[Frontiers in Bioscience 16, 698-706, January 1, 2011]
Cryptic activities of fibronectin fragments, particularly cryptic proteases
Maurice Pagano, Michele Reboud-Ravaux
Enzymology laboratory, Research Unit Number 4, University Pierre and Marie Curie, Postal Case 256, 7 Quai Saint Bernard, 75252 Paris Cedex 05, France
TABLE OF CONTENTS
1. ABSTRACT
Fibronectin (FN) is a modular glycoprotein encoded by a single gene. A soluble form of this protein is found in the plasma of several animals. Alternative splicing of pre-mRNA at three sites produces cellular and plasma FNs. The plasma form contributes to blood clotting and thrombosis. Many extracellular matrices (ECM) contain an FN network associated with a variety of cell activities through binding to cell surface integrin receptors. Fragments of FN can have cryptic activities that are specific to these fragments rather than to the intact protein. The metalloprotease activity present in the basement membrane and plasma fibronectins has been intensively studied in humans, bovine and rats. Organic inhibitors that are selective for the human cryptic enzyme have been produced.
2. INTRODUCTION
Fibronectin (FN) is a modular dimeric disulfide-bonded glycoprotein. The molecular mass of each subunit is about 230-270 kDa. Each subunit has three types of repeating modules, type I, II, and III (Figure 1). Types I and II modules each have two intrachain disulfide bonds, but type III modules have none (1). A single gene encodes FN. Alternative splicing of pre-mRNA at three sites produces the cellular and plasma FNs. This complex splicing mechanism generates 20 FN variants in human (2). Many mouse models with targeted mutations have been constructed and used to identify the possible roles of these variants (3). The assembly of the ECM FN network depends on the binding of FN to cellular integrin receptors and the activation of intracellular signaling pathways. These stepwise mechanisms involve numerous conformational changes in the structure of the FN dimer leading to the formation of FN fibrils. This supramolecular structure takes part in cell adhesion and movement (4). FN also has cryptic activities that are specific to FN fragments and not the intact protein. These activities have been associated with cartilage metabolism (5), proliferative diabetic retinopathy (6) adipocyte differentiation (7) and the initiation of fibrillogenesis (8). Some fragments have cryptic protease activities. The first report did not clearly characterize these activities of human plasma FN (9) but a second has provided more information on a collagenase located inside the gelatin binding domain (GBD) of this type of FN (10). We have described a similar gelatinase activity located in the same domain of both plasma and basement membrane FNs (11). This activity is related structurally and functionally to the matrix metalloproteinase 2 and 9 (MMP-2 and MMP-9) and has be found in humans, bovine and rats (10-12).
3. FIBRONECTINS: STRUCTURE, GENE EXPRESSION AND POLYMORPHISM
The modular structure of FN is dictated by the modular structure of its gene (2). Alternative mRNA splicing of the primary transcript of a single gene gives rise to a complex pattern of FN variants. The processing of this primary transcript involves three cleavage sites: IIICS, EDI and EDII, the so-called V, EDA and EDB sites. IIICS processing gives several variants because of exon subdivisions, while EDA and EDB are single exons each coding for a single type III repeat (2). The results of this complex gene expression mechanism in some species are summarized in Figure 2. The inactivation of the FN gene is lethal in the mouse embryo, indicating the essential nature of FN (13). The functions of these polypeptides variants in vivo are still not understood, but cells involved in skin wound healing contain increased quantities of FN with EDA and EDB domains, i.e cellular FN (cFN) (14). Similar patterns are found in other regenerating tissues, such as regenerating rat liver and lung fibrosis (15-17). A tissue injury leads to plasma FN (pFN) rapidly binding to fibrin and fibrinogen to form hemostatic clots (18). Thombin is also able to bind fibronectin containing extracellular matrix (19). More recent in vivo experiments using a model of ferric chloride arterial injury indicate that plasma FN (pFN) takes part in the formation of thrombi in the arterial wall (20,21). Hepatocytes synthesize pFN and secrete it as a heterodimer, one of whose subunits contains the IIICS variant (22, figure 2). FN also binds to the cellular heterodimeric transmembrane integrin receptors. It binds to the a5b1 integrin via its RGD tripeptide, located in an accessible loop of FN (23). Numerous integrin receptors can react with the RGD site (23, 24). The interaction between FN and the integrin receptors initiates the formation of a multimeric FN structure; this also activates intracellular signaling pathways (4). The three-dimensional structure of the GBD fragment of FN has been reported recently (25).
