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Nectins and nectin-like molecules: roles in contact inhibition of cell movement and proliferation

Nature Reviews Molecular Cell Biology volume 9, pages 603–615 (2008)Cite this article

Key Points

  • Nectins and nectin-like molecules (Necls) have recently emerged as cell adhesion molecules that have a variety of cellular functions, including cell movement, proliferation, differentiation, polarization and survival, as well as cell–cell adhesion.

  • The nectin–afadin complex that localizes at adherens junctions (AJs) has a crucial role in the formation of not only cadherin-based AJs but also claudin-based tight junctions (TJs) in epithelial cells. However, it remains unclear how nectins and afadin participate in the positioning of TJs, which are always formed at the apical side of AJs, in epithelial cells.

  • The activation of integrin αvβ3 and its downstream signalling molecules is necessary for the nectin-induced formation of AJs; in turn, integrin αvβ3 is inactivated by the trans-interaction of nectins after the establishment of AJs, indicating that nectins and integrin αvβ3 are involved in the crosstalk between cell–cell and cell–matrix junctions during the formation of AJs.

  • NECL-5, one of the members of the Necl family, significantly promotes cell movement and proliferation in cooperation with the PDGF receptor and integrin αvβ3, but NECL-5 is downregulated from the cell surface after NECL-5 interacts with nectin-3 at the primordial intercellular adhesion sites. This downregulation reduces cell movement and proliferation, indicating the primary involvement of NECL-5 in the contact inhibition of cell movement and proliferation.

  • The expression of NECL-5 is upregulated in cancer cells and this upregulation is correlated with the increased metastatic ability of cancer cells.

Abstract

Nectins and nectin-like molecules (Necls) are immunoglobulin-like transmembrane cell adhesion molecules that are expressed in various cell types. Homophilic and heterophilic engagements between family members provide cells with molecular tools for intercellular communications. Nectins primarily regulate cell–cell adhesions, whereas Necls are involved in a greater variety of cellular functions. Recent studies have revealed that nectins and NECL-5, in cooperation with integrin αvβ3 and platelet-derived growth factor receptor, are crucial for the mechanisms that underlie contact inhibition of cell movement and proliferation; this has important implications for the development and tissue regeneration of multicellular organisms and the phenotypes of cancer cells.

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Figure 1: Molecular structures and modes of interaction of nectins, Necls and afadin.
Figure 2: Dynamic reorganization of the actin cytoskeleton in the formation of adherens junctions.
Figure 3: Nectin-induced intracellular signalling during and after the formation of adherens junctions.
Figure 4: Leading-edge dynamics regulated by the NECL-5–integrin αvβ3–PDGF receptor complex.
Figure 5: Contact inhibition of cell movement and proliferation by the downregulation of NECL-5 and the inactivation of integrin αvβ3 during adherens-junction formation.

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Acknowledgements

The work presented in this review began at ERATO (Exploratory Research for Advanced Technology of Japan; 1994–1999) and was subsequently performed at the Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine and Faculty of Medicine, Suita, Japan, with the support of grants-in-aid for Scientific Research and for Cancer Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (2000–2008). Many faculty members, including H. Nakanishi, K. Mandai, T. Matozaki, K. Shimizu, K. Irie, T. Sakisaka and N. Fujita, and many graduate students, postdoctoral fellows and collaborators have made great contributions to this work. We thank all of them for their excellent achievements.

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  1. Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan

    Yoshimi Takai, Wataru Ikeda & Hisakazu Ogita

  2. Department of Molecular Biology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, 537-8511, Japan

    Jun Miyoshi

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  1. Yoshimi Takai
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Correspondence to Yoshimi Takai.

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Glossary

Adherens junction

This junction comprises two types of cell adhesions: cell–extracellular matrix and cell–cell. In the context of this article, 'adherens junction' refers to the latter. Adherens junctions contain classical cadherins and catenins that are attached to cytoplasmic actin filaments and mechanically connect two apposing cells.

Tight junction

The most apical intercellular junction, which functions as a selective (semi-permeable) diffusion barrier between individual cells and as a fence to prevent the intermingling of basolateral cell-surface molecules with apical molecules. Tight junctions are identified as a belt-like region in which two lipid-apposing membranes lie close together.

Focal complex

A small (<0.5 μm diameter) immature cell–extracellular matrix junction that is observed at the peripheral region of the leading edge of moving cells.

Focal adhesion

A mature cell–extracellular matrix junction that associates with integrin signalling factors, filamentous-actin-binding proteins and actin stress fibres.

PDZ domain

A protein–protein interaction domain that was first found in postsynaptic density protein-95 (PSD95), Discs-large (DLG) and zona occludens-1 (ZO1).

Small G protein

A monomeric GTP-binding protein with a molecular mass of 20–30 kDa that has intrinsic GTPase activity. It has two interconvertible forms: a GDP-bound inactive form and a GTP-bound active form. The GTP-bound form interacts with and activates several effector proteins that mediate downstream signalling events.

Filopodium

A thin cellular protrusion that is formed by bundle-type reorganization of filamentous actin through the activation of CDC42.

Lamellipodium

A broad and flat cellular protrusion that is formed by meshwork-type reorganization of filamentous actin through the activation of Rac.

Peripheral ruffle

A membrane ruffle that localizes at peripheral regions of the cell, such as the leading edge of moving cells. Membrane ruffles are formed by lamellipodia that have lifted from the substratum along which they previously extended.

SH2 domain

(Src-homology-2 domain). A protein motif that recognizes and binds sequences that have been phosphorylated on Tyr and thereby has a key role in relaying cascades of signal transduction.

Plus-end-tracking protein

A common designation for the proteins that accumulate at the plus end of microtubules.

Clathrin

The main component of the surface of clathrin-coated vesicles, which are involved in membrane transport in the endocytic pathway.

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Takai, Y., Miyoshi, J., Ikeda, W. et al. Nectins and nectin-like molecules: roles in contact inhibition of cell movement and proliferation. Nat Rev Mol Cell Biol 9, 603–615 (2008). https://doi.org/10.1038/nrm2457

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