Extracellular

matrix regulation of growth protease activity

Robert

Flaumenhaft

New York University

and Daniel

factor

and

B. Rifkin

Medical Center and the Raymond Foundation, New York, USA

and Beverly

Sackler

Extracellular matrices bind many growth factors, proteases, and protease inhibitors. These interactions not only localize these molecules to the pericellular environment, but also modulate their biological activities. Recent evidence suggests that some growth factors may be active in vivo primarily in complexes with extracellular matrix molecules and that this interaction may be essential to their activity.

Current

Opinion

in Cell

Biology

Introduction

1991,

3:817-823

act specifically with heparan sulfate proteoglycans within these ECMs [9-l 11.

factors interact with a variety of molecules in the extracellular environment other than their cell-surface receptors. Among these are components of the extracellular matrix (ECM). Although the significance of this interaction is unknown, in rWo studies suggest that the binding of growth factors to the ECM is critical for their biological activity. Growth factors bound to ECM often have altered potency, increased stability and modified diffusion properties, and are concentrated in the vicinity of the cell. In turn, growth factors can affect ECM chemistry by regulating the synthesis of particular matrix components as well as proteases which modify matrix molecules. This proteolysis can be modulated via components of the ECM and may mediate growth factor release and/or activation. These interactions form regulatory loops which may control the duration, localization, and degree of growth factor stimulation.

Growth

The ability of heparin to enhance the mitogemc activity of aFGF by 20-100.fold is well established [ 121. Although the mechanism of potentiation is unclear, heparin appears to induce a conformational change in aFGF and to enhance the affinity of the growth factor for its receptor [ 13,141. Subpopulations of heparan sulfate proteoglycans from ECM which bind strongly to aFGF [IS] and bFGF [ 161 have been isolated by growth factor affinity columns. The heparan sulfate proteoglycans that bind aFGF can be subdivided into those which enhance the mitogenic potential of the growth factor and those which inhibit it. Thus, the expression and/or occurrence of different proteoglycan subspecies may regulate aFGF activity. The role of heparin and heparan sulfate proteoglycans in the binding of FGFs to cell-surface receptors is an issue of great interest. Heparan sulfate proteoglycans act as low-akity binding sites for FGFs, but do not appear to be responsible for signal transduction [ 171. Recently, a heparan sulfate proteoglycan which has a high affinity for aFGF has been isolated from a parathyroid cell line [ 18.1. Although it is uncertain whether this heparan sulfate proteoglycan is involved in signal transduction, the molecule binds aFGF with a & of 3.9pM and its gfycosaminoglycan moieties are necessary for binding aFGF. A requirement for heparan sulfate in the biological activ ity of bFGF is suggested by the observation that mutant Chinese hamster ovary (CHO) cells defective in the ability to synthesize heparan sulfate glycosaminoglycans are unable to bind bFGF when transfected with cDNA encoding the bFGF receptor [ 19**]. However, the binding of bFGF to its receptor in these cells is reconstituted after the addition of heparin. This is the first demonstration

Interaction of acidic and basic fibroblast growth factor with heparin species The best characterized growth factors with respect to ECM interactions are acidic and basic fibroblast growth factors (aFGF and bFGF), which belong to a family of seven heparin-binding molecules that share 30-50% sequence homology [ 1,2]. Acidic and bFGF were purified to homogeneity owing to their strong binding to heparin [ 3-51. Consistent with their interaction with heparin, aFGF and bFGF have been immunolocalized to [6,7], and isolated from 181, the basement membranes of a variety of tissues, and have been demonstrated to interAbbreviations CHSChinese bFG&basic

hamster fibroblast

ovary;

ECh+-extracellular

growth factor; IL-interleukin;

matrix;

ECkpidermal

CM-CSF-granulocyte-macrophage PAI-plasminogen activator

@

Current

Biology

growth

factor;

colony-stimulating inhibitor; TGF-transforming

Ltd

ISSN

0955+674

aFCLacidic

fibroblast

factor; HCF-hepatocyte growth factor.

