The Role of Proteoglycans in Cell Adhesion, Migration and Proliferation Thomas N

Home , Membrane glycoproteins

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 marrow (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 melanoma cells or inhibition of CSPG synthesis by these receptors with their specific ECM ligands by steric exclu- cells prevents their migration and invasion into type I sion [28]. In addition, cell surface associated PGs may collagen gels without affecting adhesion to a collagen interact with other anti-adhesive ECM molecules such as substratum [33*]. The cell surface PG responsible for thrombospondin [29] and tenascin [30-l to destabilize this activity is a CSPG whose core protein is immuno- cell contact points (reviewed in [3I--1). logicaLly related to CD44. Furthermore, a spliced variant of CD44 is selectively expressed in metastasizing rat carcinoma cells and is capable of conferring metastatic behav- Cell migration ior to non-metastasizing carcinoma cells [34-l. Although CD44 is not expressed by all cells during migration, other Adhesion sites are continually disrupted and reformed as cell surface PGs may serve a similar role. For example, cells change shape and move. Cell movement is also in the healing of cutaneous wounds, the migrating and accompanied by changes in the cellular micro-environ- proliferating epithelial cells and endothelial cells forming ment involving the replacement of dense fibrous ECM new blood vessels show increased expression of synde- that serves to stabilize stationary cells with a loose hy- can [35*]. While changes in specific PGs are associated drated micro-environment that creates pathways for cell with the onset of cell migration, the precise mechanism migration. Proteoglycans and hyaluronan, a GAG that oc- by which PGs influence this cellular event is not under- cupies large solvent domains, influence these processes. stood. Generally, the molecules that destabilize adhesion sites (e.g. CSPGs and hyaluronan) promote cell motility, while Although certain PGs facilitate or promote celJ migration the PGs that contribute to the formation of tight cellular in some systems, other PGs inhibit or establish barri- adhesion sites (i.e. HSPGs) inhibit cell migration. In fact, ers to migrating cells. For example, regions enriched in when stationary vascular endothelial cells are induced to CSPG in the developing mammalian retina exclude ad- migrate, they switch from synthesizing an ECM enriched vancing growth cones [36**]. Removal of CSPG from in HSPG to an ECM enriched in CUDS PG [ 321. these regions results in new axonal growth. Localized 7% Cell-to-ceil contact and extracellular matrix

accumulation of CSPG also correlates with restriction suggest that the uranic acid moiety in the GAG chain is of neural crest cell migration in developing chick em- important as a structural determinant for the anti-pro- bryos [37*]. m another mode1 of axonal guidance, ax- liferative activity of these GAGS. Unusual disaccharides onal extensions of dorsal root ganglia avoid contact with containing a 2sulfated uronate have been found in the explants of epidermis in co-culture [38*]. Inhibition of nucleus of growth-arrested hepatoma cells [49,50], al- CSPG synthesis with P-xyloside, or incubation of the though similar structures have not been found in the co-cultures with anti-CSPG antibodies, results in con- nuclei of smooth muscle cells that are growth arrested tact between extended axons and epithelial explants, with heparin [45]. The fmding of GAG fragments within abolishing avoidance of contact that is seen in control the nucleus suggests that GAGS might influence prolif- cultures. Also consistent with the conclusion that CSPGs erative activity by interacting with transcription factors delimit the pathways of neuronal outgrowth is the obser- that are critical for ceU replication. For example, hep- vation that CSPGs isolated from rat brain inhibited nerve at-in treatment of 3T3 cells blocks phorbol ester induc- growth factor-induced neurite extension when bound to tion of c-myc and c-fos, two proto-oncogene products pheochromocytoma cells [39*]. Thus, it may be that necessary for ceU replication in some cells [51,52] .Re- PGs function as ‘avoidance’ molecules in the nervous cent experiments suggest that heparin interferes with system by acting as steric blockers for receptors in the the activation of these proto-oncogenes by interacting growth cone of elongating axons (discussed in [31*-l >. with specific transcription factors, inhibiting the bind- Two recent papers, however, suggest novel mechanisms ing of these trans-acting factors to DNA [53--l. Many by which matrix PGs may influence ceU migration. For ex- of the transcription factors have heparin-binding basic ample, HS and CS signilicantly increase activation of plas- amino acid sequences (discussed in [6-l). These ob- minogen by urokinase-type plasminogen activator [40-l, servations raise the distinct possibility that GAGS may, which has been previously localized to ceU adhesive sites, under some circumstances, regulate gene activity at nu- where it is thought to be involved in proteolytic events clear sites. that are associated with ceU migration. Also, in a model of Proteoglycans may also function as mitogens.The 80 kD embryonic smooth muscle ceU migration in the ductus ar- subunit of colony stimulating factor-l (CSF-1) contains a teriosus, a critical event is the penetration of cells through single chain of CS [ 54*]. This PG regulates the prolifera elastic laminae. This process may involve shedding of a tion and differentiation of mononuclear phagocytic cells cetl surface elastin receptor, in a process induced by CS in bone marrow. As CSF-1 PG possesses the same bio- [41*]. logical activity as its lower molecular weight counterpart, The GAG, hyaluronan, formerly termed hyaluronic acid, which does not bear GAG chains, it is unlikely that the also plays a role in ceU migration. Although the man GAG chain participates