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• W2005013263 abstract "Two nervous tissue-specific chondroitin sulfate proteoglycans, neurocan and phosphacan (the extracellular domain of protein-tyrosine phosphatase-ζ/β), are high-affinity ligands of tenascin-C. Using portions of tenascin-C expressed as recombinant proteins in human fibrosarcoma cells, we have demonstrated both by direct radioligand binding assays and inhibition studies that phosphacan binding is retained in all deletion variants except those lacking the fibrinogen-like globe and that phosphacan binds to this single domain with nearly the same affinity (K d ∼12 nm) as to native or recombinant tenascin-C. However, maximum binding of neurocan requires both the fibrinogen globe and some of the adjacent fibronectin type III repeats. Binding of phosphacan and neurocan to intact tenascin-C, and of phosphacan to the fibrinogen globe, is significantly increased in the presence of calcium. Chondroitinase treatment of the proteoglycans did not affect their binding to either native tenascin-C or to any of the recombinant proteins, demonstrating that these interactions are mediated by the proteoglycan core proteins rather than through the glycosaminoglycan chains. These results are also consistent with rotary shadowing electron micrographs that show phosphacan as a rod terminated at one end by a globular domain that is frequently seen apposed to the fibrinogen globe in mixtures of phosphacan and tenascin-C. C6 glioma cells adhere to and spread on deletion variants of tenascin-C containing only the epidermal growth factor-like domains or the fibronectin type III repeats and the fibrinogen globe. In both cases cell adhesion was inhibited by similar concentrations of phosphacan, demonstrating that the fibrinogen globe is not necessary for this effect, which is apparently mediated by a direct action of phosphacan on the cells rather than by its interaction with the proteoglycan binding site on tenascin-C. Two nervous tissue-specific chondroitin sulfate proteoglycans, neurocan and phosphacan (the extracellular domain of protein-tyrosine phosphatase-ζ/β), are high-affinity ligands of tenascin-C. Using portions of tenascin-C expressed as recombinant proteins in human fibrosarcoma cells, we have demonstrated both by direct radioligand binding assays and inhibition studies that phosphacan binding is retained in all deletion variants except those lacking the fibrinogen-like globe and that phosphacan binds to this single domain with nearly the same affinity (K d ∼12 nm) as to native or recombinant tenascin-C. However, maximum binding of neurocan requires both the fibrinogen globe and some of the adjacent fibronectin type III repeats. Binding of phosphacan and neurocan to intact tenascin-C, and of phosphacan to the fibrinogen globe, is significantly increased in the presence of calcium. Chondroitinase treatment of the proteoglycans did not affect their binding to either native tenascin-C or to any of the recombinant proteins, demonstrating that these interactions are mediated by the proteoglycan core proteins rather than through the glycosaminoglycan chains. These results are also consistent with rotary shadowing electron micrographs that show phosphacan as a rod terminated at one end by a globular domain that is frequently seen apposed to the fibrinogen globe in mixtures of phosphacan and tenascin-C. C6 glioma cells adhere to and spread on deletion variants of tenascin-C containing only the epidermal growth factor-like domains or the fibronectin type III repeats and the fibrinogen globe. In both cases cell adhesion was inhibited by similar concentrations of phosphacan, demonstrating that the fibrinogen globe is not necessary for this effect, which is apparently mediated by a direct action