Fell‐Muir Lecture: Syndecans: from peripheral coreceptors to mainstream regulators of cell behaviour

Abstract

SUMMARYIn the 25 years, as the first of the syndecan family was cloned, interest in these transmembrane proteoglycans has steadily increased. While four distinct members are present in mammals, one is present in invertebrates, including C. elegans that is such a powerful genetic model. The syndecans, therefore, have a long evolutionary history, indicative of important roles. However, these roles have been elusive. The knockout in the worm has a developmental neuronal phenotype, while knockouts of the syndecans in the mouse are mild and mostly limited to post-natal rather than developmental effects. Moreover, their association with high-affinity receptors, such as integrins, growth factor receptors, frizzled and slit/robo, have led to the notion that syndecans are coreceptors, with minor roles. Given that their heparan sulphate chains can gather many different protein ligands, this gave credence to views that the importance of syndecans lay with their ability to concentrate ligands and that only the extracellular polysaccharide was of significance. Syndecans are increasingly identified with roles in the pathogenesis of many diseases, including tumour progression, vascular disease, arthritis and inflammation. This has provided impetus to understanding syndecan roles in more detail. It emerges that while the cytoplasmic domains of syndecans are small, they have clear interactive capabilities, most notably with the actin cytoskeleton. Moreover, through the binding and activation of signalling molecules, it is likely that syndecans are important receptors in their own right. Here, an overview of syndecan structure and function is provided, with some prospects for the future.

Transmembrane Protein 184A Is a Receptor Required for Vascular Smooth Muscle Cell Responses to Heparin

“…Their protein cores can be type I transmembrane proteins linked to the actin cytoskeleton with matrix metalloproteinase-sensitive domains (which allow shedding of soluble ectodomains carrying HS chains), glycosylphosphatidylinositol-linked proteins requiring association with other membrane components to signal to the inside of the cell, or extracellular matrix proteins, which must link to the membrane through the HS chains and/or the protein core (reviewed in Ref. 39). The possibility that each of these HSPGs could also function through interactions between the HS chains and the heparin receptor, in cell types where it is expressed, significantly increases the possible mechanisms by which HSPGs can function.…”

Extracellular matrix component signaling in cancer

“…In the case of fibrillin-1 and fibronectin, heparin-binding and integrin-binding motifs are separate yet adjacent [160,163,164] allowing ternary complexes of syndecan, integrin and ECM molecule to form, although integrins themselves are not heparin-binding. This is best characterised with respect to fibronectin, where the crystal structures of the integrin-binding site in repeat III 10 and the HepII domain (repeats III [12][13][14] ) have been solved [165,166] and the receptor binding and cell adhesion events associated with them have been well characterised [164][165][166][167][168]. These ternary complexes may be involved in cell-ECM junction assembly (e.g.…”

“…shown to be co-receptors with DDR proteins, they have been associated with integrins in many cases [168]. In epithelial cells, syndecan-1 has been reported to interact directly with αvβ3 and αvβ5…”

Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: mechanisms and mysteries

“…One of the key functions of HSPGs stemming from this unique feature is their ability to interact with numerous proteins bearing a reciprocally charged HS-binding domain (HBD). The HS-binding proteins include plasma proteins, extracellular matrix components, cell surface proteins, and members of the major growth factor and signaling protein families including Wnt, hedgehog, bone morphogenetic protein, fibroblast growth factor and vascular endothelial growth factor families ( 9,10,11 ). The protein-HS interactions are very important and serve multiple functions including: modulating protein function and distribution; limiting protein range of action on target cells; stabilizing proteins and protect them from degradation; setting up morphogen protein gradients during development and growth; and presenting specific proteins to their cognate receptors for activation of signaling ( 2, 3 ).…”