4 . THE CRYPTIC ACTIVITIES OF FIBRONECTINS
4.1. General cryptic activities
The group directed by Homandberg has studied the cryptic activity of FN that is involved in cartilage breakdown. They used cultured bovine cartilage explants to demonstrate large increases in gelatinase and collagenase activities and the release of proteoglycans. These properties are associated with the 29 kDa amino-terminal fragment and the 50 kDa gelatin-binding fragments, whereas intact FN has no enzymatic activity (5). The mechanism involved has recently been elucidated. FN fragments act via the MAP-kinases activation pathway to upregulate the synthesis of MMP3 and MMP13. The most potent fragment is the 29 kDa amino-terminal fragment (26). Another group obtained similar results with the 45 kDa FN fragment, the so-called GBD (27). They found that an aggrecanase activity was also liberated by the action of the FN-GBD fragment. These cryptic fragments could be associated with the cartilage damage that occurs in osteoarthisis (5, 26, 27). Fukai and collaborators described three FN fragments involved in adipocyte differentiation. These properties are linked to conformational changes or limited proteolysis by MMP2 (8). The most potent activity was located inside the heparin 2 C-terminal binding domain. This domain was exposed by urea treatment, which gave an unfolded fragment, or by limited proteolysis with MMP-2 (28). FN fragments may also be associated with angiogenesis, the proliferation and migration of vascular cells in a model of retinal diabetic retinopathy (7). The III1 domain has a cryptic activity that is important for the formation of fibrils. This III1 domain binds essentially to the III5 and III7 modules (29). Tomasini-Johansson et al have shown that binding of the N-terminal 70-kDa (70K) fragment of FN to fibroblasts blocks assembly of intact FN and is an accurate indicator of the ability of various agents to enhance or inhibit the assembly of FN (30).
4.2. Cryptic protease activity
We digested an intact basement membrane isolated from bovine lens capsule with the lysosomal cysteine proteases, cathepsins B, H and L in order to monitor the fragmentation of collagen IV, laminin and FN. These enzymes became bound to this ECM model in a saturable fashion, with Kd values of 1 to 6 10-7 M and 4-22.5 1012 binding sites per capsule (31). This digestion led to the production of gelatinase activities that were detected by gelatin zymography. We obtained similar results when the active fragments were isolated on heparin agarose and gelatin agarose (32). These observations agree well with the work of Keil-Doulha and colleagues on plasma FN (33). The gelatin zymography revealed several activities (32, 33). We are now convinced that the multiple bands observed on gelatin gels are best explained by a precursor-product relationship, as reported for the gelatinases MMP2 and MMP9 (34, 35). The well-characterized cryptic protease is located inside the gelatin binding domain (GBD) (12), whose structure was solved recently by X-ray crystallography (25). This zinc-dependent metalloproteinase is present in both the extracellular matrix and the plasma FNs (12). Sequence alignments indicate that the minimum consensus sequence HEXXH characteristic of zinc metalloproteinase is located in the I8 domain. It is present in all three of mammalian species that have been studied intensively, humans, bovine and rat (1). Our group has also studied this protease in the three species and demonstrated its general character (12, 13). It is related to the metalloproteinases MMP2 and MMP9, both structurally and functionally, (12) (Figure 3, from 12) despite the putative active site having a non-classical signature (25). The group led by Tschesche have expressed a cDNa coding for the GBD fragment in E. coli and used it to characterize a similar protease activity (36). The same group have identified another protease activity located in the central domain of fibronectin. This aspartyl protease was characterized using biochemical methods (37). We have recently demonstrated that a N-terminal proline-rich peptide (14 amino acids) is released from the FN-protease by autoproteolysis (38; Figure 4). The three-dimensional structure of GBD shows that this N-terminal tail is freely accessible (25). Similar proline-rich peptides have been found in bovine and rats (39-41), (Figure 5). The FN of all these three species may be involved in signaljng as it can be cleaved in a very peculiar manner to give rise to the prolyl-endopeptidase activity that is characteristic of the FN-protease (12, 13). Proline-rich peptides are associated with gene expression and intracellular signaling pathways (42). It has been postulated that FN protease activity arises after an FN