of phosphacan on the cells rather than by its interaction with the proteoglycan binding site on tenascin-C. We have previously reported that neurocan and phosphacan/protein-tyrosine phosphatase-ζ/β, two major nervous tissue-specific chondroitin sulfate proteoglycans, are high affinity ligands of tenascin-C (apparent K d ∼3 nm) and that phosphacan inhibits the adhesion of C6 glioma cells to tenascin-C (1Grumet M. Milev P. Sakurai T. Karthikeyan L. Bourdon M. Margolis R.K. Margolis R.U. J. Biol. Chem. 1994; 269: 12142-12146Abstract Full Text PDF PubMed Google Scholar). Neurocan is a multidomain proteoglycan with a 136-kDa core protein (2Rauch U. Karthikeyan L. Maurel P. Margolis R.U. Margolis R.K. J. Biol. Chem. 1992; 267: 19536-19547Abstract Full Text PDF PubMed Google Scholar) and together with versican and brevican is a member of the aggrecan family of hyaluronan-binding proteoglycans (3Margolis R.K. Rauch U. Maurel P. Margolis R.U. Perspect. Dev. Neurobiol. 1996; 3: 273-290PubMed Google Scholar). It contains N-terminal immunoglobulin-like and hyaluronan-binding domains, a C-terminal domain consisting of EGF-, lectin-, and complement regulatory protein-like sequences, and a nonhomologous central domain of 593 amino acids, which contains the attachment sites for the three chondroitin sulfate chains and a large number ofO-glycosidic oligosaccharides. In contrast, phosphacan (4Maurel P. Rauch U. Flad M. Margolis R.K. Margolis R.U. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 2512-2516Crossref PubMed Scopus (258) Google Scholar,5Maurel P. Meyer-Puttlitz B. Flad M. Margolis R.U. Margolis R.K. DNA Sequence. 1995; 5: 323-328Crossref PubMed Scopus (22) Google Scholar), which contains a 173-kDa core protein and three chondroitin sulfate chains, is an mRNA splicing product that represents the entire extracellular domain of a receptor-type protein-tyrosine phosphatase that also occurs as a chondroitin sulfate proteoglycan in brain (3Margolis R.K. Rauch U. Maurel P. Margolis R.U. Perspect. Dev. Neurobiol. 1996; 3: 273-290PubMed Google Scholar). Phosphacan and protein-tyrosine phosphatase ζ/β have an N-terminal carbonic anhydrase-like domain followed by a fibronectin type III sequence. The phosphatase has, in addition to two cytoplasmic catalytic domains, an extracellular juxtamembrane sequence of 860 amino acids that may be deleted by alternative splicing (6Levy J.B. Canoll P.D. Silvennoinen O. Barnea G. Morse B. Honegger A.M. Haung J.-T. Cannizzaro L.A. Park S.-H. Druck T. Huebner K. Sap J. Ehrlich M. Musacchio J.M. Schlessinger J. J. Biol. Chem. 1993; 268: 10573-10581Abstract Full Text PDF PubMed Google Scholar) and appears to contain most of the chondroitin sulfate attachment sites that are actually utilized (7Sakurai T. Friedlander D.R. Grumet M. J. Neurosci. Res. 1996; 43: 694-706Crossref PubMed Scopus (78) Google Scholar). The binding of phosphacan/protein-tyrosine phosphatase ζ/β to tenascin-C is mediated at least in part byN-linked oligosaccharides on the proteoglycan (8Milev P. Meyer-Puttlitz B. Margolis R.K. Margolis R.U. J. Biol. Chem. 1995; 270: 24650-24653Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar).In addition to their high-affinity binding to tenascin-C, neurocan and phosphacan also interact with several immunoglobulin superfamily neural cell adhesion molecules including Ng-CAM/L1, N-CAM, TAG-1/axonin-1, Nr-CAM, and contactin (9Friedlander D. Milev P. Karthikeyan L. Margolis R.K. Margolis R.U. Grumet M. J. Cell Biol. 1994; 125: 669-680Crossref PubMed Scopus (389) Google Scholar, 10Milev P. Friedlander D.R. Sakurai T. Karthikeyan L. Flad M. Margolis R.K. Grumet M. Margolis R.U. J. Cell Biol. 1994; 127: 1703-1715Crossref PubMed Scopus (285) Google Scholar, 11Milev P. Maurel P. Häring M. Margolis R.K. Margolis