John Gallagher - Overview
Heparan sulphate proteoglycans (HSPGs) are common
constituents of cell surfaces and the extracellular matrix, including
basement membranes. There is now ample evidence that HSPGs are essential
for normal cell growth and development. Biochemical and cell culture studies
have suggested a key co-receptor function for HSPGs, in cooperation with
specific tyrosine kinase receptors, in mediating cellular responses to
a number of major growth factors and cytokines. Likewise, they also act
in concert with cell surface integrins to direct stable cell attachments
to various cell adhesion proteins of the extracellular matrix. More recently,
genetic studies have demonstrated that alterations in HSPG synthesis or
structure lead to phenotypic changes indicative of aberrant control of cell growth, differentiation
and organogenesis. Heparan sulphate (HS) is a highly complex polysaccharide
which displays cell-specific polymorphisms. It is believed that its capacity
to interact with, and modulate the activity of, a wide variety of regulatory
proteins is due to its extensive sequence variability encompassing a multiplicity
of protein-specific binding motifs.
The research in our laboratory is geared towards trying to elucidate the
structure-function relationships for HS in its interaction with a number
of key proteins which are of major importance in regulating cell behaviour.
These include growth factors such as basic fibroblast growth factor (bFGF
or FGF-2), hepatocyte growth factor/scatter factor (HGF/SF) and vascular
endothelial growth factor (VEGF), as well as cell adhesion molecules such
as fibronectin, thrombospondin and endostatin. In parallel with these
studies we are also interested in further understanding the complex structure
of the HS polysaccharide, and the biosynthetic controls which dictate
the unique pattern of this polysaccharide. This includes the analysis
of the structure and function of mutant HS species derived from cells
deficient in specific HS-sulphotransferases. Analysis of HS structure
and its protein-binding motifs also drives a continued interest in the
development of new sequencing techniques which allow us to access complex
oligosaccharide sequence information.
Understanding how HS sequence regulates key protein functions will hopefully
provide new therapeutic opportunities (e.g. via small HS oligosaccharide
mimetics) for normalising the activities of proteins which are functioning
aberrantly in cancer and contributing to tumour growth and dissemination.
Themes:
Sequence analysis and domain organisation of heparan sulphate
Co-receptor functions in growth factor signalling
Cell and developmental biology
Cell adhesion and angiogenesis
Growth factor antagonists
Growth factors and cytokines interact with cells by binding to the heparan
sulphate (HS) chains of cell surface heparan sulphate proteoglycans (HSPGs)
in addition to the previously-known interactions with their specific tyrosine
kinase signalling receptors. In a significant and increasing number of
cases this additional interaction has been found to be necessary for receptor
activation. Various models have been proposed to explain the co-factor
requirements for such proteoglycans, including the induction of activatory
conformational changes in the ligand, the dimerisation of ligands, and
the formation of an active ternary complex (i.e. ligand, receptor
and proteoglycan) in which the proteoglycan may interact with the receptor
as well as the ligand. HSPGs are also involved, in cooperation with the
specific integrin receptors, in the regulation of cell adhesion via interactions
with extracellular proteins such as fibronectin and thrombospondin. All
these HS-protein interactions appear to be mediated by specific sequence
motifs within the complex and polymorphic structures of the HS polysaccharide
chains.