directly in growth factor activa- ner in which this GAG exhibits its effect is not clear, tion. However, the GAG chain might permit the interac- several studies have shown an increased but transient tion of the growth factor with the ECM in the haemopoi- production of hyaluronan that coincides with rapid cell etic micro-environment for utilization by target cells in a migration during processes of in&nmation, wound re- manner similar to that described for the binding of other pair, tumor invasion and morphogenesis (reviewed in growth factors in bone marrow stroma [55,56]. [16*]). Addition of hyaluronan to some cells in culture promotes their migration [42*,43-l, an activity that Proteoglycans may also influence cell proliferation by in- can be eliminated by removing hyaluronan with either teracting with growth factors either acting as growth fac- enzyme treatments or blocking antibodies against ceU tor receptors [57-l or modifying the interaction of the surface hyaluronan-binding proteins. Thus, hyaluronan- growth factors with their high-affinity receptors [ 58,59*]. binding proteins are required for hyaluronan to influence Such interactions are believed to induce conformational ceU migration and they are associated with the leading changes in the growth factor [6O*] or possibly in the 1arneUae of rapidly migrating cells [43*-,44*]. This family growth factor receptor, perhaps involving dimerization, of integral membrane glycoproteins and PGs has been re- such that high-affinity interactions between Ugand and cently named the hyaladherins, although synonyms such receptor are possible. Removing HS from the surface as ‘HAHAgrins’ and ‘gripabags’ have also been proposed of 3T3 cells and skeletal muscle myoblasts dramatically [WI! reduces the binding of basic Iibroblast growth factor (bFGF) to these cells [6l*] while leaving the mitogenic Cell proliferation activity of other growth factors such as of platelet-derived growth factor (PDGF) and epidemlal growth factor un- affected. Recent studies indicate that HS chains contain a Different PGs can function to either inhibit or pro- specific carbohydrate sequence in which N-sulfate groups mote ceU proliferation (Fig. 3). Several laboratories have and iduronate-2-sulfates are essential for binding of bFGF demonstrated that heparin and HS suppress the entry [62**]. This is in contrast to the binding of transforming of cells into S phase in response to some mitogens growth-factor (TGF)-PI to the PG component of the (reviewed in [45] > but the mechanism(s) remains un- TGF-P receptor, betaglycan, in which the GAG chains clear. A number of studies have addressed several pos- are not required [63,64-l. These different binding sites sible mechanisms. For example, for some cells and n-r- allow for the binding of more than one growth factor to togens, growth inhibition may involve the inactivation of the same PG [65*]. the mitogen by heparin [46*,47-l. Although heparin and HS are usually considered the only GAGS with anti-prolif Proteoglycans may also sequester growth factors in the erative properties, DS of high iduronate content inhibits ECM in a form protected from proteolysis [66**,67] and the proliferation of human fibroblasts [48*]. Such studies thereby regulate their availability and/or activity. Release Proteoglycans in cell adhesion, migration and proliferation Wight, Kinsella, Qwarnstrdm 797

I=> Division

Fig. 3. Proposed mechanisms in which proteoglycans (PCs) may participate in the regulation of cell proliferation. (a) PC binds growth factors in the extracellular matrix. (b) PC as a membrane- bound facilitator in high-affinity binding of growth factors to their recep- + Growth factor receptor tor. (c) PC as a mitogen. cd) Processing of 68 Transcription factor Phosphatidylinositol phosphatidylinositol-linked PC to generate growth inhibitory glycosaminogly- M Growth factor 0 Core protein Proteoglycan can (GAG) fragments, which are inter- - Glycosaminoglycan I nalized. GAG binds to nuclear transcription factors, which inhibits their activity.

of the growth factor-PG complex could occur by the ac- Conclusion tion of proteases, glycosidases or phospholipases [68*] made available during events associated with develop- We have reviewed a number of examples published ment, tissue injury and formation of new blood vessels within the last year that implicate PGs in the regula- 169,701. Support for an effect by PGs on growth factor action of cell adhesion, migration and proliferation. While tivity comes from studies that demonstrate that the small some of the evidence is still circumstantial, several studies interstitial DSPGs, decorin and biglycan, can inactivate the suggest that PGs can effect the biological activity of com- mitogenic activity of TGF-j31 [71]. Interestingly, TGF-p1 ponent molecules involved in these processes through stimulates the synthesis of these small DSPGs in some highly specific interactions. The remarkable structural di- cells (reviewed in [8*] ), and this reciprocal relationship versity of the Merent families of PGs provides a mul- may be one way in which specific PGs regulate the activity tiplicity of ways in which these interactions can occur. of growth factors. The challenge for the future will be to define the nature of these molecular interactions and the biological conse- Cell proliferation is often accompanied by the selective quence( s) of such interactions in regulating cell function. expression of specific PGs. For example, syndecan is expressed by proliferating cells in the mesenchyme dur- Acknowledgements ing tooth bud morphogenesis [72*]. In addition, the stimulation of arterial smooth muscle cell proliferation This work was supported by NIH grants HL-18645, DE-0889 (TNW) by PDGF is accompanied by specific changes in the and DE.08172 (EQ). The authors expresssincere appreciation to Dr. transcription/translation and post-translational process- Susan Potter-Per&o for her critical reading of the manuscript and to ing of