R.U. J. Biol. Chem. 1996; 271: 15716-15723Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, 12Peles E. Nativ M. Campbell P.L. Sakurai T. Martinez R. Lev S. Clary D.O. Schilling J. Barnea G. Plowman G.D. Grumet M. Schlessinger J. Cell. 1995; 82: 251-260Abstract Full Text PDF PubMed Scopus (368) Google Scholar). Most of these interactions have apparent dissociation constants in the subnanomolar range, and they are affected in different ways by the removal of N-linked oligosaccharides or chondroitin sulfate chains (8Milev P. Meyer-Puttlitz B. Margolis R.K. Margolis R.U. J. Biol. Chem. 1995; 270: 24650-24653Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 11Milev P. Maurel P. Häring M. Margolis R.K. Margolis R.U. J. Biol. Chem. 1996; 271: 15716-15723Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). Immunocytochemical studies of embryonic and early postnatal nervous tissue showed an overlapping localization of the proteoglycans with all of their identified ligands, further supporting the biological significance of their ability to interact in vitro. In addition to their demonstrated high-affinity interactions with neural cell adhesion and extracellular matrix proteins, neurocan and phosphacan are also potent inhibitors of cell adhesion and inhibit or stimulate neurite outgrowth depending on the cell type and other factors (1Grumet M. Milev P. Sakurai T. Karthikeyan L. Bourdon M. Margolis R.K. Margolis R.U. J. Biol. Chem. 1994; 269: 12142-12146Abstract Full Text PDF PubMed Google Scholar, 9Friedlander D. Milev P. Karthikeyan L. Margolis R.K. Margolis R.U. Grumet M. J. Cell Biol. 1994; 125: 669-680Crossref PubMed Scopus (389) Google Scholar, 10Milev P. Friedlander D.R. Sakurai T. Karthikeyan L. Flad M. Margolis R.K. Grumet M. Margolis R.U. J. Cell Biol. 1994; 127: 1703-1715Crossref PubMed Scopus (285) Google Scholar, 12Peles E. Nativ M. Campbell P.L. Sakurai T. Martinez R. Lev S. Clary D.O. Schilling J. Barnea G. Plowman G.D. Grumet M. Schlessinger J. Cell. 1995; 82: 251-260Abstract Full Text PDF PubMed Scopus (368) Google Scholar, 13Maeda N. Noda M. Development ( Camb .). 1996; 122: 647-658PubMed Google Scholar). Our data therefore suggest that these two chondroitin sulfate proteoglycans are components of a multidimensional mechanism for the regulation of cell-cell and cell-matrix interactions at different sites and periods during nervous tissue histogenesis and that the multiplicity of ligands with differing affinities and properties could provide a means for the fine tuning of various regulatory processes.To better understand the molecular basis for these multiple but differentially regulated interactions, and perhaps to eventually design agents that will affect the binding process, we have begun studies aimed at identifying the functionally active regions of these large multidomain proteins. In the present report we demonstrate the critical role of the fibrinogen globe at the C terminus of tenascin-C for its interactions with both neurocan and phosphacan/protein-tyrosine phosphatase-ζ/β. We also show that some of the adjacent fibronectin type III repeats are involved in interactions of tenascin-C with neurocan and that the inhibitory effect of phosphacan on the adhesion of rat C6 glioma cells is attributable to a direct action of phosphacan on the cells rather than by blocking adhesion sites on tenascin-C.DISCUSSIONThis study has utilized a new approach to identify the regions of tenascin-C that are involved in its interactions with two nervous tissue-specific chondroitin sulfate proteoglycans, neurocan and phosphacan. Rather than expressing and studying only isolated domains, whose properties may not reflect those seen when they are present in the context of the entire molecule, we have employed deletion variants of tenascin-C