growth growth

factor; factor;

817

818

Cell-to-cell

contact

and extracellular

matrix

.

that a matrix-derived glycosaminoglycan may be required for the binding of a growth factor to its cell-surface receptor, perhaps by inducing a conformational change in bFGF. The binding of heparin and heparan sulfate to acidic and bFGF also increases the stability of the complex. Heparin protects the FGFs from thermal denaturation, deactivation by acid and proteolytic degradation [20,21 I, and increases their half-lives in u&o [ 221. Protection of FGFs from proteolytic degradation may be important in their biology as FGFs may function in processes in which proteaSe activity is high (e.g. angiogenesis, wound healing) and both acidic and bFGF stimulate the secretion of proteases. Basic FGF bound to matrix in a protected state retains activity for an extended period of time [23*,24,25]. Cells exposed to bFGF for as little as 10 min bind the growth factor and demonstrate bFGF-stimulated increases in DNA synthesis and protease production at least 24 h later. This long-term stimulation after short-term exposure is inhibited if bFGF is prevented from binding to heparan sulfate proteoglycans in the matrix. Thus, the ECM functions as a reservoir of bFGF, allowing the sustained release of active growth factor. The FGF is probably solubilized as a FGF-heparan sulfate complex which is relatively resistant to proteolytic degradation. Once solubilized, the bFGF-heparan sulfate complex possesses an increased ability to d&se in an environment rich in insoluble acidic glycosaminoglycans because its heparan sulfatebinding sites are occupied. For example, bFGF-heparin diffuses over a lo-fold greater area on an endothelial cell monolayer than bFGF alone [ 260.1. Thus, the active FGF species in viuo is probably the FGF-heparan sulfate complex. Although binding to heparin and heparan sulfate proteoglycans is the best characterized interaction between FGFs and matrix molecules, FGFs appear to interact with other matrix components including immobilized collagen IV [27], syndecan, a polymorphic chondroitin sulfate/heparan sulfate proteoglycan [ 28*], fibronectin and laminin [29]. Future work is likely to reveal further subtleties in the interactions between FGFs and matrix molecules.

The interactive relationship between transforming growth factor-@ and the extracellular matrix

Transforming growth factor (TGF)-Pl is the prototypical member of a family of proteins which affect diierentiation, morphogenesis, and growth [30]. Unlike the FGFs, which interact most avidly with the glycosaminoglycans of ECM proteoglycans, TGF-Pl interacts primarily with the protein core of proteoglycans. In addition to being bound by ECM, TGF-Pl modulates many aspects of matrix biochemistry. One of the three species of cell-surface receptors with which TGF-PI associates [31] is a 250-350kD hep-

aran and chondroitin sulfate proteoglycan called betaglycan. Betaglycan is present as soluble and matrix-bound species [32,33,34]. TGF-@1 binds to the protein core of betaglycan [35] with a G of 1.9nM. This interaction is thought either to concentrate TGF-P1 at the cell surface for presentation to high-affinity receptors or to aid in the clearance of TGF-PI. TGF-01 also induces the expression of specific matrix proteoglycans. Among the proteoglycans whose synthesis TGF-PI induces are decorin and biglycan [36]. This stimulation is of particular significance because these proteoglycans bind TGF-61 and appear to inhibit its activity [37**]. Thus, TGF-PI activity may be controlled by a negative feedback system in which the induction of decorin and biglycan synthesis by TGF-PI produces a molecule which inhibits further TGF-PI activity, The significance of the binding of TGF-fll to other matrix molecules such as libronectin [ 381 and collagen IV is less apparent [ 391.