versican, which is a principle PG present in blood Ms. Barbara Kovacich for the typing of the manuscript. vessels [ 73.1. Although the relevance of these changes to the growth state of the cell is not yet understood, such modifications in specific PGs may alter the binding char- References and recommended reading acteristics of the micro-environment surrounding cells af fecting growth factor availability and/or activity. It should Papers of particular interest, published within the annual period of re. view, have been highlighted as: be emphasized that although increased PG synthesis is . of special interest correlated with cell proliferation, induction of PG syn- . . of outstanding interest thesis does not always appear to be a prerequisite for 1. HAY ED: Cell Biology o/ ExtraceNtclar Mah-ix, 2nd edn. New cell proliferation as interruption of PG synthesis by /3- . . York: Plenum Press; 1991. o-xylosides can be uncoupled from the anti-proliferative in outstanding concise oveniew and up-to-date account of what is new effect of this molecule [74*,75*]. and exciting in extracellular matrix biology. Chapters are written for 798 Cell-to-cell contact and extracellular matrix

beginning srudents but also serve the investigator as a quick update. A The importance of this paper lies in the demonstration that melanoma ‘must’ for your bookshelf! cells adhere to the heparimbinding domain of tibronectin by at lest two mechanisms - one that involves a phosphatidylinositol-linked 2. WICHT TN, HEINEG&~D DK, HASCAU VC: ProteogIycans: Struc- HSPG while the other involves non-RGD-dependent integrin (a-iBl ). . ture and Function. In CeN Biology o/‘ Extracellular MaIrk Edited by Hay ED. New York: Plenum Press; 1991:45-78. 13. LEPPA S, MALI M. MIE-ITINEN HIM. JAU~ANEN M: Syndecan Ex- This review discusses the StNCNre and function of selected classes of . . pression Regulates CeU Morphology and Growth of Mouse PGs. Emphasis is on tissue location and strucNre of PC& as related to Mammary EpitheIiaI Tumor CeIIs. Pros Nat/ Acad Sci USA function. There are several excellent illustrations as part of this review. 1992. 89:932-936. One of a few recent studies that uses gene transfer technok>m to 3. HASCAU VC, HE~NEGARD DK, WICHT TN: ProteogIycans: demonstrate the involvement of a particular PG in the regulation of . Metabolism and Pathology. In Cell Biolo@r o/ f3iraceC cell phenoQpe and growth characteristics. Such an approach is one of l&r Man-is Edited by Hay ED. New York: Plenun Press; the most convincing ways to implicate PGs directb in regulating cellular 14’t175. events. This review summarizes current concepts and problems concerning biosynthesis, catabolism and pathology of PGs. Excellent diagrams and 11. BROU;~ TA, BOLICHAKD T. ST. JOHN T, WA\?XR E. CARTER WG: illustrations facilitate the understanding of some of the complexities . . Human Keratinocytes Express a New CD44 Core Protein associated with these topics. (CD44E) as a Heparan SuIfate Intrinsic Proteoglycan with Additional Exons. J Cell Biol 1991, 113:X-221. 4. HARDINGHAM TE, FOSANG AJ: Proteoglycans: Many Forms and A thorough study. which demonstrates that CD+i is a polymorphic fam . Many Functions. FASEB J 1992, 6:861-870. ily of related membrane PGs and glycoproteins possessing extensive di- A concise and well written summary that emphasizes the StruCNre of versity in both glyco.sylation and core protein sequence. An important the diRerent domains of the core proteins of several PGs and how these aspect of this work is the demonstrdtion that some of this divers@’ is domains influence PG function. generated by alternate splicing of the CD14 mRNA

5. KJEU.EN 1 L~NDAHL U: Proteoglycans Structures and Interdc- 15. AR~IFFO A, STA~IENKOVIC 1, MELNICK M. I’NDEKHIII. CB. S~XD . . tions. Annu Reu Biocbem 1991, 60:44w75. 8: CD44 is the Principle CeU Surface Receptor for A comprehensive, detailed and up-to-date account of how the StNCNre Hyaluronate. Cell 1990, 61:1303-1313. of the GAG chains and the core proteins of PGs influence the binding capacity and function of these molecules. The authors give considerable 16. TOOLE B: Proteoglycans and Hyaluronan in Morphogenesis attention to the importance of the GAG chains in defining the interdc- . and Differentiation. In CeN Biology of E.~tracellrdur ~Ilrrlri\: tion of the PGs and this coverage is often lacking in other reviews. An Edited bv Hay E. New York: Plenum Press; 1991:305-341. extensive bibliography is included. An excellent &ew of the importance of PGs and hyaluronan in refl- lating the behavior and differentiation of cells. Pleasant to rt-Id. 6. JACKSON RL, BUSCH SJ. CARDIN AD: Glycosaminoglycans: NISHIYA~IA A. DAHUN KJ, PRINCE JT, JOHSTONE SR. STAII.CIIP . . Molecular Properties, Protein Interactions and Role in 17. . WB: The Primary Structure of NG2, a Novel Membrane Physiological Processes. Plysiol Ret’ 1991. 71:481-539. Spanning Proteoglycan. J Cell Biol 1991, 114:359-371. A detailed and thorough up-to-date summav of evidence indicates that Complete sequence of a cell surface PG. NG2, from rat neural cell lines a key biological property of PGs is their ability to form specilic associ- has been deduced from cDNA clones. This newly cloned PG contains ations with critical molecules involved in several biological processes. a different c>qoplasmic domain from other membrane PGs and is thus More than 550 references are cited and this review is an excellent re- considered novel. Comparison of amino.terminal sequences shows that source for those investigators interested in PG interactions. a PG previous$ characterized as the human melanoma PG is the hu- 7. JALKANEN M, J-EN S, BERNFIELD M: Binding of Extracel- man homologue of this PG. Sequence infon-nation will be valuable in . . lti Molecules by CeII Surface Proteoglycans. In Biology fUNre studies designed to investigate the role of this PG in both human of E~1racdiuk.v Matrix: Rectpors $or Ektracellrtkzr Alaltix. melanoma and neuronal function. Orlando: Academic Press; 1991: l-37. 