that lack one or more homology domains and compared their effects in molecular and cell interactions with those obtained using native or full-length recombinant tenascin-C. All tenascin-C variants assembled correctly to hexameric molecules of the expected characteristics as determined by gel electrophoresis, their reactivity with monoclonal antibodies, and their molecular dimensions as revealed by electron microscopy. The expression of these tenascin-C variants by mammalian cells also increases the probability that they will be properly folded and glycosylated. Our studies demonstrated both by direct radioligand binding assays and by inhibition experiments that phosphacan binding is retained in all deletion variants except those lacking the fibrinogen globe and that phosphacan binds to this single domain with nearly the same high affinity as to native or recombinant tenascin-C. However, maximum binding of neurocan and inhibition of its interactions with tenascin-C require both the fibrinogen globe and some of the adjacent fibronectin type III repeats.The C-terminal globular region of tenascin-C is homologous to the globular domain of the β and γ chains of fibrinogen and contains a sequence that is similar to the calcium-binding site identified in the fibrinogen γ chain (21Spring J. Beck K. Chiquet-Ehrismann R. Cell. 1989; 59: 325-334Abstract Full Text PDF PubMed Scopus (322) Google Scholar, 25Dang C.V. Ebert R.F. Bell W.R. J. Biol. Chem. 1985; 260: 9713-9719Abstract Full Text PDF PubMed Google Scholar). This site has been defined as the EF hand (consisting of an α-helix, a calcium binding loop, and another α-helix) based on a structural analysis of parvalbumin (26Kretsinger R.H. Nockolds C.E. J. Biol. Chem. 1973; 248: 3313-3326Abstract Full Text PDF PubMed Google Scholar). It has been shown that 45Ca binds to tenascin-C immobilized on nitrocellulose (27Jones F.S. Hoffman S. Cunningham B.A. Edelman G.M. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 1905-1909Crossref PubMed Scopus (152) Google Scholar) and that the binding of cytotactin-binding proteoglycan to tenascin-C in covasphere coaggregation assays is decreased in the presence of EDTA (28Hoffman S. Crossin K.L. Edelman G.M. J. Cell Biol. 1988; 106: 519-532Crossref PubMed Scopus (197) Google Scholar). Based on this information, it has been proposed that the fibrinogen globe contains an EF hand calcium binding site and that binding of calcium to this region may determine a specific conformation that is important for its function (29Jones F.S. Copertino D.W. Crossin K.L. Tenascin and Counteradhesive Molecules of the Extracellular Matrix. Harwood Academic Publishers, Amsterdam1996: 1-22Google Scholar).It was therefore of interest to examine the effects of divalent cations on the interactions of phosphacan and neurocan with tenascin-C. Our results indicate that calcium is required for maximal binding of phosphacan to both native and full-length recombinant tenascin-C as well as to the fibrinogen globe alone (∼75% decrease in binding in the absence of calcium; Fig. 6), whereas in the case of neurocan interactions this requirement for calcium was seen only with respect to the complete tenascin-C molecule. Local changes in the concentration of extracellular calcium could play a regulatory role in tenascin-proteoglycan interactions, both directly by affecting the conformation of the proteoglycan binding site in the fibrinogen globe of tenascin-C, and because calcium may serve as a major counterion for the carboxyl and sulfate groups on the chondroitin sulfate chains of neurocan and phosphacan. However, it must also be recognized that the calcium-binding site in the fibrinogen globe of tenascin-C is only putative and that other regions of the molecule may be affected, as would appear to