Other

matrix-binding

growth

factors

Although the interactions of matrix molecules with the FGFs and TGF-j% are the best-studied growth factor-matrix interactions, other growth factor-ECM interactions have been identified. For example, perfusion of rat liver with 1 M NaCl releases a large amount of hepatocyte growth factor (HGF) from the ECM in the subendothelial space of the liver [40]. HGF contains kringle domains, a protein motif known to modulate the interaction of plasmin with fibrin [41-l. It is probable that the HGF-matrix interaction is mediated through this strutture. The int-1 proto-oncogene product, like the FGFs, is bound to the ECM of cultured cells which synthesize this factor [42]. Molecules in the ECM have been shown to cooperate with ciliaty neurotrophic factor to induce astrocyte differentiation in serum free cultures [43]. An epidermal growth factor (EGF)-like molecule recently isolated from macrophage cultures probably binds tightly to the ECM, as it dissociates from heparin only at salt concentrations of l.O-1.2M NaCl or greater [44*]. A number of other growth factors, such as the bone morphogenetic proteins and the colony-stimulating factors (e.g. granulocyte-macrophage colony-stimulating factor), may also be localized to matrix (see below).

Protease-matrix interactions for growth factors

and consequences

Although the ECM acts as a repository for growth factors, it is not an inert reservoir. Matrix is a dynamic environment which binds numerous biologically active molecules, including proteases and their inhibitors. For example, thrombin binds to dermatan sulfate in the subendothelial ECM and, once bound, is protected from inactivation by circulating thrombin inhibitors [451. However, the thrombin inhibitors, anti-thrombin ILI, heparin

Extracellular

matrix

regulation

cofactor II and protease nexin I, bind heparan sulfates in the ECM, and this binding enhances their inhibitory activity [ 461. By concentrating growth factors, proteases, and protease inhibitors to the pericellular arena, the matrix facilitates both the activation of latent growth factors and the release of bound factors via specific proteolytic reactions. The ability of ECM to regulate protease activity is demonstrated by the interactions between matrix and many components of the plasminogen activator system. The binding of plasminogen to ECM accelerates the rate of the activation of the zymogen to plasmin. Plasmin generated on the matrix is protected from inhibition by a*-plasmin inhibitor, the major plasmin inhibitor in serum [47]. Matrix molecules such as heparan sulfate, collagen, and laminin markedly enhance the activation of plasminogen by tissue plasminogen activator [48,49*]. Thrombospondin, an adhesive glycoprotein, may catalyze the production of plasmin by localizing plasminogen activator and plasminogen to the cell surface [50]. In addition, both plasminogen and tissue plasminogen activator bind to immobilized libronectin [51]. Matrix components also bind and regulate inhibitors of the plasminogen activator system. Vitronectin binds plasminogen activator inhibitor (PAI)-I, stabilizing the inhibitor and increasing its half-life [ 521. The activity of PAI- is also enhanced by heparin [ 53.1, as is that of plasminogen activator. The concentration and enhancement of both activation and inhibition reactions might result in expedient plasmin generation followed directly by inhibition of excess activity. One function of matrix-associated proteases may be to release growth factor stored in the ECM. Basic FGF bound to heparan sulfate proteoglycans in the matrix can be released by digestion with plasmin, heparinase, or phospholipase C [23*,54]. 1251.bFGF bound to the ECM of cultured cells can also be released when the cells are incubated with plasminogen. This release is enhanced af ter exposure of the cells to bFGF, which stimulates plasminogen activator production by the cells, or decreased by exposing the cells to TGF- pl, which inhibits such production [23*]. Thus, the plasminogen activator system is involved in mobilizing growth factor bound to ECM molecules. While other enzymes, such as heparinase, may release bFGF from the matrix, bFGF released as a complex with heparan sulfate by plasmin cleavage of the proteoglycan core protein of the heparan sulfate proteoglycans will remain both active and protected from further proteolytic degradation. Matrix-associated protease activity may also be involved in the activation of latent growth factors. For example, TGF-01 is secreted in a latent form consisting of a noncovalent complex of an amino-terminal latency-associated peptide and the mature cytokine [30]. Inhibition of plasminogen activator activity inhibits the activation of latent TGF-PI observed upon the culturing of endothehal cells with smooth muscle cells [55,561, suggesting that plasminogen activator is involved in the activation of latent TGF-/31 in co-cultures. The activation of latent TGF-PI in this co-culture system is self-limiting, how-

of growth

factor

and protease

activity

Flaumenhaft

and Rifkin

ever, because active TGF-fil stimulates synthesis of PAI-1, which inhibits further plasminogen activator-mediated activation of latent TGF-Pl [ 57.1.

