β1-Integrin-mediated Glioma Cell Adhesion and Free Radical-induced Apoptosis Are Regulated by Binding to a C-terminal Domain of PG-M/Versican

Integrins are cell-surface glycoproteins that mediate cell activities, including tissue morphogenesis, development, immune response, and cancer, through interaction with extracellular proteins. Here we report a novel means by which integrin signaling and functions are regulated. In pull-down assays and immunoprecipitation, β1-integrin bound to the C-terminal domain of PG-M/versican, an extracellular chondroitin sulfate proteoglycan. This was confirmed by cell-surface binding assays. Binding was calcium- and manganese-dependent. Upon native gel electrophoresis, β1-integrin comigrated with the C-terminal domain of PG-M/versican. The interaction of β1-integrin with the C-terminal domain of PG-M/versican activated focal adhesion kinase, enhanced integrin expression, and promoted cell adhesion. As a result, cells expressing the C-terminal domain of PG-M/versican were resistant to free radical-induced apoptosis. As the PG-M/versican peptide used in this study does not contain the RGD consensus-binding motif for integrins, the mechanism of the observed binding represents an entirely new function. Integrins are cell-surface glycoproteins that mediate cell activities, including tissue morphogenesis, development, immune response, and cancer, through interaction with extracellular proteins. Here we report a novel means by which integrin signaling and functions are regulated. In pull-down assays and immunoprecipitation, β1-integrin bound to the C-terminal domain of PG-M/versican, an extracellular chondroitin sulfate proteoglycan. This was confirmed by cell-surface binding assays. Binding was calcium- and manganese-dependent. Upon native gel electrophoresis, β1-integrin comigrated with the C-terminal domain of PG-M/versican. The interaction of β1-integrin with the C-terminal domain of PG-M/versican activated focal adhesion kinase, enhanced integrin expression, and promoted cell adhesion. As a result, cells expressing the C-terminal domain of PG-M/versican were resistant to free radical-induced apoptosis. As the PG-M/versican peptide used in this study does not contain the RGD consensus-binding motif for integrins, the mechanism of the observed binding represents an entirely new function. Integrins are the major cell-surface receptors expressed by all cell types. They are composed of α and β transmembrane subunits (1.Hynes R.O. Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (8987) Google Scholar). The fundamental cellular function of integrins is their adhesive properties, which mediate extensive and important cellular functions by interacting with the extracellular matrix (ECM) 1The abbreviations used are: ECMextracellular matrixEGFepidermal growth factorCRDcarbohydrate recognition domainCBPcomplement-binding proteinFAKfocal adhesion kinaseDMEMDulbecco's modified Eagle's mediumFBSfetal bovine serumNTAnitrilotriacetic acidBSAbovine serum albuminTBSTris-buffered salineFITCfluorescein isothiocyanate 1The abbreviations used are: ECMextracellular matrixEGFepidermal growth factorCRDcarbohydrate recognition domainCBPcomplement-binding proteinFAKfocal adhesion kinaseDMEMDulbecco's modified Eagle's mediumFBSfetal bovine serumNTAnitrilotriacetic acidBSAbovine serum albuminTBSTris-buffered salineFITCfluorescein isothiocyanate (2.Miyamoto S. Teramoto H. Coso O.A. Gutkind J.S. Burbelo P.D. Akiyama S.K. Yamada K.M. J. Cell Biol. 1995; 131: 791-805Crossref PubMed Scopus (1103) Google Scholar, 3.Gumbiner B.M. Cell. 1996; 84: 345-357Abstract Full Text Full Text PDF PubMed Scopus (2917) Google Scholar, 4.Palecek S.P. Loftus J.C. Ginsberg M.H. Lauffenburger D.A. Horwitz A.F. Nature. 1997; 385: 537-540Crossref PubMed Scopus (1184) Google Scholar, 5.Condic M.L. Letourneau P.C. Nature. 1997; 389: 852-856Crossref PubMed Scopus (159) Google Scholar). The interactions of integrins with the ECM also activate signal transduction (6.Clark E.A. Brugge J.S. Science. 1995; 268: 233-239Crossref PubMed Scopus (2811) Google Scholar, 7.Zachary I. Rozengurt E. Cell. 1992; 71: 891-894Abstract Full Text PDF PubMed Scopus (387) Google Scholar). Many known ECM molecules that interact with integrins, including fibronectin, collagen, and vitronectin, contain an RGD consensus sequence (8.Ruoslahti E. Pierschbacher M.D. Cell. 1986; 44: 517-518Abstract Full Text PDF PubMed Scopus (1035) Google Scholar, 9.D'Souza S.E. Ginsberg M.H. Burke T.A. Lam S.C. Plow E.F. Science. 