion, sorting, and tissue morphogenesis. Genes & Development 20: 3199–3214.

Hay E, Laplantine E, Geoffroy V et al. (2009) N‐cadherin interacts with axin and LRP5 to negatively regulate Wnt/beta‐catenin signaling, osteoblast function, and bone formation. Molecular and Cellular Biology 29: 953–964.

Huber AH and Weis WI (2001) The structure of the beta‐catenin/E‐cadherin complex and the molecular basis of diverse ligand recognition by beta‐catenin. Cell 105: 391–402.

Lai‐Cheong JE, Arita K and McGrath JA (2007) Genetic diseases of junctions. Journal of Investigation and Dermatology 127: 2713–2725.

Le Borgne R, Bellaiche Y and Schweisguth F (2002) Drosophila E‐cadherin regulates the orientation of asymmetric cell division in the sensory organ lineage. Current Biology 12: 95–104.

Lechler T and Fuchs E (2005) Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437: 275–280.

Leckband D and Prakasam A (2006) Mechanism and dynamics of cadherin adhesion. Annual Review of Biomedical Engineering 8: 259–287.

Lorger M and Moelling K (2006) Regulation of epithelial wound closure and intercellular adhesion by interaction of AF6 with actin cytoskeleton. Journal of Cell Science 119: 3385–3398.

MacDonald BT, Tamai K and He X (2009) Wnt/beta‐catenin signaling: components, mechanisms, and diseases. Developmental Cell 17: 9–26.

Maher MT, Flozak AS, Stocker AM, Chenn A and Gottardi CJ (2009) Activity of the beta‐catenin phosphodestruction complex at cell‐cell contacts is enhanced by cadherin‐based adhesion. Journal of Cell Biology 186: 219–228.

McCrea PD and Park JI (2007) Developmental functions of the P120‐catenin sub‐family. Biochimica et Biophysica Acta 1773: 17–33.

McLachlan RW and Yap AS (2007) Not so simple: the complexity of phosphotyrosine signaling at cadherin adhesive contacts. Journal of Molecular Medicine 85: 545–554.

Michels C, Buchta T, Bloch W, Krieg T and Niessen CM (2009) Classical cadherins regulate desmosome formation. Journal of Investigation and Dermatology 129: 2072–2075.

Nejsum LN and Nelson WJ (2009) Epithelial cell surface polarity: the early steps. Frontiers in Bioscience 14: 1088–1098.

Nelson WJ (2003) Adaptation of core mechanisms to generate cell polarity. Nature 422: 766–774.

Nelson WJ (2008) Regulation of cell‐cell adhesion by the cadherin‐catenin complex. Biochemical Society Transactions 36: 149–155.

Nelson WJ and Nusse R (2004) Convergence of Wnt, beta‐catenin, and cadherin pathways. Science 303: 1483–1487.

Niessen CM and Gumbiner BM (2002) Cadherin‐mediated cell sorting not determined by binding or adhesion specificity. Journal of Cell Biology 156: 389–399.

Niessen CM and Gottardi CJ (2008) Molecular components of the adherens junction. Biochimica et Biophysica Acta 1778: 562–571.

Nollet F, Kools P and van Roy F (2000) Phylogenetic analysis of the cadherin superfamily allows identification of six major subfamilies besides several solitary members. Journal of Molecular Biology 299: 551–572.

Pannekoek WJ, Kooistra MR, Zwartkruis FJ and Bos JL (2009) Cell‐cell junction formation: the role of Rap1 and Rap1 guanine nucleotide exchange factors. Biochimica et Biophysica Acta 1788: 790–796.

Peinado H, Olmeda D and Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nature Review. Cancer 7: 415–428.

Perez‐Moreno M, Jamora C and Fuchs E (2003) Sticky business: orchestrating cellular signals at adherens junctions. Cell 112: 535–548.

Perez‐Moreno M, Davis MA, Wong E et al. (2006) p120‐catenin mediates inflammatory responses in the skin. Cell 124: 631–644.

Pokutta S, Drees F, Yamada S, Nelson WJ and Weis WI (2008) Biochemical and structural analysis of alpha‐catenin in cell‐cell contacts. Biochemical Society Transactions 36: 141–147.

