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Adhesion molecule signalling: not always a sticky business

Nature Reviews Molecular Cell Biology volume 12, pages 189–197 (2011)Cite this article

Subjects

Key Points

  • Cell adhesion molecules (CAMs) of the cadherin and immunoglobulin superfamilies mediate cell–cell adhesion by engaging in homophilic and heterophilic interactions and, therefore, promote the formation and stabilization of adhesive structures.

  • Cell–cell adhesion triggers CAM-mediated signalling, which regulates cytoskeletal dynamics, permeability, cell polarity, contact inhibition of growth and other processes.

  • Besides adhesion-dependent signalling, cadherins and immunoglobulin-like CAMs (Ig-CAMs) are also able to induce signal transduction in the absence of cell–cell adhesion. Such adhesion-independent CAM signalling occurs with different modalities and influences various cellular responses, including migration, proliferation, survival and differentiation.

  • Growth factor receptors represent prominent effectors in adhesion-independent CAM signalling. CAMs can either modulate the receptor response to their cognate ligand or they can act themselves as non-canonical ligands that activate receptor-mediated signalling cascades.

  • The shedding of CAM ectodomains generates biologically active fragments that can stimulate signalling by interacting with cell surface molecules.

  • CAMs also have an important function in gene expression, for example, by regulating the nuclear trafficking of proteins involved in transcription (for example, catenins) or through the nuclear translocation of CAM-derived cytoplasmic fragments that have transcription-modulating properties.

Abstract

The signalling activity of cell adhesion molecules (CAMs) such as cadherins, immunoglobulin-like CAMs or integrins has long been considered to be a direct consequence of their adhesive properties. However, there are physiological and pathological processes that reduce or even abrogate the adhesive properties of CAMs, such as cleavage, conformational changes, mutations and shedding. In some cases these 'adhesion deficient' CAMs still retain signalling properties through their cytoplasmic domains and/or their mutated or truncated extracellular domains. The ability of CAMs to activate signal transduction cascades in the absence of cell adhesion significantly extends their range of biological activities.

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Figure 1: Signalling through cadherins.
Figure 2: Adhesion-dependent signalling of Ig-CAMs.
Figure 3: Modulation of FGFR signalling by NCAM and N-cadherin.
Figure 4: Ectodomain shedding and nuclear function of Ig-CAMs.
Figure 5: Function of the L1 ectodomain and cytoplasmic fragments.

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Acknowledgements

We apologize to all those colleagues whose important work could not be discussed owing to space limitations. We are particularly grateful to F. Orsenigo for his help in preparing the figures of this manuscript. The work is supported by Associazione Italiana Ricerca sul Cancro and AGIMM consortium, the Telethon Foundation, the Italian Ministry of Health, the Association for International Cancer Research, the CARIPLO Foundation and European Community (EUSTROKE, ANGIOSCAFF, OPTISTEM, ENDOSTEM, JUSTBRAIN networks) and Fondation Leducq Transatlantic Network of Excellence.

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  1. Ugo Cavallaro

    Present address: Present address: Molecular Medicine Program, IFOM–IEO Campus, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. ugo.cavallaro@ifom-ieo-campus.it; elisabetta.dejana@ifom-ieo-campus.it,

Authors and Affiliations

  1. Cell Adhesion and Signalling, FIRC Institute of Molecular Oncology (IFOM), Via Adamello 16, 20139, Milan, Italy

    Ugo Cavallaro

  2. Angiogenesis and Vascular Biology, FIRC Institute of Molecular Oncology (IFOM), Via Adamello 16, 20139, Milan, Italy

    Elisabetta Dejana

  3. Department of Biomolecular Sciences and Biotechnologies, School of Sciences, University of Milan, Via Celoria 26, 20133, Milan, Italy

    Elisabetta Dejana

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Glossary

Adherens junction

Protein complex that forms at the boundaries between epithelial or endothelial cells and promotes and stabilizes cell–cell adhesion.

Tight junction

Protein complex (usually apical to adherens junctions) that 'seal' the cell–cell contacts, thus preventing the diffusion of substances across epithelial or endothelial barriers.

Intercellular boundary

The narrow space between two tightly adjacent cells.

Desmosome

Protein complex that forms spot-like adhesive structures that are randomly located along the intercellular boundaries.

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Cavallaro, U., Dejana, E. Adhesion molecule signalling: not always a sticky business. Nat Rev Mol Cell Biol 12, 189–197 (2011). https://doi.org/10.1038/nrm3068

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