18. ORTEGA-BARRLA E. PEKEIRA EA A Novel r cruzi Heparin-bind- An excellent current account of cell surface PGs that function either . ing Protein Promotes Fibroblast Adhesion of Engineered as ECM receptors or as growth factor receptors. Considenble atten- Bacteria and Trypanosomes into Mammalian Cells. Cell 1991, tion is given to the concept that several different cell surface PGs share 67:il l--121. StrucN~ features that implicate these mOkculeS in SignaUing ever&s One of the tirst studies to demonstrate that a unique protein on the associated with specilic Ugand interactions. Consideration is also given surface of pansites interacts a-ith HSPGs on the surface of mammalian to evidence that indicates individual classes of PGs undergo StnIcNti cells. An important contribution that addresses a new role for cell sur- modifications during morphogenic events, which may lead to altered face PGs. PG function. 19. PAIXAKE SJ, HOLT GD. IMEUO~~K S, HoFFIWN 51.: Malaria Sporo- 8. RUOSLAHn E, YAMAGUCHI Y: Proteoglycans as Modulators of . zoites and Circumsporozoite Proteins Bind Specifically to . Growth Factor Activities. Cell 1991, 64:867-869. Sulfated Glycoconjugates. .I Cell Biol 1992. 117:1351-1357. A short review that stresses the importance of PG interactions v+ith Demonstrates that circumsporozoite proteins. which coat malaria growth factors as potential regulators of the gro& of specific cells sporozoites, contain sequences that specifically bind sulfidted glyco- in several different systems. conjugates. Sporozoite invasion into hepatoc)$es could be inhibited b! 9. AKNAMA SK, NAGATA K, YA!.~A KM: CeII Surface Receptors heparin, suggesting that parasitic infection may depend on PGs. These for ExtraceUular Matrix Components. Biodim Rio&a Acla obsen;ations have significant clinical relevance and lay the foundation 1990, 1031:91-110. for important additional studies to determine the speciticitv of such interactions and for additional approaches for limiting parasitic infection 10. WOODS A, COUCHMAN JR, JOHN~ZN S, HOOK M: Adhesion by targeting development of novel vaccines and drugs. and Cytoskeleton Organization of Fibroblasts in Response to Fibronectin Fragments. EMBO J 1986. 5:66=70. 20. SHIE~I M-T, W~IDUNN D. MONTCOMEK~ RI, ESKO JD, SI+AH PG: . CeU Surface Receptors for Herpes Simplex Virus Are Hep- 11. LEBARON RG, ESKO JD, WEEDS A, JOHN%~N S, HOOK M: Adhe- aran Sulfate Proteoglycans. .I Cell Biol 1992, 116:12731281. sion of GlycosamInogIycan - Deficient Chinese Hamster Taking advantage of cell mutants defective in HSPG synthesis. these in- Ovary CelI Mutants to Fibronectln Substrata J Cell Biol1988, vestigators demonstrated that high efficiency HSV infection is speci6- 106:94>952. tally dependent on the presence of HSPG. As with [ 18.1 and [19*]. these obsewtions have tremendous clinical rele\mce. The impor- 12. DRAKE SL, KLEM DJ, MICKEISON DJ, OEGE~IA TR. FL~RCHT LT, tance of PG in the infectivity of cells by micro-organisms constirutes . MCCARTHY JB: CeU Surface Phosphatldylinositol-anchored a new and exciting ared of biomedical research. Heparan Sulfate Proteoglycan Initiates Mouse Melanoma CeU Adbesion to a Fibronectin Derived Heparin-binding 21. NOONAN DM. Ft1~ 4 V..ut?n% P, CAI S, HORICAN E, SA%XI Synthetic Peptide. J Cell Biol 1992, 117:1331-1341. . M. YM~,V)A Y, HAssEu JR: The Complete Sequence of Per- Proteoglycans in cell adhesion, migration and proliferation Wight, Kinseila, Qwarnstrdm 799

lecan, a Basement Membrane Heparan Sulfate Roteoglycan, 31. SAGE EH, BORNSTEIN P: Extracellular Proteins that Modulate Reveals Extensive Similarity with Laminin A-Chain, Low . . Cell-matrix Interactions. J Biol cbem 1991, 266:14831-14834, Density Lipoprotein-receptor and the Neural CeU Adhe- An excellent, concise, but thorough review of the major glycoprotelns sion Molecule. J Biol Chem 1991, 266:2293&22947. that influence adhesion and migration. Although this review does not See [23*]. consider PGs, it is still worth reading!

22. MURDOCH AD, DODGE GR, COHEN 1. THAN RS, lozzo RV: PI-I- 32. KINSEUA MG, WIGHT TN: Modulation of Sulfate Roteogly- . mat-y Structure of the Human Heparan Sulfate Proteoglycan can Synthesis by Bovine Aortic Endothelial Cells during from Basement Membrane (HSPG Z/Perlecan): A Chimeric Migration. J Cell Biol 1986, 102:67%6%7. Molecule with Multiple Domains Homologous to the Low 33. FAA~SEN AE, SCHRAGER JA, KLEIN DJ, OEGEMA TR, Couwhw JR, Density Lipoprotein Receptor, Laminin, Neural Cell Adhe- . McC~~nrv JB: A CeU Surface Chondroitin Sulate Roteogly- sion Molecules and Epidermal Growth Factor. J Biol Cbem can, ImmunologicaUy Related to CD44 Is Involved In w 1992, 267:8544-8557. 1 Collagen-mediated Melanoma CeU Motility and Invasion. See [23*]. J Cell Biol 1992, 116:521-531. 23. KALLUNKI P. TRYGGVA.SON K: Human Basement Membrane Conlirms recent work suggesting CD44-related antigens may bear chon- . Heparan Sulfate ProteogIycan Core Protein: A 467-kD droitin sulfate chains and serve as matrix receptors by binding collagen. Protein Containing Multiple Domains Resembling Elements Moreover, inhibition of melanoma cell invasion of type I collagen gels of the Low Density Lipoprotein Receptor, Laminin, Neural was inhibited by treatments that remove the chondroitin sulfate, sug Cell Adhesion Molecules and Epidermal Growth Factor. J gesting that this moiety may be required to confer metastatic potential. Cell Biol 1992, 116:55‘+571. 34. G~NIHERT U, HoF,~ M, RUDY W, REBER S. ZOUER M, These papers [21*-23.1 an*e the deduced amino acid sequences . . H~usshv.~~ I, MA-IZKU S, WENZEL A, PONTA P, HERRIJCH P: from cDNA clones of the extremely large core protein of the basement A New Variant of Glycoprotein CD44 Confers Metastatic membrane HSPG, termed perlecan or HSPGZ. These ‘Herculean’ efforts Potential to Rat Carcinoma Cells. Cell 1991, 65:13-24. reveal that this large protein contains multiple domains capable of a Perhaps one of the most compelling studies implicating a specific variety of interactions. An understanding of the structure of perlecan molecule in a causal way in the regulation of tumor metastasis. Al- will help our understanding of the role of this PG in matrix assembly though the mechanism by which this spliced variant of CD44 exerrs as well as in possibly regulating cell adhesion and migration. it5 effect is unclear, these studies highlight the need to explore this experimental system. 