THE FAMILY OF THE SMALL LEUCINE-RICH PROTEOGLYCANS - KEY REGULATORS OF MATRIX ASSEMBLY AND CELLULAR GROWTH

The focus of this review is on conceptual and functional advances in o ur understanding of the small leucine-rich proteoglycans. These molecu les belong to an expanding gene class whose distinctive feature is a s tructural motif, called the leucine-rich repeat, found in an increasin g number of intracellular and extracellular proteins with diverse biol ogical attributes. Three-dimensional modeling of their prototype prote in core proposes a flexible, arch-shaped binding surface suitable for strong and distinctive interactions with ligand proteins. Changes in t he properties of individual proteoglycans derive from amino acid subst itutions in the less conserved surface residues, changes in the number and length of the leucine-rich repeats, and/or variation in glycosyla tion. These proteoglycans are tissue organizers, orienting and orderin g collagen fibrils during ontogeny and in pathological processes such as wound healing, tissue repair, and tumor stroma formation. These pro perties are rooted in their bifunctional character: the protein moiety binding collagen fibrils at strategic loci, the microscopic gaps betw een staggered fibrils, and the highly charged glycosaminoglycans exten ding out to regulate interfibrillar distances and thereby establishing the exact topology of fibrillar collagens in tissues. These proteogly cans also interact with soluble growth factors, modulate their functio nal activity, and bind to cell surface receptors. The latter interacti on affects cell cycle progression in a variety of cellular systems and could explain the purported changes in the expression of these gene p roducts around the invasive neoplastic cells and in regenerating tissu es.