Trends in Cell Biology
Volume 11, Issue 2, 1 February 2001, Pages 75-82
Journal home page for Trends in Cell Biology

Review
Heparan sulfate: decoding a dynamic multifunctional cell regulator

https://doi.org/10.1016/S0962-8924(00)01897-3Get rights and content

Abstract

The heparan sulfates are a family of cell-surface and matrix polysaccharides with an incredible degree of structural diversity that are distributed widely in virtually all metazoan organisms. Recent genetic, biochemical and cell-biological studies have led to increased understanding of the biosynthetic mechanisms that produce these complex molecules, as well as their functional versatility in regulating protein activities. The dynamic expression of heparan sulfates with differing sugar sequences suggests a new concept in which the repertoire of sequences produced by a particular cell or tissue is designated its ‘heparanome’. This review discusses recent developments and surveys emerging experimental strategies that hold promise for revealing the functional specificity and mechanisms of action of heparan sulfates as multifunctional cell regulators.

Section snippets

Biosynthesis creates structurally diverse heparan sulfate sequences

The biosynthesis of HS occurs mainly in the Golgi apparatus and involves a complex set of enzyme reactions that first create a non-sulfated polysaccharide chain precursor and then modify it by a sequential series of reactions that superimpose complex patterns of sulfation at selective positions (see Box 1; for recent reviews, see 4., 5., 6., 7.). The crucial points to note are that the system is not template-driven and these reactions do not go to completion. This results in a high degree of

Heparan sulfates as multifunctional cell regulators

Bearing in mind the highly sulfated nature of HS, it is hardly surprising that it interacts with a wide variety of proteins. These include growth factors, enzymes, ECM proteins and proteins found on the surface of pathogens. The almost bewildering number of examples has led to the perception by some that the interactions are relatively nonspecific. This view is steadily giving way under the weight of evidence for interactions between specific consensus structural motifs in HS and many

Essential roles for HS in development

Recent striking evidence of an in vivo regulatory role for HS has come from genetic studies in Drosophila, Caenorhabditis elegans and mouse. Mutations or knockouts of HS biosynthetic enzymes or HSPG core proteins have been shown to dramatically perturb various aspects of development and indicate that HS has functional roles in cell–cell signalling and morphogenesis. Drosophila studies have been particularly revealing as genetic screens for functional mutations in signaling pathways involving

Decoding the messages in HS sequences

The potential informational content in HS sequences is truly vast and is translated into biological effects through interactions with protein ligands. A major impediment to progress in determining the ligand-specific sequences encoded in HS chains has been the lack of practical and direct sequencing methods. Previously, structural characterization relied on NMR spectroscopy (which requires milligrams of sample) or indirect analysis involving laborious and time-consuming enzymic and chemical

New strategies for revealing functional specificity

The past decade has seen a dramatic shift in our view of HS. We now have a clear picture of a molecule that is produced by a tightly regulated biosynthetic mechanism in order to perform distinct and diverse regulatory roles. Much current research is now aimed at increasing our understanding of the functional specificity of HS. Recently, a new array of approaches has begun to illuminate HS structure–function relationships, especially in relation to FGF signalling.

In order to study the link

Future challenges and prospects – exploring the ‘heparanome’

It is apparent that HS acts as a multifunctional regulator of protein activities through a range of different mechanisms dependent on specific HS–protein interactions. Emerging data on the diversity and dynamic synthesis of HS sequences indicate that we need a radically different mind set when thinking about these molecules in comparison to the sequences of proteins and DNA. An analogy can be drawn with the proteome, and we propose the concept of the ‘heparanome’ as a descriptor for the

Acknowledgements

We thank members of the Turnbull laboratory and collaborators for contributing to the work and critically reviewing the manuscript, and Kathy Drummond and Miriam Ford-Perriss for sharing unpublished results. The experimental work of the authors is supported by the Medical Research Council (Senior Research Fellowship to JET), The Royal Society, the European Union, and the Human Frontier Science Program. We apologize to those authors whose work we were unable to cite owing to space constraints.

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