24. CLEMENT B, SEGLIIXEAL B, HA..EL JR, MARTIN GR, AND YAMADA Y: ldentilication of a Cell Surface-binding Protein for the 35. ELENIUS K, VAINIO S, LAATo M, SALMMRTA M, THESLEFF 1: ln- Core Protein of tbe Basement Membrane Proteoglycan. J . duced Expression of Syndecan in Healing Wounds. J Cell Biol C%em 1989, 264:12467-12471. Biol 1991, 144:585-595. An important study that associates increased syndecan expression with 25. ~ANKES W, FURTHMAYR H: Moesin: a Member of the Protein the migntion and proliferation of epithelial cells during wound heal- . 4.1- talin-ezrin Family of Proteins. Proc Null Acad Sci USA ing. This study also notes that expression of syndecan occurs, appar- 1991, 88:8297-8301. ently transiently, in endothellal cells in growing capillaries of granulation The cloning and sequencing of this heparin-binding protein reveals an tissue. absence of a signaIling and transmembrane domain and a homology to other proteins thought to function intracellularly fo link the cytoskele- 36. BRITIX PA, CANNING DR, SILVER J: Chondroitin Sulfate as a ton to the plasma membrane. . . Regulator of Neuronal Patterning in the Retina. Science 1992, 255~733736. 26. L~wwww K, CHOI HU. ROSENBERG LC, SASSE J, NEA~~E PJ, This exciting study provides important new evidence that the temporally . CULP IA: Extracellular Matrix Adhesion-promoting Activi- regulated patterning of CSPG can serve to control the onset of retinal ties of a Dermatan Sulfate Roteoglycan-associated Protein ganglion cell differentiation and direct initial axonal outgrowth. Clear (22K) from Bovine Fetal Skin. J Cell Sci 1991, 99:657a. evidence is presented to show that disruption of the endogenous pat- A 22kD protein isolated from bovine skin, which co-purifies with a fern of CSPG deposition results in ectopic ganglion ceU differentiation DSPG, is shown to promote the adhesion of fibroblasts. The interaction and disorganization of axonal outgrowth. of these two molecules eliminates the adhesive properties of the 22 kD FERRIS R, KROTOSKI D. tiER T, DOMINGO c, %RRELL M, protein. This is a classic example of a PG modifying the activity of an 37. BRONNER-FRASER M: Spatial and Temporal Changes in the adhesive &and. . Distribution of Roteoglycans During Avian Neural Crest 27. WINNEMOUER M, SCHMIDT G, KRESSE H: lntluence of Decorin Development. DeL’elopmenl 1991, 111:583-599. . on Fibroblast Adhesion to Fibronectin. Euu,- J Cell Biol 1991, This study describes, by histochemical and immunochemical means, 54:1&17. changes in distribution of hyaluronan and families of PGs during neu. Further proof that a small interstitial DSPG can interfere with cell adhe- ral crest migration and gangliogenesis. Most interestingly, of the several sion by binding fo adhesive ligands such as fibronectin. This paper is general distributions recognized for dierent PG,families, subsets of 6- particularly instructive regarding the need fo use caution in preparing sulfated and unsulfated CSPGs were found to be present in prospective the PG for these types of studies. neural crest migratory pathways, prior to appearance of the cells, and in areas from which these cells are excluded. This observation supports 28. YAMACATA M, SUZUKI S, AK~‘AMA S. Y~hu\~n KM, KI,MATA K: a general role of these currently incompletely characterized CSPGs in Regulation of Cell-substrate Adhesion by Roteoglycans directing ceU migration via exclusion mechanisms. Immobilized on Extracellular Substrates. J Biol Chem 1989, 264:8012-8018. 38. FICHAKD A, VERNA JM, OIJVARES J, SAXOD R: lnvolvement of a . Chondroitin Sulfate Roteoglycan in the Avoidance of Chick 29, MURPHY-UUXKH JE, HOOK M: Tbrombospondin Modulates Epidermis by Dorsal Root Ganglia Firs: a Study Using p- Focal Adhesions in Endothelial Cells. J Cell Biol 1989. o-xyloside. Dell Biol 1991, l&:1-9. 109:13oe1319. This SNdy uses an interesting co.culmre system to explore the phe nomenon of exclusion of contact between elongating neurltes and SAUZ~~~TA M, ELENI~S K, VAINIO S, HOFER U, CHIQUET- 30. epidermal cells. The experiments implicate soluble chondroitin sulfate . . EHIUSMANN, THESWFF I, JAIXANEN M: Syndecan from Em- chains, which are borne on a yet unidentified CSPG and synthesized by bryonic Tooth Mesenchyme Binds Tenascin. J Biol Ckm epidermal cells, in forming a barrier preventing innenation by CUlNred 1991, 266:773>7739. dorsal root ganglia. An imponant obsenation, which reveals that syndecan isolated from mesenchyme differs in snucmre from syndecan isolated from epithelia. 39. OOHIRA A, MA-I-XII F, KATOH-SEMBA R Inhibitory Effects of These structural differences contribute to differences in the ability of . Brain Chondroitin Sulfate Roteoglycans on Neurite Out- this molecule fo bind tenascin. An excellent example of post-tnnsla- growth from PC 12D Cells. J Newosci 1991, 11:822-827. tional modiication contributing to differences in the functional prop- The experiments reported in this study indicate that brain CSPGs may erties of a PG. inlluence neurite outgrowth by the mechanism of inhibition of elonga- 800 Cell-to-cell contact and extracellular matrix

tion. Unlike other work suggesting that similar inhibit&y activity is as. factors (IL-2) are not inactivated by heparin. This paper indicates that sociated with chondroitin sulfate chains, this work found isolated core suppression of cell proliferation by heparln and HS must involve multi. proteins from brain CSPCs to be effective inhibitors in their system, ple mechanisms that depend on the nature of the mitogen and the ceU and chondroitin chains and cartilage CSPG to be ineffective. type studied.