Growth factor-matrix systems

interactions

in organ

The sequestration of growth factors in matrices has lead to the development of models suggesting functional significance of this interaction in the physiology of various organs. For example, the development and growth of osseous tissue may be controlled by the variety and quan tity of growth factors stored in its matrix. The concentrations of mitogens in bone powder is 20-times greater (per volume) than in serum and IOO-times greater than is required to maximally stimulate osteoblasts [ 581. Growth factors identified in bone matrix Include latent TGF-Pl and the related molecules cartilage-induction factors type A and B, insulin-like growth factors I and II, acidic and basic FGF, osteogenin, and bone morphogenetic proteins. It is possible that these factors are sequestered in an inactive form (i.e. unable to interact with their cell-surface receptor) and solubilized through the activity of proteases and osteoclasts during bone remodeling. Other processes in which the compartmentalization of growth factors by ECM molecules has been implicated include hematopoiesis and T-cell proliferation in the thymus. The proliferation and maturation of hematopoietic progenitor cells is dependent on factors including the colony-stimulating factors. Granulocyte-macrophage colony-stimulating factor (GM-CSF) can be eluted from the ECM of cultured bone marrow stromal cells [59]. The moiety responsible for this binding is thought to be heparan sulfate [6O], which binds GM-CSF and interleukin (IL)-3 in a biologically active form. The retention of growth factors by the heparan sulfate proteoglycans of bone marrow stromal cells may contribute to a microenvironment permissive for hematopoiesis. Similarly, thymic stroma-derived T-cell growth factor, which supports the growth of IL-2-dependent thymic stromal cells, binds to heparin and heparan sulfate [6I*] and thus might be retained in the ECM.

Conclusion

The availability of an increasing number of growth factors and the characterization of new proteoglycans will enable investigators to clarify the nature of growth factor-matrix interactions and better establish the biological significance of this interaction. A central problem in the regulation of growth factors in the extracellular environment is how the activities of these potent polypeptides are limited to an appropriate duration, location, and degree following their release from cells. Molecules of the ECM contribute to the solution of this problem by regulating growth factor action in time, space, and extent in the following ways:

819

820

Cell-to-cell

contact

and extracellular

matrix

First, the sequestration and orotection of growth factors by matrix molecules proloigs their a&o\ beyond the the of their synthesis and secretion. The time course of their activity is extended by binding to the ECM and by the action of other molecules, such as proteases, heparanases, and phospholipases, which effect their release from the matrix. In contrast, negative effects in which growth factor activity is inhibited by matrix molecules, whose synthesis is induced by these factors, limits the duration of growth factor activity. Second, binding to the ECM localizes growth factors to the immediate environment of the cells from which they are secreted. This binding enhances the autocrine potential of growth factors. Growth factor-ECM interactions might also contribute to the creation of microentironments within anatomical compartments in which the proliferation and maturation of specialized cells can occur (e.g. hematopoiesis and lymphopoiesis). Keating and Gordon [62] have suggested that the variation of proteoglycan expression in tissues of diRerent origin may constitute a code which determines the localization of growth factors and provides the appropriate microentironment for that tissue. Third, the ability of ECM molecules to enhance or inhibit growth factor activity affords for a variation in the intensity of response to a single factor dictated by the ECM molecules which it encounters. Many issues need to be examined in the future to understand the nature and significance of growth factor-matrix interactions. To clarify the function of ECM molecules in the regulation of growth factor activity, the specificity of these interactions at the molecular level must be defined. Once the details of growth factor-ECM binding are appreciated in three dimensions, general principles may emerge to allow us to understand, and perhaps predict, the effects of specific ECM molecules on individual growth factors. For example, what are the domains in heparan sulfate responsible for binding FGFs? Are unique domains present in subpopulations of heparan sulfates which have different affinities for and influences on FGFs or are these properties a function of the threedimensional configuration of the heparan sulfate-FGF interaction? The role that the growth factor-ECM interaction has in l&and-receptor binding must be determined. tie there examples, other than bFGF, of a requirement for matrix molecules in the binding of a growth factor to its cell-surface receptor? Is the matrix molecule internalized along with the receptor? Can various matrix molecules affect the ligand-receptor binding in diierent ways, stimulating alternate second messenger systems and varying cellular responses? The conditions and mechanisms by which growth factors are retreived from the ECM must be further characterized. Is delivery to receptors a function of mass action (resulting from higher a&-&y of the growth factor for the receptor than for the ECM) or a function of protease activity releasing the factor from matrix molecules?