becomes bound to integrins on the cell surface. This enzyme could liberate its proline-rich peptide which, in turn, activates intracellular signaling pathways that are linked to cell motility. Schor et al (43) showed that the GBD fragment can stimulate the migration of fibroblasts onto a 3D collagen I matrix. These results were obtained with femtomolar concentrations of GBD purified by several methods and apparently devoid of possible contaminants. These findings support the above hypothesis. The same group reported that fetal and cancer fibroblasts produce the migration stimulating factor (MSF). The MSF is a truncated isoform of FN; it is the 70 kDa N-terminal fragment of FN that contains the GBD/FN-protease (Figure 6). This truncated FN has a cryptic motogenic activity on fibroblast migration that is associated with the IGD tripeptide in type I FN motifs (44). NMR studies have shown that a mutation in that part of the gene that encodes the IGD motifs located within the modules I8 and I9 (45; Figure 6) leads to the loss of the motogenic activity but no significant changes in the structure of the FN in solution (45). MSF also has FN protease activity (46). Thus the FN protease could be involved in cell migration in pathological states, such as cancer progression. The evidence supporting this is that the 45 kDa FN protease is enzymatically active in a low zinc ion concentration and when zinc ions are absent (Figure 7). The activity was measured with a fluorogenic peptide whose structure mimics a collagen helix (47). The 45 kDa FN protease also binds to a labeled collagen peptide (25). Ultracentrifugation studies showed that the 45 kDa FN is a monomer in the absence of zinc ions (25). The enzymatic activity is gradually lost as the zinc ion concentration is increased (Figure 8). This loss of enzyme activity by the 45k Da FN protease is accompanied by the molecules forming dimers that do not bind to labeled collagen peptides and crystallizes as a dimer (25). The observations summarized in Figure 7 indicate that the 45 kDa monomeric FN protease is the active enzyme in the absence of zinc and when its concentration is low (66 mM). The dimeric, inactive FN protease is formed in the presence of high zinc ion concentrations, and this form tends to crystallize. We conclude that the monomeric 45 kDa FN protease is a biologically relevant enzyme.
Specific inhibitors of this new enzyme target could be useful for studying the biological role of this protease and may lead to potential drugs. We have developed coumarin-derived compounds in order to obtain specific inhibitors of FN protease (48).
Fibronectin (FN) (Cleaved into: Anastellin)
5. ACKNOWLEDGEMENTS
This work is dedicated to Vera-Keil-Doulha, research scientist at the Pasteur Institute (Paris), who first described the protease activities of fibronectin. I thank Professor S. Tabibzabeh, Editor-in-Chief of Frontiers in Bioscience for inviting me to organize this special issue. I am indebted to two graduate students, Nathalie Guinec (1988-1993), and Laziz Boudjennah (1992-1998), who both worked on the cryptic basement membrane protease from fibronectin. This work was performed in the "Biochemistry Laboratory, Medical School Broussais Hôtel-Dieu, University Pierre et Marie Curie". Financial support was provided by: Broussais Hôtel-Dieu Medical School, University Pierre et Marie Curie: 1980-1998. The French Agency for Cancer Research (ARC): 1984-1992. The French Agency for Research Promotion (ANVAR), in collaboration with Pierre Burtin (died 1993): 1984-1988. The French Agency for Medical Research (FRM): 1992-1994. The French League against Cancer, with Professor Michèle Reboud-Ravaux: 2004-2006, I thank Professor Michèle Reboud-Ravaux for encouraging me to continue my research in her group (Enzymologie Moléculaire et Fonctionnelle).
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Keys Words: Mammalian Fibronectins, Cryptic Activities, Fn-Proteinase, Small Molecular Mass Inhibitors, Review
Send correspondence to: Maurice Pagano, Enzymologie Moleculaire et Fonctionnelle, UR4, UPMC, Case 256, 7 Quai Saint Bernard, 75252 Paris Cedex 05, France, Tel:33- 144275993, Fax :33-1-44275022, E mail:maurice.pagano@upmc.fr
http://dx.doi.org/10.1016/joca.2008.02.015
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http://dx.doi.org/10.1074/jbc.M31278500
http://dx.doi.org/10.1016/j.matbio.2006.02.002
http://dx.doi.org/10.1016/0014-5793(92)81299-2
http://dx.doi.org/10.1111/j.1432-1033.1990.tb19462.x
http://dx.doi.org/10.1021/bi00028a038
http://dx.doi.org/10.1023/A:1007104420017
http://dx.doi.org/10.1023/A:1020684508212
http://dx.doi.org/10.1016/jabb.2008.08.016
http://dx.doi.org/10.1016/jbbapap.2007.08.012
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