The role of proteoglycans in cell adhesion, migration and proliferation Thomas N. Wight, Michael G. Kinsella and Eva E. QwarnstrGm University of Washington, Seattle, Washington, USA Proteoglycans comprise a part of the extracellular matrix that participates in the molecular events that regulate cell adhesion, migration and proliferation. Their structural diversity and tissue distribution suggest a functional versatility not generally encountered for other extracellular matrix components. This versatility is mainly dictated by their molecular interactions and their ability to regulate the activity of key molecules involved in several biological events. This molecular cooperativity either promotes or inhibits cell adhesion, migration and proliferation. A growing number of studies indicate that proteoglycans can play a direct role in these cellular events by functioning either as receptors or as ligands for molecules that are required for these events to occur. Such studies support a role for proteoglycans as important effecters of cellular processes that constitute the basis of development and disease. Current Opinion in Cell Biology 1992, 4:793401 Introduction surface heparan sulfate (HS) PGs are necessary for the formation of stable focal adhesion sites on fibronectin- Adhesion of cells to their micro-environment and their coated substrates [lO,ll]. Recent studies have identified subsequent proliferation and migration are regulated in a sequence within fibronectin that interacts specifically part by their interaction with various components of with a cell surface phosphatidylinositol-anchored HSPG the extracellular matrix (ECM) [I**]. This regulation in mouse melanoma cells [ 12*]. These observations in- involves molecular interactions that govern the attach- dicate that specific classes of PGs can mediate integrin- ment of cells to specific ECM components, detachment independent adhesion events. of cells from these components and molecular rearrange- ments in the ECM that allow cells to change shape dur- Expression of cell surface PGs that interact with ECM lig- ing division and/or migration. Proteoglycans (PGs) are ands appears to be critical for some cells to maintain their one of the ECM components that participate in these differentiated phenotype. Sll5 mouse mammary epithe- regulatory events [ 2*-4*,5**--7**,8*]. Their involvement liaf cells lose their flattened epithelial morphology and with a number of component molecules that take part become tumorigenic when exposed to steroids. These in these processes is mediated either through charge changes are reversed when the cells are transfected with a interactions via the glycosaminoglycan (GAG) chains full length cDNA to human syndecan, which is an interca- (carbohydrate-protein) or through protein-protein in- lated membrane PG [ 13**]. The importance of syndecan teractions via specific domains within the core proteins in cell adhesion is further illustrated by the obsetvation of the PGs. Recent reviews that stress the interactive na- that this membrane PG is transiently expressed on pre- ture of PGs and the role that they play in regulating cell p- and immature p-lymphocytes when in contact with the behavior are available (Fig. 1) [ 5**-7**,8*] bone marrow stroma, but is absent from circulating and peripheral lymphocytes following release from the mar- row (reviewed in [ 7**] ). As syndecan is known to exist in Cell adhesion different polymorphic forms and bind a variety of ECM ligands (reviewed in [7**] ), either transient expression Cells form stabilized contacts with the ECM by a complex and/or structural modifications in this PG may regulate process that depends on multiple interactions between the adhesion of cells to different ECMs at different times ECM receptors and their various ligands and elements of during development. the cytoskeleton [ 91. These contacts must be broken and reformed as cells proliferate and migrate. Proteoglycans CD44 is another family of polymorphic integral mem- promote cell adhesion by facilitating attachment of cells brane glycoproteins and PGs that participate in ceUu- to specific ECM components (Fig. 2). For example, cell lar adhesion [7=*,14**]. There are both low (80-90kD) Abbreviations bFCF-basic fibroblast growth factor; CSchondroitin sulfate; DSdermatan sulfate; ECM-extracellular matrix; GAG-glycosaminoglycan; HS-heparan sulfate; PDCF-platelet-derived growth factor; PC-proteoglycan; TCF-pl-transforming growth factor p-1. @ Current Biology Ltd ISSN 0955%74 793 794 Cell-to-cell contact and extracellular matrix Proliferation Basic fibroblast growth factor Acidic fibroblast growth factor Adhesion and migration Endothelial cell growth factor Vitronectin Platelet-derived growth factor Transforming growth factor, TGF-pl