be the case for neurocan-tenascin interactions.We also examined the effects of reducing disulfide bonds in tenascin-C to evaluate their importance for its binding properties. Treatment of tenascin-C with dithiothreitol would be expected to convert the tenascin hexabrachions to trimers and possibly to monomers, since the trimers are thought to be formed by a triple coiled-coil region in the molecule that is stabilized by disulfide bonds, and hexamers are formed by disulfide linkage of two trimers. Reduction should also alter the conformation of the disulfide-bonded EGF-like repeats and the fibrinogen globe (21Spring J. Beck K. Chiquet-Ehrismann R. Cell. 1989; 59: 325-334Abstract Full Text PDF PubMed Scopus (322) Google Scholar). Our data indicate that the integrity of disulfide-stabilized structures in tenascin-C contributes significantly to its interaction with phosphacan, because treatment of TN 190 with dithiothreitol reduced binding by >70%, and reduction had a lesser but still significant effect on binding to the fibrinogen globe (Fig.7). In contrast, interactions with neurocan were not affected by reduction of TN 190, and in the case of some deletion variants binding of neurocan was actually increased. These results support other evidence that the fibronectin type III repeats have an ancillary role in neurocan-tenascin interactions, since they do not contain cysteine residues and would therefore not be expected to be directly affected by reducing agents.We have demonstrated previously that two tryptic glycopeptides derived from the N-terminal carbonic anhydrase-like and fibronectin type III domains of phosphacan bind to tenascin-C. This interaction is mediated at least in part by sialylated complex-type oligosaccharides occupying the single N-glycosylation site on each glycopeptide, insofar as their binding is abolished following treatment of phosphacan with peptide N-glycosidase (8Milev P. Meyer-Puttlitz B. Margolis R.K. Margolis R.U. J. Biol. Chem. 1995; 270: 24650-24653Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). It has also recently been reported that a 35-kDa human serum protein with a fibrinogen domain has C-type lectin activity that is thought to be mediated by this domain (30Matsushita M. Endo Y. Taira S. Sato Y. Fujita T. Ichikawa N. Nakata M. Mizuochi T. J. Biol. Chem. 1996; 271: 2448-2454Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar). Rotary shadowing electron micrographs of phosphacan show a rod that is terminated at one end by a globular domain that interacts with the fibrinogen globe of tenascin-C (Fig. 8). The results of our deglycosylation studies indicate that the globular domain represents the N-terminal portion of phosphacan, and this conclusion is supported by the distribution of O-glycosylation sites on the phosphacan core protein. From the concentration and monosaccharide composition of glycoprotein-type oligosaccharides in phosphacan (originally designated the 3F8 proteoglycan; 18), it can be calculated that the number of GalNAc residues in phosphacan from 7-day postnatal brain (64 mol/mol for a 173-kDa core protein) is in excellent agreement with the sum of 33 threonine and 30 serine GalNAc-Ser/ThrO-glycosylation sites indicated by a neural network analysis (31Hansen J.E. Lund O. Engelbrecht J. Bohr H. Nielsen J.O. Hansen J.-E.S. Brunak S. Biochem. J. 1995; 308: 801-813Crossref PubMed Scopus (235) Google Scholar, 32Hansen J.E. Lund O. Nielsen J.O. Hansen J.-E.S. Brunak S. Nucleic Acid Res. 1996; 24: 248-252Crossref PubMed Scopus (34) Google Scholar) of the phosphacan amino acid sequence. All of these sites (which account for only 17% of the total serine and threonine residues) are in the C-terminal portion of the protein outside of the carbonic anhydrase and fibronectin type III homology domains (3Margolis R.K. Rauch U. Maurel P. Margolis R.U. Perspect. Dev. Neurobiol. 