40. EDEIBERG M, WEISSIER M, PLZZO SV: Kinetic Analysis of 47. FAGER G, CAMEJO G. BONDJER~ G: Heparin-like Glycosamino- . the Effects of Glycosaminoglycans and Lipoproteins on . glycans Influence Growth and Phenotype of Human Arterial Urokinase-mediated Plasminogen Activation. Biocben~ J Smooth Muscle CeUs in Vitro I. Evidence for Reversible 1991, 276~785-791. Biding and Inactivation of the Platelet-derived Growth These kinetic studies indicate that heparin, heparan sulfate and Factor by Heparin In Vitro. Cell Dal Biol1992, 2&l&-175. chondroitin-6-sulfate all increase the catalytic rate of the activation of This paper presents indirect evidence that heparin blocks PDGF-stimu. plasminogen by urokinase, which may be involved in migration-related lated proliferation of human arterial smooth muscle cells by binding to proteolytic events at the cell surface. This work provides, indirectly, an and inactivating serum mitogens. Other studies using different sources explanation for the mechanism by which PGs might influence cell mi- of arterial smooth muscle cells indicate that heparin has no effect on gration. PDGF binding to its receptor. These differences need to be reconciled.

41. H~NEK 4 Boyle J, RABINOVITCH M: Vascular Smooth Muscle 48. WESTERGREN-THORSSON G, ONNERVIK P-0, FRANSSON L-4 . Detatchment from Elastin and Migration through Elastin . MAINSTROM A: Proliferation of Cultured Fibroblasts is Inhib- Laminae is Promoted by Chondroitin Sulfate Shedding of ited by L-iduronate-containing Glycosaminoglycans. / CeN the 67KD Cell Surface Elastin-binding Protein. Exp cell Res f/+-id 1991, 147:523530. 1992, in press. A careful comparison of the effect of different GAGS on the inhibition of The ability of fetal smooth muscle cells to penetrate an elastin matrix proliferation of human lung libroblasts. The authors conclude that GAG scaffold in culture correlates with reduced expression of elastin recep- structure (i.e. sulfation and percentage iduronate) and plating density tor. The authors found that galactosaminoglycans promoted penetra- are determining factors for this anti.proliferative activity. tion of the elastin scaffold and speculate that secretion of CSPGs or DSPGs by migrating cells may allow shedding of the elastin receptor 49. FEDARKO NS, CONRAD HE: A Unique Heparan Sulfate in the and enhance penetration of elastic laminae. Nuclei of Hepatocytes: Structural Changes with the Growth State of the CeU. J Cell Biol 1986, 102:587-599. 42. BOLJDREAU N, TURLF~ E, RABMOVrrCH M: Fibronectin, Hyaluro- . nan and an Hyaluronan Binding Protein Contribute to In- 50. ISHIHARA M, CONRAD HE: Correlations between Hep- creased Ductus Arteriosus Smooth Muscle CeU Migration. aran Sulfate Metabolism and Hepatoma Growth. J Celf Dew Biol 1991, 143:235-247. Pbysicd 1989, 138:467-176. This study uses a collagen gel matrix to model migration of ductal cells 51. WRIGHT TC, PUKAC IA, CASIIZLLOT JJ, KARNO~~KY MJ, LEVINE RA and aortic fetal smooth muscle cells. Ductal cells specifically respond ffihl-P.w( HY, CA~~PISI J: Heparin Suppresses the Induction of with increased migration after inclusion of hyaluronan in the gel. The c-fos and c-myc mRNA in Murine Fibroblasts by Selective increased migration of these cells in hyluronan-supplemented gels is Inhibition of a Protein Kinase C Dependent Pathway. Proc blocked by antibodies against a cell surface hyaluronan-biding pro- Nafl Acud Sci USA 1989, 86:3199-3203. tein, suggesting an alternative set of receptor-matrix ligands may be operating in hyaluronan-specific migration events. 52. PUKAC L4, CASTELIOT JJ. WRIGHT TC, CALEB BL, KARNOVSKV MJ: Heparin Inhibits c-fos and c-myc Expression in Vascular 43. Tuw?f EA, ALISTEN I VANDEUGT K, CHARY C: Hyaluronan Smooth Muscle Cells. Cell Regul 1990, 1:435-%43. . . and a Cell-associated Hyaluronan Binding Protein Regu- late the Locomotion of Ras-transformed Cells. / Cell Biol 53. BLI~CH SJ, MAnN GA BARNF~IWT RL, MANO M, CARDIN 1991, 104-1047. . . AD, JACOON RL Trans.repressor Activity of Nuclear Gly- Using Ras-transformed cells, driven by a Zn*+inducible metallo. cosaminoglycans on Fos and Jun/AP-I Oncoprotein-medi- thionein promoter, the authors have conlirmed that the transient, ated Transcription. J Cell Biol 1992, 116:311/2. dramatic stimulation of ceU locomotion after ru.s gene induction is A provocative study that uses transient transfections and DNA-binding accompanied by a burst of hyaluronan synthesis. Additionally, pro- assays to demonstrate that heparin blocks AP-l-mediated gene expres motion of ras gene expression induces the synthesis of a complex sion by forming a complex with Fos-Jun/Al-1 transcription factor. Such of hyluronan-binding proteins, upon which the ceUs are dependent observations have important implications for the role of GAGS in dif- for locomotion during an initial early phase of hyzluronan-dependent ferentiation and support the hypothesis that matrix molecules may reg rapid migration. ulate gene activity at nuclear sites.