GM colony stimulating factor-l Neural cell adhesion molecule l I -- Disease Apoprotein Viral and parasitic coat proteins Amyloid Calcium Fig. 1. Some of the molecular interactions in which proteoglycans participate and high (200 kD) molecular weight forms of CD44. The virus infection has recently been shown by demonstrat- smaller form, which lacks GAG chains, predominates on ing that Chinese hamster ovary mutant cells defective in lymphocytes and is responsible for the adherence of HSPG synthesis are resistant to infection by the virus lymphocytes to the surface of high endothelial venules, [20*]. Such studies point towards an important new area a process referred to as lymphocyte homing. The high of investigation of clinical relevance concerning plasma molecular weight form bears chondroitin or heparan sul- membrane PGs. fate chains and participates in cell adhesion through the ability of the GAG chains to bind ECM ligands such as fi- Proteoglycans within the ECM or within specialized struc- bronectin. Many cells express PG forms of CD44 that can tures such as basement membranes may themselves serve be localized to filopodia and zones of cell contact [ 14-I. as ECM ligands for adhesion. For example, the principal CD44 also contains a domain that possesses homology PG in basement membranes is a large HSPG, perlecan. to the hyaluronan-binding region of cartilage link protein Recent studies reveal that the core protein in both mouse and the amino-terminal portion of two interstitial CSPGs, [21-l and human [ 220, 23-l perlecan contains multiple aggrecan and versican (reviewed in [7*-l >. This domain domains with homology to adhesive molecules such as allows these molecules to interact with hyaluronan, an in- laminin and neural cell adhesion molecule, suggesting teraction that is important in the adhesion and migration perlecan may also serve as a ligand for cell surface re- of cells in ECM enriched in hyaluronan [ 15,16*]. ceptors. A 38 kD membrane protein has been tentatively identified as the cell surface receptor for this PG in Syndecan and CD44 are members of different families of cultured hepatocytes [24]. In addition, a heparin-bind- intercalated membrane PGs that have conserved cytoplas- ing 78kD protein (moesin) [25*] has homology to a n-tic domains containing potential phosphorylation sites number of proteins that form structural links between (reviewed in (7-I). Intercalated membrane PGs such as the cell membrane and elements of the cytoskeleton. It NG2 [17*] do not contain these specific sequences, but remains to be shown whether the interaction of these do contain potential phosphorylation sites. The pres- membrane-associated proteins with extracellular HSPG ence of such sites has led to the suggestion that these affects adhesion and modulates the behavior of cells that molecules are important in signal transduction during cell synthesize perlecan or other HSPGs. adhesion. Whereas the interactions described above promote ad- Cell surface PGs also promote the adhesion of micro- hesion, PGs can also interfere with adhesion in several organisms to cells. Parasites such as Tgpancxoma cruzl ways. PGs in the ECM may interact with other ECM ad- [18*] and malaria (Phsmodia) sporozoites [ 19.1 contain hesion ligands, such as fibronectin, and block the inter- membrane proteins that specifically bind heparin- or HS- action of the ligand with its cell surface integrin receptor containing PGs. Invasion of these parasites into cells can (Fig. 2) [8*]. The small interstitial dermatin sulfate (DS) be blocked by competition with heparin or HS. The im- PGs, decorin and biglycan, interact with a number of portance of surface-associated HSPG in Herpes simplex adhesive ECM kgdnds, either through their GAG chains Proteoglycans in cell adhesion, migration and proliferation Wight, Kinsella, QwarnstrBm 795 - Core protein Receptor 0 Proteoglycan $ 3 Phosphatidylinositol Glycosaminoglycan > Fig. 2. Possible models in which proteoglycans (PCs) may regulate adhesive, anti-adhesive and migratory events. (a) PC as an adhesive ligand. (b) PC as a receptor for an adhesive ligand. (c) PC linked to phosphatidylinositol. (d) Selective synthesis of hyaluronan to facilitate movement of the cell. (e) Secretion of proteases and glycosidases to break adhesive bonds. (13 Selective expression of PCS to create migration pathways. (g) PC binds anti-adhesive molecules such as tenascin. (h) PC binds to the adhesive ligand fibronectin preventing ligand binding to receptor [ 26.1, or their core proteins [ 27*] and interfere with cell The importance of CSPGs in cell migration is well es- attachment. The presence of large interstitial PGs at the tablished. Removal of CSPG from the surface of mouse cell surface may prevent the interaction of cell surface