Finally, the significance of growth factor-matrix interactions in viuo must be established. Do some growth factors act in llizlo only while bound to certain matrix molecules? Can this interaction be modulated to affect the activity of the factor? Are changes in matrix composition causal in affecting developmental potential? Understanding the extracellular regulation of growth factors is important if we are to know the role of these modulators in normal physiology and during pathological processes. It appears that the characterization of their interactions with ECM molecules will contribute to understanding this regulation.

Acknowledgements The authors thank Dr David Moscatelli for helpful comments on the manuscript. Our work is supported by a Berlex Laboratories Predcxtonl Fellowship Award (R Flaumenhaft). and grants T32GM07308 (R Flaumenhti). CA23753 (DB Rifkin). and CA34282 (DB Rifkin) from the National Institutes of Health and BE 12 (DB Rifkin) from the American Cancer Society.

References

and recommended

Papers of special interest, published have been highlighted as . of interest .. of outstanding interest 1.

BCIRGESS WH.

RIFKIN

Biology 109:14. 3.

DB,

Family

7.

MACLAG T, h&HlhMN

GOSPODAROWICZ

T, FIUESEL. R, ~CHlWHtx

D,

AB: Heptin Binds Factor, the Principal EndotheUal Brain. Science 1984, 225:932-935.

CHENG

J, LLII GM,

BAN

4

Endothelial

R, B~I-E~I~I~

Purilication Cell Growth

P:

C,

BUSCAGUA

M, ONG

of Basic Fibroblast Growth Factor tus: Localization in the Basement Tissues. J Cell Biol 1990, 110:75+765.

MAIMS

J,

of a TumorFactor. Science

CORDON-Cm C. VLODAmh?’ 1. HAIhiOWITFRIEDhtAN D, FLIKS Z: Expression of Basic Fibroblast Growth Normal Tissues. Lab fnvesl 1990, 63:832&O. A-M,

BOHUN

Fibroblast Growth Factor by HeparinChromatography: Identity with Pituitary Factor. Proc Nat/ Acad Sci [&I 19%.

SHING Y, FOLUAN J, SIILLIVAN KIAGSHR~N M: Heparin Afkity:

GONUEZ

of review,

D: Recent Developments in the Cell Fibroblast Growth Factor. J Cell Viol 1989,

Derived Capillary 1984, 223:12961299. 6.

petitd

MOSCATEIU

of Basic

Isolation of Brain Sepharose AtYinity Fibroblast Growth 816963-6967. 5.

the annual

Heparin-Biding (Fibroblast) of Proteins. Ann Re?’ Rio&em 1989.

Endothelial Cell Growth Cell Mitogen in Bovine 4.

nithin

f’dAClAG T: The

Growth Factor 58:57+606 2.

reading

A, HICKUN

Factor

in

A: Distribution in the 18.Day Rat FeMembranes of Diverse

M, BAIRD

8.

