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Syndecans: proteoglycan regulators of cell-surface microdomains?

Nature Reviews Molecular Cell Biology volume 4, pages 926–938 (2003)Cite this article

Key Points

  • Syndecans are a small family of transmembrane proteoglycans that are widespread in invertebrates and vertebrates. They have an ability to interact with a variety of ligands through their core proteins and heparan-sulphate chains.

  • Recent data indicate that the conserved cytoplasmic domains of syndecans can interact with PDZ (Psd95, Discs large, Zona occludens 1) proteins, signalling molecules and cytoskeletal proteins, strongly indicating that these molecules are more than just co-receptors.

  • These cytoplasmic domains have a unique structural organization that probably facilitates dimer and oligomer formation and is essential for signalling.

  • Examples including dendritic spines, focal adhesions and association with lipid rafts indicate that syndecans might regulate cellular responses in membrane microdomains.

  • While information from invertebrates is still to come, syndecan-knockout mice show deficits not in development, but in tissue repair and response to injury.

  • Syndecan-specific functions will be further uncovered by a combination of structural, glycomic, genetic and cellular biological approaches.

Abstract

Syndecans function as membrane receptors for a bewildering array of ligands through their glycosaminoglycan chains but their precise roles have been hard to pin down. Syndecans have previously been considered as ligand gatherers, working as co-receptors in collaboration with signalling receptors, but their potential to signal independently is now clear. New structural features of syndecan cytoplasmic domains have been described, together with new insights into signalling across the cell membrane that might involve the concentration of ligands in membrane microdomains.

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Figure 1: Syndecan core-domain structure and potential interactions.
Figure 2: Syndecan-4 cytoplasmic domain and its interaction with PtdIns(4,5)P2.
Figure 3: Phosphorylation of syndecan 2.
Figure 4: Syndecan 2, EphB2 receptors and dendritic-spine maturation.
Figure 5: Left–right asymmetery in Xenopus.
Figure 6: A ternary complex of PtdIns(4,5)P2, syndecan 4 and protein kinase Cα.

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Acknowledgements

The author is supported by a Wellcome Trust Programme Grant.

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Authors and Affiliations

  1. Division of Biomedical Sciences, Faculty of Medicine, Imperial College London, Exhibition Road, London, SW7 2AZ, UK

    John R. Couchman

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DATABASES

LocusLink

Dia

Swiss-Prot

CASK

caveolin 1

Cdc42

cortactin

E-cadherin

EphB2

ezrin

fascin

FGF2

Lin2

matrilysin

paxillin

PKCα

PKCδ

PKCγ

RhoA

Src

synbindin

syndecan 1

syndecan 2

syndecan 3

syndecan 4

syntenin

TIMP3

TSP1

Glossary

GLYCOSAMINOGLYCAN

A heteropolysaccharide that contains an N-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1,4- and 1,3-linkages that consist of either N-acetylglucosamine or N-acetylgalactosamine.

EXTRACELLULAR MATRIX

(ECM). A complex, three-dimensional network of very large macromolecules that provides contextual information and an architectural scaffold for cellular adhesion and migration.

GLYCOSYLPHOSPHATIDYL- INOSITOL (GPI)-ANCHOR

Proteins that are anchored to the non-cytoplasmic part of the membrane bilayer solely by a single molecule of glycosylphosphatidylinositol, which is covalently linked to a lipid anchor that is added to the carboxyl terminus in the endoplasmic reticulum.

FOCAL ADHESIONS

Signalling organelles and sites of strong adhesion between cells and their extracellular matrix. They are characterized by integrin–receptor linkages between the actin cytoskeleton and the matrix, and are frequently located at the termini of microfilament bundles.

EPIMERASE

Any enzyme that catalyses the process of converting an epimer into its diastereoisomer by altering the configuration at the epimeric chiral centre.

TYPE-1 MEMBRANE PROTEIN

A single membrane-spanning protein in which the amino terminus is extracellular and the carboxyl terminus is cytoplasmic.

OUTER PLASMA-MEMBRANE LEAFLET

A lipid layer that faces the outside of the cell.

INNER LEAFLET

A lipid layer that faces the inside of the cell.

EPITHELIAL–MESENCHYMAL TRANSITION

The transformation of an epithelial cell into a mesenchymal cell with migratory and invasive properties.

MICROSPIKES

Actin-rich filamentous protrusions from the cell surface that are similar to filopodia.

COS CELLS

Cells from the monkey CV1 cell line that have an integrated SV40 genome lacking an origin of replication. Plasmids with an SV40 origin of replication are replicated to a high copy number when transfected.

GLYCANATION

Covalent substitution of a core protein with one or more glycosaminoglycan chains as part of the biosynthetic process.

DENDRITIC SPINES

Protrusions from neuronal dendrites that form the main postsynaptic compartment for excitatory input.

SH2 DOMAIN

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

GASTRULATION

The morphogenetic movements of the early embryo that lead to the generation of the third embryonic layer — the mesoderm.

DOMINANT-NEGATIVE

A defective protein that retains interaction abilities and so distorts or competes with normal proteins.

ECTODERM

The outer of the three embryonic germ layers, which gives rise to epidermis and neural tissue.

PHORBOL ESTERS

Polycyclic esters that are isolated from croton oil. The most common is phorbol myristoyl acetate (PMA, also known as 12,13-tetradecanoyl phorbol acetate or TPA). They are potent co-carcinogens or tumour promoters because they mimic diacylglycerol, thereby irreversibly activating protein kinase C.

VANADATE

An inorganic phosphatase inhibitor.

LYSOPHOSPHATIDIC ACID

(LPA). Any phosphatidic acid that is deacylated at positions 1 or 2. LPA binds to a G-protein-coupled receptor, which results in the activation of the GTPase Rho and the induction of stress fibres.

CAVEOLA

A specialized raft that contains the protein caveolin and forms a flask-shaped, cholesterol-rich invagination of the plasma membrane that might mediate the uptake of extracellular materials. Caveolae are probably involved in cell signalling.

PDZ DOMAIN

Protein-interaction domain that often occurs in scaffolding proteins and is named after the founding members of this protein family (PSD95 (postsynaptic-density protein of 95kDa), Discs large, Zona occludens 1).

GRANULATION TISSUE

A contractile, myofibroblast-containing tissue formed in wounds.

LIPOPOLYSACCHARIDE

(LPS). A component of the outer membrane of Gram-negative bacteria that is made of a lipid, a core oligosaccharide and an O-linked-sugar side chain.

MACROPHAGE

Cell of the mononuclear phagocyte system that can phagocytose foreign particulate material. Macrophages are present in many tissues and are important for nonspecific immune reactions.

CARRAGEENAN

An inflammatory agent extracted from seaweed that induces localized swelling and pain which peaks three hours after injection. It is used to model inflammatory pain states observed in the clinic.

HYPOXIA

The presence of less-than-normal amounts of dioxygen in a vertebrate or in its blood.

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Couchman, J. Syndecans: proteoglycan regulators of cell-surface microdomains?. Nat Rev Mol Cell Biol 4, 926–938 (2003). https://doi.org/10.1038/nrm1257

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