1996; 3: 273-290PubMed Google Scholar), and the high concentration of O-glycosidic oligosaccharides would tend to give this region an extended conformation. GalNAc-linked oligosaccharides essentially disappear from phosphacan during the course of postnatal brain development (18Rauch U. Gao P. Janetzko A. Flaccus A. Hilgenberg L. Tekotte H. Margolis R.K. Margolis R.U. J. Biol. Chem. 1991; 266: 14785-14801Abstract Full Text PDF PubMed Google Scholar), but these are replaced by a significant number of oligosaccharides (and keratan sulfate chains) containing mannosyl-O-serine/threonine linkages (33Krusius T. Finne J. Margolis R.K. Margolis R.U. J. Biol. Chem. 1986; 261: 8237-8242Abstract Full Text PDF PubMed Google Scholar, 34Krusius T. Reinhold V.N. Margolis R.K. Margolis R.U. Biochem. J. 1987; 245: 229-234Crossref PubMed Scopus (48) Google Scholar). Based on the concentration of mannose residues and the proportion of these that are converted to mannitol after alkaline borohydride treatment of the proteoglycan (18Rauch U. Gao P. Janetzko A. Flaccus A. Hilgenberg L. Tekotte H. Margolis R.K. Margolis R.U. J. Biol. Chem. 1991; 266: 14785-14801Abstract Full Text PDF PubMed Google Scholar), it can likewise be calculated that the number of oligosaccharides containing O-glycosidic mannose linkages increases during the course of postnatal development to 73 mol/mol of protein in adult brain. Both types ofO-glycosidic oligosaccharides would confer mucin-like properties on the protein and in the case of the transmembrane phosphatase would also serve to extend the N-terminal ligand-binding domain away from the cell surface.The three potential chondroitin sulfate attachment sites that are most likely to be utilized are all located in the C-terminal portion of the phosphacan core protein, although additional attachment sites may be present more N-terminally at Ser-595 and Ser-645 (3Margolis R.K. Rauch U. Maurel P. Margolis R.U. Perspect. Dev. Neurobiol. 1996; 3: 273-290PubMed Google Scholar, 4Maurel P. Rauch U. Flad M. Margolis R.K. Margolis R.U. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 2512-2516Crossref PubMed Scopus (258) Google Scholar). In electron micrographs one sees fine thread-like structures (Fig. 8) that extend laterally from the core protein and are consistent in appearance with that of glycosaminoglycan chains visualized in other proteoglycans (35Paulsson M. Mörgelin M. Wiedemann H. Beardmore-Gray M. Dunham D. Hardingham T. Heinegård D. Timpl R. Engel J. Biochem. J. 1987; 245: 763-772Crossref PubMed Scopus (89) Google Scholar,36Mörgelin M. Paulsson M. Heinegård D. Aebi U. Engel J. Biochem. J. 1995; 307: 595-601Crossref PubMed Scopus (40) Google Scholar). Although these appear to arise from sites throughout the core protein, some of those seen near the globular region may in fact represent chondroitin sulfate chains with attachment sites in the C-terminal half of the proteoglycan but that follow the core protein before reaching out into the surrounding space (as has been observed previously in the case of aggrecan (35Paulsson M. Mörgelin M. Wiedemann H. Beardmore-Gray M. Dunham D. Hardingham T. Heinegård D. Timpl R. Engel J. Biochem. J. 1987; 245: 763-772Crossref PubMed Scopus (89) Google Scholar)).Recent investigations have shown a complex pattern of tenascin-C effects on cell adhesion and the promotion of neurite outgrowth, in which the concerted action of several domains leads to the diverse cellular responses observed (16Fischer, D., Brown-Lüdi, M., Schulthess, T., and Chiquet-Ehrismann, R. (1997) J. Cell Sci., in press.Google Scholar). The effects of phosphacan on C6 cell adhesion to tenascin-C are similar to the previously observed inhibition