F0IJchi.m J, KIAGSHRUN M, SASSE J, WALXINSKI M, INGBER D. VIDDAvsh1’ I: A Heparin-Binding Angiogenic Protein - Basic Fibroblast Growth Factor-is Stored within Basement Membrane. Am J Pal/d 1988, 130:393400.

9.

ROSENCART TK, KUPERSCHMID JP. MACIAG T, CIARK R: Heparin-Binding

FERRANS

Factor-l

VJ,

CASSEIS

(Endothelial

W,

Extracellular Cell Growth 19fM,

Srr?g

Factor) 7:31 I-317.

Binds

matrix

to Endothelium

regulation

In

Vlvo.

J Vast

of growth 21.

factor

and protease

GOSPODAROU~~CZ

and

Acidic

D,

FGF

activity CHENC

from

Flaumenhaft J:

Inactivation.

Heparin J

Cell

and Rifkin Basic

Protects P&siol

1986,

128:4754X 10.

JFANNY JC, FAYEIJN N. MOENNI:R D. CO~RTOIS Y: Spectic Fixation

B, BARRITA‘A~~LT

of Bovine Brain and Retiand Basic Fibroblast Growth Factors to Mouse Eye Basement Membranes. EQ Cell Res 1987,

22.

VIGNY M, OUJER-HARThiANN MP, LAVIGNE M. FAY~IN N. JEXNNY JC, LAURENT M. COIIRTOIS Y: Specific Binding of Basic Fibrob-

23. .

nal Acidic Embryonic 17 1:6375. 1 I.

M. CHE~AUJER

last Growth Factor to Basement Membrane-Like and to Purified Heparan Sulfate Proteoglycans Tumor. / Cell P&iol 19t?A. 137:321-328. 12.

SC, MLIEILER SN. LEVINE EM: Human Use of Purified Heparin in Cloning and Cultivation. Science 1983. 22Z623-625.

Endothelial Long-Term

THORTON

Cells: Serial 13.

Structures of the EHS

kXw33ER

!&,

UNNEY

J.

KOWAISKI

WJ,

PRIESIX

R,

KAI%ow fect of

the

15.

JM. BEIJDOT F. CRIIMIXY Heparin on the Binding

Cloned

Hiopjqs

Human

Res Commlctl

G, DIONNE GA, JAYX h4: EfAffinity of Acidic FGF for FGF Receptors, Fig and Bek. RimJxm 1990. 172:107-l 12.

GORDON PB, CHOI IN. ROSENREHG I, HATCHER

Sulfate Proteoglycans of Acidic Fibroblast

CONN G, &IhiED VB: Extracellular

Modulate the Growth Factor.

A, EHKMANN B, Matrix Heparan

Mitogenic J Cell

Capacity 1989.

PJnGol

140:5n4-589.

16.

SAKXIA

17.

MO%ZA~:IJJ

0, MOSCATIUI D. SOhlhiER 4 RIFKIN DB: Endothelial Cell-Derived Heparan Sulfate Binds Basic Fibroblast Growth Factor and Protects it from Proteolytic Degradation. ./ Cell Rio1 1988, 107:7‘43-751. D: High

and

Low

Af%ity

Binding

Sites

for

Basic

Fibroblast Growth Factor on Cultured Cells: Absence of a Role for Low Atlinity Binding in the Stimulation of Plasminogen Activator Production by Bovine CapUaUary Endothelial Cells. J Gel PJqiol 1987. 131:123-130. 1X. .

SAKAGIICHI

19.

Y. AIIRIIACH GD: IdenSulfate Proteoglycans as a High AUinity Fibroblast Growth Factor (aFGF) in a

tification of Heparan Receptor for Acidic Parathyroid Cell Line. J Biol &WI

YAYON A, KIACSHRIIN Surface, Heparin-Like

M. ESKO JD.

IEIXR

P, ORNrrL

Molecules are Required of Basic Fibroblast Growth Factor to its High ceptor. CeU 1991. 64:84-pk8.