44. HARDWICK C, HOARE K, OWENS R. HOHN HP, HOOK M, MOORE 54. PRICE KH, CHOI HU, ROSENBERG 1 STANZEY ER: The Predom- . D, CR~PPS V, AUSTEN L, NANCE DM, TUWY EA: Molecular . inant Form of Secreted Colony Stimulating Factor-l is a Cloning of a Novel Hyahuonan Receptor that Mediates Proteoglycan. J Biol C&em 1992, 267~2190-2199. Tumor Cell Motility. J Cell Biol 1992, 117:134>1350. Evidence that one of the monomeric subunits of CSF-1 contains a CS This study describes the cloning of a novel hyaluronan-binding com- chain. One of the first mitogens to have been identified as a PG. The ponent, which is part of a Ras-induced complex of cell surface binding biological significance of CSF.1 as a PG needs to be established. An proteins involved in hyluronan-mediated motility. This protein, despite interesting discussion of why the higher molecular weight structure has its ability to bind hyluronan, apparently does not contain a domain not been recognized earlier is presented. homologous to the hyaluronan-binding domain present in aggrecan, link protein, versican and CD44. The lack of a transmembrane domain 55. GOREON MY, RIIXY GP, WA’IT MF: Compartmentalization Suggests that this molecule is associated with other ceU surface proteins. of a Haematopoietic Growth Factor (GM-CSF) by Gly- cosaminoglycans in the Bone Marrow Microenvironment. 45. WIUGHT TC, C~LLOT JJ, KARNOVSKY MJ: Regulation of Cel- Nature 1987, 326:403405. lular Proliferation by Heparin and Heparan Sulfate. In Hep arim Edited by lane DA, Lindahl U. London: Edward Arnold; 56. ROBERTS R, GAUAGHER J, SPOONCER E, AUEN TD, BLOOMFIEID 1989295316. F, DEXTER TM: Heparan Sulfate Bound Growth Factors: a Mechanism for Stromal CeU Haemopoiesis. Nufure 1988, 46. KMJRA K, MATXJBARA H, S-H S. KITA Y, SAKATA T, NISHITANI 332:376378. . Y, WATANABE S, HANAOKA T, FUJIWARA H: Role of Glycosamino- glycans in the Regulation of T Cell Proliferation Induced 57. SAKAGLICHI K, YANAGISH~A M, TAKEUCHI Y, AURBACH GD: Iden- by Thymic Stromaderlved T-cell Growth Factor. / fmmunol . tification of Heparan Sulfate Proteoglycans as a High Affinity 1991, 146:261%2624. Receptor for Acidic Fibroblast Growth Factor (aFGF) in a Many studies have indicated that the anti-proliferative effect of heparin Parathyroid Cell Line. J Biol &em 1991. 266:727&7278. is not due to the inactivation of a growth factor. This study argues that Characterization of a parathyroid ceU 150 kD receptor for acidic FGF a stroma-derived T ceU growth factor binds to heparin and is inacti- reveals that it bears a heparan sulfate chain that is critical for high-atfinity vated. This effect appears to be specific because other T ceU growth binding. These results indicate that ceU surface HSPGs dilfer in their Proteoglycans in cell adhesion, migration and proliferation Wight, Kinsella, Qwarnstrijm 801 binding affinities for Merent growth factors although the signUicance Factor and Protects it from Proteolytic Degradation. J Celf of these differences needs to be elucidated, Biol 1988, 197:743751. 58. YAYON 4 ~GSBURN M, ESKO JD, LEDER P, ORNI?Z DM: CelJ 68. BRIJNNER G, GABRILOVE J. R~FKIN DB, WILSON ET: Phospho- Surface, Heparin-like Molecules Are Required for Biding . Upase C Release of Basic Fibroblast Growth Factor from of Basic Growth Factor to Its High A&dry Receptor. Cell Human Bone Marrow Cultures as a Biologically Active Com- 1991. 64:841+48. plex with a Phosphatidylinositol-anchored Heparan Sulfate Roteoglycan. J Cell Biol 1991, 114:127>1283. 59. GTTA-GOREN H. SOKER S, VLODAVSKY I, NEUFEID G: The Bind- One of a number of recent papers demonstrating that PGs can asso- . ing of Vascular Endothelial Growth Factor to Its Recep- ciate with the surface of some cells via a phosphotidylinositol anchor tors is Dependent on CeU Surface Associated Heparin-like in the plasma membrane. This phosphatidylinositolassociated HSPG Molecules. J Biol Uwm 1992, 267:609+-C&98. binds bFGF and this complex can be released as a biologically active Another study that illustrates the importance of cell surface associated form by phospholipase C. This mechanism, together with the prote- hepatin-like molecules in the binding of a growth factor to its high- olytic cascade of plasminogen activation and plasmin ECM degradation, afTinity receptor. The potential significance of this interaction in the may generate bFGF-HSPG bioactive complexes and explain regulated regulation of angiogenesis needs to be explored. control of growth factor release from the ECM. 60. PRESTRELSKI SJ, FOX FM, ARAKAWA T: Binding of Heparin to 69. Rt~tu~ DB, MOSCATEUI: Recent Developments in the CeU . Basic Fibroblast Growth Factor Induces a Conformational Biology of Basic Fibroblast Growth Factor. J Cell Biol 1989, Change. Arch Bibem Bicp& 1992, 293:314-319. 109+6. This paper identifies highly reproducible and localized conformational changes in bFGF induced specifically by heparin through the use of 70. FOU(MAN J, KL4GSBURN M: Angiogenic Factors. Science 1987, infrared spectroscopy. Such changes suggest alterations in the number 235:442A47. of @urns. It remains to be shown whether these alterations inlktence 71. YAMAGUCHI Y, MANN DM, Ruoxwn E: Negative Regula- high-affinity binding of bFGF to its receptor. tion of Transforming Growth Factor-b by the Proteoglycan Decorin. Nafure 1990, 346:281-284. 