of neuronal adhesion to the neural cell adhesion molecule Ng-CAM/L1. It was concluded from these studies that inhibition of neuronal adhesion by both neurocan and phosphacan (which bind to Ng-CAM/L1) is mediated by direct effects on the cells rather than via binding to the substrate, since the proteoglycans also inhibited adhesion to a substrate consisting of anti-Ng-CAM antibodies, to which the proteoglycans do not bind (9Friedlander D. Milev P. Karthikeyan L. Margolis R.K. Margolis R.U. Grumet M. J. Cell Biol. 1994; 125: 669-680Crossref PubMed Scopus (389) Google Scholar, 10Milev P. Friedlander D.R. Sakurai T. Karthikeyan L. Flad M. Margolis R.K. Grumet M. Margolis R.U. J. Cell Biol. 1994; 127: 1703-1715Crossref PubMed Scopus (285) Google Scholar). Phosphacan also inhibited the adhesion of C6 cells to Ng-CAM (7Sakurai T. Friedlander D.R. Grumet M. J. Neurosci. Res. 1996; 43: 694-706Crossref PubMed Scopus (78) Google Scholar) but not to laminin (1Grumet M. Milev P. Sakurai T. Karthikeyan L. Bourdon M. Margolis R.K. Margolis R.U. J. Biol. Chem. 1994; 269: 12142-12146Abstract Full Text PDF PubMed Google Scholar). The results obtained using an Ng-CAM substrate are probably also mediated by a direct inhibitory effect of phosphacan on the cells, although this question has not yet been addressed experimentally, whereas the lack of an inhibitory effect on a laminin substrate could be due to the involvement of different cell receptors as well as to stronger cell-matrix interactions that are not susceptible to inhibition by phosphacan (at least at the concentrations tested).Our studies provide the first direct biochemical and electron microscopic evidence for specific, high-affinity binding of proteins to the fibrinogen globe of tenascin-C. The terminal globular domain of fibrinogen is involved in protein-protein interactions in the process of fibrin polymerization, binding of fibrinogen to bacteria, and to receptors on platelets (37Doolittle R.F. Annu. Rev. Biochem. 1984; 53: 195-229Crossref PubMed Scopus (524) Google Scholar). Thrombospondin also binds to distinct sites on the distal parts of the β and α chains of fibrinogen (38Bacon-Baguley T. Kudryk B.J. Walz D.A. J. Biol. Chem. 1987; 262: 1927-1930Abstract Full Text PDF PubMed Google Scholar), and by analogy with fibrinogen it has been suggested that the fibrinogen globe of tenascin-C may play a role in its association with other proteins (39Erickson H.P. Bourdon M.A. Annu. Rev. Cell Biol. 1989; 5: 71-92Crossref PubMed Scopus (525) Google Scholar). The fibrinogen globe of tenascin-C has been indirectly implicated in binding to β-integrins (40Joshi P. Chung C.Y. Aukhil I. Erickson H.P. J. Cell Sci. 1993; 106: 389-400Crossref PubMed Google Scholar) and has been shown by electron microscopy to be attached to collagen fibrils in chicken vitreous humor (41Wright D.W. Mayne R. J. Ultrastruct. Mol. Struct. Res. 1988; 100: 224-234Crossref PubMed Scopus (88) Google Scholar). Because of its location at the C-terminal tips of the hexabrachion arms, the fibrinogen globe is ideally situated to mediate the interactions of tenascin-C with cells and with other proteins. Phosphacan and neurocan bound to this domain may serve as a bridge between tenascin-C and neural cell adhesion molecules to which these proteoglycans also bind with high affinity (3Margolis R.K. Rauch U. Maurel P. Margolis R.U. Perspect. Dev. Neurobiol. 