DM:

CeU

RO~ENGAU~ TK. WARREN JV. FIUESEL R, CIARK R, MACIAC T: Heparin Protects Heparin-Binding Growth Factor-l from Proteolytic Inactivation In Vitro. Biocbem Bi@ys Res Common

1988.

24.

152:432440.

SAKSEIA 0.

RIFKIN DB: Release of Basic Flbroblast Growth Factor-Heparan Sulfate Complexes from Endothelial Cells by Plasminogen Activator-Mediated Proteolytic Activity. J

Cell Riol FGF-binding

FIALI~IENHAFT of Extracellular

R, MOSCATEIJJ

Matrix Growth Factor: Matrix Long-Term Stimulation Synthesis. J Cell P@sioI

D,

SAKSEIA 0,

RIFIUN

in the Action of Basic as a Source of Growth of Plasminogen Activator 1989, 140:75+X.

DB:

Role

Fibroblast Factor for and DNA

25.

PKESTA M, MAIER JAM, RUSNATI M, RAGNOT~ G: Basic Firoblast Growth Factor is Released from Endothellal Extracellular Matrix in a Biologically Active Form. J Cell P&i01 1989, 14068-74.

26. ..

PIAIIMENHAFT

aran tion

D. RIFK~ DB: Heparin the Radius of Dtision Growth Factor. J Cell

R. MOSCATEUJ

Sulfate Increase of Basic Fibroblast

and Hepand Ac-

Biol 1990, 111:1651-1659. To stimulate anglogenesis, bFGF must diffuse from an avascular tissue through an environment rich in insoluble glycosaminoglycans to blood vessels some distance away. This paper demonstrates that bFGF alone is unable to ditise in an ECM because it binds to insoluble glycosaminoglyc~ns. whereas hFGF complexed with heparin or heparan sulfate partitions into the soluble phase and is able to diKuse. The techniques described in this paper may be used to evaluate the ability of other matrix-binding molecules to diffuse within the ECM.

27.

THOMPSON

J&

ANDER~N

KD,

DIPETRO

JM.

M, ANDERK)N WF. MACIAG T: Site-Directed tion In Vioo. Science 1988, 241:1349-1352.

2% .

ZWrEBEL JA, ZAMEITA

Neovessel

Forma-

RD: Syndecan, a Developmentally Regulated Cell Surface Proteoglycan that Binds Extracellular Matrix and Growth Factor. Phil Trams R Sot Land 1990,

BER~~FI~~D M, SANDERSON

B327:171-186. This paper reviews the suucture and expression of syndecan and proposes how this proteoglycan may function in development by binding both ECM and growth factors. The authors have ob.served that the heparan sulfate side chains of syndecan bind bFGF and discuss how the developmentally regulated expression of this characterized proteogly can may modulate the localization of growth factor to the ceU surface.

29.

for Binding AtTiniry Re-

This paper is the lirst demonstmtion of a requirement for a g$‘cosaminoglycan in the binding of a growth factor fo its cell-surface receptor. The authors demonstrate that bFGF does not hind to FGF receptors rxpressed by heparan sulfate-deficient mutants tmns. fected with FGF receptor DNA Binding of hFGF, however, is reconstituted in the presence of free heparin or heparan sulfate. The use of glycosaminoglycan.dtilicient mutants transfected with growth factor receptor may provide a valuable technique in evaluating the role of gly cosaminoglycans in the binding of other growth factors to their receptors. 20.

RR, D’AMORE PA, WAGNER JA: Heparln PoAction of Acidic Fibroblast Growth Factor its Biological Half Life. J Cell Pbysiot 1989,

L~HR

1990, 110:767-776. heparan sulfate proteoglycans can be released from endothelial cell monolayers by plasmin digestion. The release of these heparan sulfate proteoglycans is regulated by factors which modulate the proteolytic balance in the pericellular environment. These studies demonstrate how proteobis at the cell surface may contribute to growth factor release from the ECM. Basic

K, YANAC;ISHTTA M, TAKI