Prasad R, Gu Y, Alder H et al. (1993) Cloning of the ALL‐1 fusion partner, the AF‐6 gene, involved in acute myeloid leukemias with the t(6;11) chromosome translocation. Cancer Research 53: 5624–5628.

Reiss K, Ludwig A and Saftig P (2006) Breaking up the tie: disintegrin‐like metalloproteinases as regulators of cell migration in inflammation and invasion. Pharmacological Therapy 111: 985–1006.

Reynolds AB (2007) p120‐catenin: past and present. Biochimica et Biophysica Acta 1773: 2–7.

Rivard N (2009) Phosphatidylinositol 3‐kinase: a key regulator in adherens junction formation and function. Frontiers in Bioscience 14: 510–522.

Sawyer JK, Harris NJ, Slep KC, Gaul U and Peifer M (2009) The Drosophila afadin homologue Canoe regulates linkage of the actin cytoskeleton to adherens junctions during apical constriction. Journal of Cell Biology 186: 57–73.

Scott JA and Yap AS (2006) Cinderella no longer: alpha‐catenin steps out of cadherin's shadow. Journal of Cell Science 119: 4599–4605.

Silvera D, Arju R, Darvishian F et al. (2009) Essential role for eIF4GI overexpression in the pathogenesis of inflammatory breast cancer. Nature Cell Biology 11: 903–908.

Speicher S, Fischer A, Knoblich J and Carmena A (2008) The PDZ protein Canoe regulates the asymmetric division of Drosophila neuroblasts and muscle progenitors. Current Biology 18: 831–837.

Stehbens SJ, Akhmanova A and Yap AS (2009) Microtubules and cadherins: a neglected partnership. Frontiers in Bioscience 14: 3159–3167.

Takai Y, Ikeda W, Ogita H and Rikitake Y (2008) The immunoglobulin‐like cell adhesion molecule nectin and its associated protein afadin. Annual Review of Cell and Developmental Biology 24: 309–342.

Takeichi M (1977) Functional correlation between cell adhesive properties and some cell surface proteins. Journal of Cell Biology 75: 464–474.

Tunggal JA, Helfrich I, Schmitz A et al. (2005) E‐cadherin is essential for in vivo epidermal barrier function by regulating tight junctions. EMBO Journal 24: 1146–1156.

van Hengel J and van Roy F (2007) Diverse functions of p120ctn in tumors. Biochimica et Biophysica Acta 1773: 78–88.

Warzecha CC, Sato TK, Nabet B, Hogenesch JB and Carstens RP (2009) ESRP1 and ESRP2 are epithelial cell‐type‐specific regulators of FGFR2 splicing. Molecualr Cell 33: 591–601.

Wildenberg GA, Dohn MR, Carnahan RH et al. (2006) p120‐catenin and p190RhoGAP regulate cell‐cell adhesion by coordinating antagonism between Rac and Rho. Cell 127: 1027–1039.

Wirtz‐Peitz F and Zallen JA (2009) Junctional trafficking and epithelial morphogenesis. Current Opinion in Genetics & Development 19: 350–356.

Yanagisawa M and Anastasiadis PZ (2006) p120 catenin is essential for mesenchymal cadherin‐mediated regulation of cell motility and invasiveness. Journal of Cell Biology 174: 1087–1096.

Further Reading

Alberts B, Johnson A, Lewis J et al. (2007) Molecular biology of the cell, chapter 19: cell junctions, cell adhesion and the extracellular matrix. Garland Science, 5th edn.

Hartsock A and Nelson WJ (2008) Adherens and tight junctions: structure, function and connections to the actin cytoskeleton. Biochimica et Biophysica Acta 1778: 660–669.

Steinberg M (1996) Adhesion in development: an historical overview. Developmental Biology 180: 377–388.

Sakisaka T, Ikeda W, Ogita H, Fujita N and Takai Y (2007) The roles of nectins in cell adhesions: cooperation with other cell adhesion molecules and growth factor receptors. Current Opinion in Cell Biology 19: 593–602.

Yap AS, Crampton MS and Hardin J (2007) Making and breaking contacts: the cellular biology of cadherin regulation. Current Opinion in Cell Biology 19: 508–514.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Michels, Christian, and Niessen, Carien M(Mar 2010) Adherens Junctions. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020876]