61. RAF%EGER AC, KRUFKA A, OLWIN BB: Requirement of Hep . amrt Sulfate for bFGF-mediated Fibroblast Growth and Myo- 72. VAtNO S, JALKANE N M, VAAHTOKARI 4 SAHIBERG C, MAP M, blast Differentiation. Science 1991, 252:1705-1798. . BERNFIEID M, THESLEW 1: Expression of Syndecan Gene is Documentation that the presence of HSPG on the surface of cells is Induced Early, is Transient, and Correlates with Changes critical for bFGF binding and subsequent cellular activation. These in Mesenchymal CeU Proliferation during Tooth Organo- studies illustrate the importance of cell surface HSPG in bFGF-directed genesis. Dev Bill 1991, 147:322-333. skeletal muscle differentiation and proliferation of 3T3 cells. This system An important study because it confirms the transient expression in should allow identification of the specific HSPGs involved. mesenchymal cells of a cell surface PG that was once thought to be restricted to the surface of epithelial cells. The significance of selective 62. TURNBULL JE. FERNIG DG, KE Y, WIWNSON MC, GALLAGHER JT: syndecan expression in the proliferative process needs to be explored. . . Identification of the Basic Fibroblast Growth Factor Binding Sequence in Fibroblast Heparan Sulfate. J Biol C5em 1992, 73. SCHONHERR E, J&VEL&INEN HT, SANDEU LJ, WIGHI’ TN: Ef- 267:10337-10341, . fects of Platelet-derived Growth Factor and Transforming A valuable report on the characterization of the oiigosaccharide struc- Growth Factor-p1 on the Synthesis of a Large Versican- ture of HS required for binding to bFGF. This report indicates that like Chondroitin Sulfate Roteoglycan by Arterial Smooth specific binding sequences are present in segments of particular GAG Muscle Cells. J Biol Ckn 1991, 266:17640-17647. chains. This may be another example in which particular sequences Demonstrates that two growth factors with opposite mitogenic activity within polysaccharides interact with proteins such as previously demon- cause significant increases in mRNA transcripts for versican. However, strated for the binding of hepdrin to antithrombin III. only the mitogen alters the sulfation pattern of the CS chain. These post-translational modifications may be characteristic of the proliferative 63. CHEIFE~L S, MASSAGU~ J: Transforming Growth Factor-P phenotype. (TGF-0) Receptor Proteoglycan. Cell Surface Expression 74. POTIER-PERIGO S, BRAUN KR, SCHONHERR E, WIGM TN: In- and Ligand Binding in the Absence of Glycosaminoglycan . hibition of CeU Proliferation by P-D-xyloside Can be Dis- Chains. J Biol Cbem 1989. 264:1202>12028. sociated from Altered Proteoglycan Synthesis via the False 64. ANDKES JL. R~NNSIRAND L, CHEIFET% S, MASSAGUE J: Putica- Acceptor Pathway. Arch Biophy Bicx-hn 1992, 297:101-109. . tion of the Transforming Growth Factor -P(TGF-l3) Binding This study addresses the question of whether altered PG synthesis in- Proteoglycan p-glycan. J Biol Chem 1991, 266:23282-23287. fluences the capacity of cells to proliferate. The main conclusion is that Confirmation that p.glycan exists in tissue and has similar properties to the inhibitory effects of some xylosides on ceU proliferation must be the form identified on the surface of cultured cells. due to effects other than altered PG synthesis via the false acceptor pathway. 65. ANDRES JL, DE FAKIS D, NODA M. MASSAGU~ J: Binding of . Two Growth Factor Families to Separate Domains of the 75. GRESSNER AM: Questioning the Reliability of p-nitrophenyl- Proteoglycan Betaglycart. J Biol Cbem 1992. 267:5927-5930. . p- D-xyloside as Probe to Study the Metabolic Effects of Ab- The first demonstrdtion that two different growth factors can bind to rogated Roteoglycan Synthesis in Cultured Cells. Biodem the same PG by different mechanisms. These br vitro observations have Pbarmacol 1991, 42:1987-1995. implications regarding possible roles that the PG may play in the co- A study that raises the possibility that some of the biological effects of ordinate regulation of two growth factors (TGF-P and bFGF), which P.o.xyloside on cells and tissues are not due to the direct effect of xylo- have frequently been shown to demonstrate antagonistic activities. side on PG synthesis but rather to the aglycone derivative p-nitrophenol attached to b-o-xyloside. Such observations stress the importance of US- 66 VLODAVSK~ I, BAR.%A\‘IT R, ISHAI.MICHAELI R, BASHKIN P, FUKS ing diierently detivated b-xylosides and appropriate controls to CO~~ITII . . Z: Extracellular Sequestration and Release of Fibroblast the importance of altered PG synthesis in biological events such as pro- Growth Factor: a Regulatory Mechanism. Trends Biochem liferation. Sci 1991, 16:26%271. An excellent minireview on the expanding area of interest concerning the interaction of growth factors with PGs present on the surface of cells and within the ECM. TN Wight, MG Kin&la and E QwznstrBm, Department of Pathol- 67. S/UCSEIA 0, MOSCA~LLI D. S~M~IER A, RIFKIN DB: Endothelial ogy, University of Washington, School of Medicine, Seattle, Washington Cell-derived Heparan Sulfate Binds Basic Fibroblast Growth 98195, USA