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  • Review Article
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Synergistic control of cell adhesion by integrins and syndecans

Key Points

  • Integrins and syndecans are two families of transmembrane matrix receptors that cooperate during cell adhesion to support focal-adhesion formation.

  • The cytoplasmic domain of syndecan-4 includes a unique motif that activates protein kinase Cα (PKCα) by direct association. The link from syndecan-4 to PKCα has the potential to regulate integrin activation, in addition to regulating signals downstream of both receptors.

  • Syndecan-4 regulates both Rac1 and RhoA GTPases through PKCα and, in the case of Rac1, is essential for adhesion-dependent activation. Adhesion-dependent regulation of GTPases has been linked to the determination of directional cell migration.

  • Disruption of either syndecan-1 or syndecan-4 genes compromises wound healing in adult animals without causing any apparent developmental defects. This phenotype suggests that syndecans have specialized roles that are dependent on the ability of cells to migrate efficiently in response to a matrix stimulus.

  • αVβ3 integrin, αVβ5 integrin and α5β1 integrin have crucial roles in the regulation of pathological angiogenesis. The authors propose that syndecans-1 and -4 have the potential to regulate angiogenesis through their synergistic relationships with these integrins and through heparan-sulphate-dependent regulation of growth-factor localization.

  • Transgenic mice that are deficient for syndecan-3 or various β1 integrin heterodimers exhibit defects in neuronal migration. In Drosophila melanogaster, both integrins and syndecan regulate axonal guidance through differential regulation of the Slit–Robo system.

  • The molecular mechanisms underlying integrin–syndecan synergy are becoming increasingly clear, and it is apparent that this is required for efficient directional migration. Accumulating in vivo data suggest that integrin–syndecan synergy might regulate biological processes that rely on the precisely coordinated regulation of directional migration.

Abstract

The ability of cells to adhere to each other and to their surrounding extracellular matrices is essential for a multicellular existence. Adhesion provides physical support for cells, regulates cell positioning and enables microenvironmental sensing. The integrins and the syndecans are two adhesion receptor families that mediate adhesion, but their relative and functional contributions to cell–extracellular matrix interactions remain obscure. Recent advances have highlighted connections between the signalling networks that are controlled by these families of receptors. Here we survey the evidence that synergistic signalling is involved in controlling adhesive function and the regulation of cell behaviour in response to the external environment.

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Figure 1: Domain structures of integrins and syndecans.
Figure 2: Adhesion formation is dependent on engagement of syndecan-4.
Figure 3: Protein kinase signalling depends on synergy between integrin and syndecan-4 and regulates endocytosis.
Figure 4: Adhesion-dependent GTPase signalling depends on synergy between integrin and syndecan-4.
Figure 5: Proposed role of syndecan-1 in the regulation of αVβ3 integrin- and VEGF-dependent vascularization.
Figure 6: Models of the complexity of integrin–syndecan synergy in vivo.

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Proposed role of syndecan-1 in the regulation of αvβ3 integrin- and VEGF-dependent angiogenesis. (PPT 310 kb)

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Glossary

Extracellular matrix

(ECM). A three-dimensional network of glycoproteins and proteoglycans that has a structural role in defining tissue architecture and that provides environmental cues to modulate cell signalling and behaviour.

Receptor crosstalk

When signalling downstream of a receptor results in direct regulation of the function or distribution of a second receptor.

Synergistic signalling

When at least two molecules and/or receptors facilitate the transduction of a common signalling pathway (signalling convergence).

FRET

A technique that allows close proximity between molecules to be visualized by energy transfer between coupled fluorophores.

PDZ domain

A protein–protein association domain that is present in the proteins post-synaptic density-95, disc large tumour suppressor and zonula occuldens-1.

Dynamin

A GTPase that is involved in pinching off membrane vesicles during endocytosis.

Endothelial cell

A specialized epithelial cell that forms a layer that lines the lumen of blood vessels, lymph vessels and the heart.

Directional migration

Cell migration directly towards a chemical gradient or along a fibrillar structure. It is distinct from random migration, in which direction is determined by chance and changes frequently.

Angiogenesis

The growth or sprouting of new blood vessels from a pre-existing vessel network.

Granulation tissue

Fibrous connective tissue that develops in wounds. Granulation tissue comprises fibroblasts, endothelial cells, myofibroblasts, inflammatory cells and provisional extracellular matrix.

Keratinocyte

An epidermal cell that expresses keratins.

Vasculogenesis

De novo formation of blood vessels, primarily during development, from the differentiation of endothelial cell precursors (angioblasts).

Functional synergy

When at least two molecules and/or receptors transduce separate intracellular signals that regulate independent cellular processes, but these processes synergize to modulate the same cellular event in vivo.

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Morgan, M., Humphries, M. & Bass, M. Synergistic control of cell adhesion by integrins and syndecans. Nat Rev Mol Cell Biol 8, 957–969 (2007). https://doi.org/10.1038/nrm2289

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