The Biology of the Small Leucine-rich Proteoglycans

Abstract

small leucine-rich proteoglycan leucine-rich repeat glycosaminoglycan transforming growth factor β epidermal growth factor EGF receptor the cyclin-dependent kinase inhibitor p21 WAF1/CIP1 discoidin domain receptor If one of the keys to biology is protein structure, then nature is an efficient operator, because it adopts a number of structurally related proteins to perform functions as diverse as maintaining the mineralized matrix of bones and teeth, the transparency of the cornea, the tensile strength of the skin and tendon, and the viscoelasticity of blood vessels. Proteoglycans play key roles in all of these fundamental biological processes and behave as potent effectors of cellular pathways. The past decade has witnessed an explosion of knowledge in the proteoglycan world, with significant advances in the genetics and cell biology of these complex macromolecules. This minireview describes recent advances in the biology of the small leucine-rich proteoglycan (SLRP)1 gene family with special emphasis on the biology of the archetype proteoglycan decorin. The focus is on the “functional network” created by these molecules in tissues, on genetic evidence for their functional roles during ontogeny, and on their activities as modulators of complex pathological processes such as fibrosis and cancer growth. Other more extensive reviews may serve to fill the gaps in this one (1Iozzo R.V. Crit. Rev. Biochem. Mol. Biol. 1997; 32: 141-174Crossref PubMed Scopus (453) Google Scholar, 2Iozzo R.V. Annu. Rev. Biochem. 1998; 67: 609-652Crossref PubMed Scopus (1341) Google Scholar, 3Hocking A.M. Shinomura T. McQuillan D.J. Matrix Biol. 1998; 17: 1-19Crossref PubMed Scopus (414) Google Scholar, 4Neame P.J. Kay C.J. Iozzo R.V. Proteoglycans: Structure, Biology and Molecular Interactions. Marcel Dekker, Inc., New York, NY1999Google Scholar). The SLRP gene family comprises at least nine members that, though structurally related, have evolved from different genes, have acquired unique functions, and have undergone a significant degree of structural sophistication (Fig. 1). They can be synthesized as either glycoproteins containing N-linked oligosaccharides or as proteoglycans containing chondroitin/dermatan sulfate or keratan sulfate chains. They can also contain Tyr sulfation, undergo proteolytic processing, and contain a pre-core that is cleaved under certain conditions and with advancing age. Moreover, the promoter architecture of various SLRP genes is quite distinctive, and this contributes to their differential tissue expression (5Iozzo R.V. Danielson K.G. Prog. Nucleic Acid Res. Mol. Biol. 1999; 62: 19-53Crossref PubMed Scopus (26) Google Scholar). Three classes of SLRPs can be easily identified based on several parameters including their evolutionary protein conservation, the presence of a distinct cysteine-rich cluster in the N-terminal region, the number of the leucine-rich repeats (LRR), and their genomic organization (Fig. 1). This group includes decorin (6Krusius T. Ruoslahti E. Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 7683-7687Crossref PubMed Scopus (414) Google Scholar) and biglycan (7Fisher L.W. Termine J.D. Young M.F. J. Biol. Chem. 1989; 264: 4571-4576Abstract Full Text PDF PubMed Google Scholar), which show the highest homology (∼57% identity) and are the only SLRP members that contain a pro-peptide. The pro-peptide is highly conserved across species and may function as a recognition signal for xylosyltransferase, the first enzyme involved in the synthesis of glycosaminoglycan (GAG) chains. These proteoglycans contain an N-terminal domain that is usually substituted with either one (decorin) or two (biglycan) chondroitin/dermatan sulfate side chains, leading to pronounced polyanionic properties. The most salient feature of decorin and biglycan is the presence of 10 LRRs (see below) flanked by cysteine-rich regions (Fig. 1). We previously identified a pattern of amino acid spacing among the four N-terminal Cys residues and predicted that this spacing would be characteristic of each class of SLRPs (1Iozzo R.V. Crit. Rev. Biochem. Mol. Biol. 1997; 32: 141-174Crossref PubMed Scopus (453) Google Scholar). Not only is the spacing of the Cys residues conserved within each subfamily but also the nature of the intervening amino acids is maintained. For example, class I has an N-terminal Cys consensus sequence that is unique (CX 3CXCX 6C) and different from the other two classes (Fig. 1). Another notable feature of class I members is that they are both encoded by genes composed of eight exons with intron/exon junctions in highly conserved positions (8Fisher L.W. Heegaard A.-M. Vetter U. Vogel W. Just W. Termine J.D. Young M.F. J. Biol. Chem. 1991; 266: 14371-14377Abstract Full Text PDF PubMed Google Scholar, 9Danielson K.G. Fazzio A. Cohen I. Cannizzaro L.A. Eichstetter I. Iozzo R.V. Genomics. 1993; 15: 146-160Crossref PubMed Scopus (90) Google Scholar). The 10 LRRs are encoded by six exons (exons III–VIII). The C-termi