Fell–Muir Lecture: Heparan sulphate and the art of cell regulation: a polymer chain conducts the protein orchestra

Abstract

SummaryHeparan sulphate (HS) sits at the interface of the cell and the extracellular matrix. It is a member of the glycosaminoglycan family of anionic polysaccharides with unique structural features designed for protein interaction and regulation. Its client proteins include soluble effectors (e.g. growth factors, morphogens, chemokines), membrane receptors and cell adhesion proteins such as fibronectin, fibrillin and various types of collagen. The protein‐binding properties of HS, together with its strategic positioning in the pericellular domain, are indicative of key roles in mediating the flow of regulatory signals between cells and their microenvironment. The control of transmembrane signalling is a fundamental element in the complex biology of HS. It seems likely that, in some way, HS orchestrates diverse signalling pathways to facilitate information processing inside the cell. A dictionary definition of an orchestra is ‘a large group of musicians who play together on various instruments …’ to paraphrase, the HS orchestra is ‘a large group of proteins that play together on various receptors’. HS conducts this orchestra to ensure that proteins hit the right notes on their receptors but, in the manner of a true conductor, does it also set ‘the musical pulse’ and create rhythm and harmony attractive to the cell? This is too big a question to answer but fun to think about as you read this review.

Extracellular matrix component signaling in cancer

“…While many ECM glycoproteins contain heparin (or HS)-binding motifs, so do many collagens, both fibrillary and non-fibrillar, and several enzymes responsible for matrix turnover are also potentially proteoglycan-binding, e.g. MMP2 and 7, ADAM12 and ADAMTS4 [159,[169][170][171][172]. However, the functions of syndecan interaction with metalloproteinases are not yet well understood [173].…”

“…In some cells, such as fibroblasts, CD44 is expressed bearing a single CS/DS chain, while the v3 splice variant contains a motif for HS substitution [192] that allows it to serve as a co-receptor for RTKs, e.g. FGFR [159]. Association of CD44 with LRP6 and Frizzled can enhance Wnt signaling with β-catenin activation and translocation to the nucleus where it functions as a transcription factor [186].…”

Incorporation of heparin-binding proteins into preformed dextran sulfate-chitosan nanoparticles

“…A heparin-binding site or domain in the primary or tertiary structure of the proteins is responsible for heparin binding, which often includes a cluster of positively charged amino acid residues (Lys, Arg, and His) that bind to heparin through electrostatic interaction. 12,13 As DS is an analog of heparin, 11 heparin-binding proteins will likely bind to negatively charged DSCS NPs. Nevertheless, excessive binding could cause NP aggregation owing to charge neutralization.…”

“…11 Proteins that contain a heparin-binding site/ domain are known to have high affinity interactions with heparin or heparan sulfate. 12,13 The authors, therefore, hypothesized that these proteins could be efficiently incorporated into preformed DSCS NPs. There are more than 435 heparinbinding proteins in humans, 14 including many growth factors and cytokines.…”

Gene polymorphisms of fibronectin rs2289202 and fibrillin 2 rs331069 associate with vascular disease, the TAMRISK study

“…HS chains mediate signaling by binding a multitude of growth factors, but also cell adhesion proteins such as fibronectin and fibrillin 2, which are unique in having cell surface integrin-and HS-binding regions (2). An alteration in cross talk between ECM and cells is most likely linked to development of diseases (1).…”