1996; 3: 273-290PubMed Google Scholar, 9Friedlander D. Milev P. Karthikeyan L. Margolis R.K. Margolis R.U. Grumet M. J. Cell Biol. 1994; 125: 669-680Crossref PubMed Scopus (389) Google Scholar, 10Milev P. Friedlander D.R. Sakurai T. Karthikeyan L. Flad M. Margolis R.K. Grumet M. Margolis R.U. J. Cell Biol. 1994; 127: 1703-1715Crossref PubMed Scopus (285) Google Scholar, 11Milev P. Maurel P. Häring M. Margolis R.K. Margolis R.U. J. Biol. Chem. 1996; 271: 15716-15723Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar) or in other ways modulate its biological properties. We have previously reported that neurocan and phosphacan/protein-tyrosine phosphatase-ζ/β, two major nervous tissue-specific chondroitin sulfate proteoglycans, are high affinity ligands of tenascin-C (apparent K d ∼3 nm) and that phosphacan inhibits the adhesion of C6 glioma cells to tenascin-C (1Grumet M. Milev P. Sakurai T. Karthikeyan L. Bourdon M. Margolis R.K. Margolis R.U. J. Biol. Chem. 1994; 269: 12142-12146Abstract Full Text PDF PubMed Google Scholar). Neurocan is a multidomain proteoglycan with a 136-kDa core protein (2Rauch U. Karthikeyan L. Maurel P. Margolis R.U. Margolis R.K. J. Biol. Chem. 1992; 267: 19536-19547Abstract Full Text PDF PubMed Google Scholar) and together with versican and brevican is a member of the aggrecan family of hyaluronan-binding proteoglycans (3Margolis R.K. Rauch U. Maurel P. Margolis R.U. Perspect. Dev. Neurobiol. 1996; 3: 273-290PubMed Google Scholar). It contains N-terminal immunoglobulin-like and hyaluronan-binding domains, a C-terminal domain consisting of EGF-, lectin-, and complement regulatory protein-like sequences, and a nonhomologous central domain of 593 amino acids, which contains the attachment sites for the three chondroitin sulfate chains and a large number ofO-glycosidic oligosaccharides. In contrast, phosphacan (4Maurel P. Rauch U. Flad M. Margolis R.K. Margolis R.U. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 2512-2516Crossref PubMed Scopus (258) Google Scholar,5Maurel P. Meyer-Puttlitz B. Flad M. Margolis R.U. Margolis R.K. DNA Sequence. 1995; 5: 323-328Crossref PubMed Scopus (22) Google Scholar), which contains a 173-kDa core protein and three chondroitin sulfate chains, is an mRNA splicing product that represents the entire extracellular domain of a receptor-type protein-tyrosine phosphatase that also occurs as a chondroitin sulfate proteoglycan in brain (3Margolis R.K. Rauch U. Maurel P. Margolis R.U. Perspect. Dev. Neurobiol. 1996; 3: 273-290PubMed Google Scholar). Phosphacan and protein-tyrosine phosphatase ζ/β have an N-terminal carbonic anhydrase-like domain followed by a fibronectin type III sequence. The phosphatase has, in addition to two cytoplasmic catalytic domains, an extracellular juxtamembrane sequence of 860 amino acids that may be deleted by alternative splicing (6Levy J.B. Canoll P.D. Silvennoinen O. Barnea G. Morse B. Honegger A.M. Haung J.-T. Cannizzaro L.A. Park S.-H. Druck T. Huebner K. Sap J. Ehrlich M. Musacchio J.M. Schlessinger J. J. Biol. Chem. 1993; 268: 10573-10581Abstract Full Text PDF PubMed Google Scholar) and appears to contain most of the chondroitin sulfate attachment sites that are actually utilized (7Sakurai T. Friedlander D.R. Grumet M. J. Neurosci. Res. 1996; 43: 694-706Crossref PubMed Scopus (78) Google Scholar). The binding of phosphacan/protein-tyrosine phosphatase ζ/β to tenascin-C is mediated at least in part byN-linked oligosaccharides on the proteoglycan (8Milev P. Meyer-Puttlitz B. Margolis R.K. Margolis R.U. J. Biol. Chem. 1995; 270: 24650-24653Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). In addition to their high-affinity binding to tenascin-C, neurocan and phosphacan also interact w" @default.
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• W2005013263 date "1997-06-01" @default.
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• W2005013263 title "The Fibrinogen-like Globe of Tenascin-C Mediates Its Interactions with Neurocan and Phosphacan/Protein-tyrosine Phosphatase-ζ/β" @default.
• W2005013263 cites W126032055 @default.
• W2005013263 cites W1483460411 @default.
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