1988; 242: 91-93Crossref PubMed Scopus (291) Google Scholar). extracellular matrix epidermal growth factor carbohydrate recognition domain complement-binding protein focal adhesion kinase Dulbecco's modified Eagle's medium fetal bovine serum nitrilotriacetic acid bovine serum albumin Tris-buffered saline fluorescein isothiocyanate extracellular matrix epidermal growth factor carbohydrate recognition domain complement-binding protein focal adhesion kinase Dulbecco's modified Eagle's medium fetal bovine serum nitrilotriacetic acid bovine serum albumin Tris-buffered saline fluorescein isothiocyanate PG-M/versican was originally isolated from human fibroblasts and chicken developing limb buds (10.Kimata K. Oike Y. Tani K. Shinomura T. Yamagata M. Uritani M. Suzuki S. J. Biol. Chem. 1986; 261: 13517-13525Abstract Full Text PDF PubMed Google Scholar, 11.Zimmermann D.R. Ruoslahti E. EMBO J. 1989; 8: 2975-2981Crossref PubMed Scopus (500) Google Scholar, 12.Landolt R.M. Vaughan L. Winterhalter K.H. Zimmermann D.R. Development. 1995; 121: 2303-2312Crossref PubMed Google Scholar, 13.Naso M.F. Zimmermann D.R. Iozzo R.V. J. Biol. Chem. 1994; 269: 32999-33008Abstract Full Text PDF PubMed Google Scholar, 14.Shinomura T. Nishida Y. Ito K. Kimata K. J. Biol. Chem. 1993; 268: 14461-14469Abstract Full Text PDF PubMed Google Scholar) and was later detected in the normal human central nervous system and brain tumors (15.Stigson M. Löfberg J. Kjellén L. J. Biol. Chem. 1997; 272: 3246-3253Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 16.Paulus W. Baur I. Dours-Zimmermann M.T. Zimmerman D.R. J. Neuropathol. Exp. Neurol. 1996; 55: 528-533Crossref PubMed Scopus (94) Google Scholar, 17.Bode-Lesniewska B. Dours-Zimmermann M.T. Odermatt B.F. Briner J. Heitz P.U. Zimmermann D.R. J. Histochem. Cytochem. 1996; 44: 303-312Crossref PubMed Scopus (162) Google Scholar). This proteoglycan is made up of a hyaluronan-binding N terminus (G1 domain) and a selectin-like C terminus (G3 domain) with a central sequence for glycosaminoglycan chain modification (14.Shinomura T. Nishida Y. Ito K. Kimata K. J. Biol. Chem. 1993; 268: 14461-14469Abstract Full Text PDF PubMed Google Scholar, 18.Margolis R.U. Margolis R.K. Methods Enzymol. 1994; 245: 105-126Crossref PubMed Scopus (88) Google Scholar, 19.Ito K. Shinomura T. Zako M. Ujita M. Kimata K. J. Biol. Chem. 1995; 270: 958-965Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar). The G1 domain is composed of an immunoglobulin-like motif and two proteoglycan tandem repeats (11.Zimmermann D.R. Ruoslahti E. EMBO J. 1989; 8: 2975-2981Crossref PubMed Scopus (500) Google Scholar, 14.Shinomura T. Nishida Y. Ito K. Kimata K. J. Biol. Chem. 1993; 268: 14461-14469Abstract Full Text PDF PubMed Google Scholar), which bind hyaluronan (20.LeBaron R.G. Zimmermann D.R. Ruoslahti E. J. Biol. Chem. 1992; 267: 10003-10010Abstract Full Text PDF PubMed Google Scholar). The G3 domain is composed of epidermal growth factor (EGF)-like repeats and lectin-like (also known as carbohydrate recognition domain (CRD)) and complement-binding protein (CBP)-like motifs (11.Zimmermann D.R. Ruoslahti E. EMBO J. 1989; 8: 2975-2981Crossref PubMed Scopus (500) Google Scholar, 14.Shinomura T. Nishida Y. Ito K. Kimata K. J. Biol. Chem. 1993; 268: 14461-14469Abstract Full Text PDF PubMed Google Scholar, 21.Dours-Zimmermann M.T. Zimmermann D.R. J. Biol. Chem. 1994; 269: 32992-32998Abstract Full Text PDF PubMed Google Scholar, 22.Krusius T. Gehlsen K.R. Ruoslahti E. J. Biol. Chem. 1987; 262: 13120-13125Abstract Full Text PDF PubMed Google Scholar, 23.Zako M. Shinomura T. Kimata K. J. Biol. Chem. 1997; 272: 9325-9331Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). PG-M/versican is known to associate with a number of molecules in the ECM and on the cell surface, including hyaluronan (20.LeBaron R.G. Zimmermann D.R. Ruoslahti E. J. Biol. Chem. 1992; 267: 10003-10010Abstract Full Text PDF PubMed Google Scholar), tenascin (24.Aspberg A. Binkert C. Ruoslahti E. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10590-10594Crossref PubMed Scopus (123) Google Scholar, 25.Aspberg A. Miura R. Bourdoulous S. Shimonaka M. Heinegard D. Schachner M. Ruoslahti E. Yamaguchi Y. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 10116-10212Crossref PubMed Scopus (240) Google Scholar), fibulin-1 and fibulin-2 (26.Aspberg A. Adam S. Kostka G. Timpl R. Heinegard D. J. Biol. Chem. 1999; 274: 20444-20449Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 27.Olin A.I. Morgelin M. Sasaki T. Timpl R. Heinegard D. Aspberg A. J. Biol. Chem. 2001; 276: 1253-1261Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar), fibronectin (28.Yamagata M. Yamada K.M. Yoneda M. Suzuki S. Kimata K. J. Biol. Chem. 1986; 261: 13526-13535Abstract Full Text PDF PubMed Google Scholar), and CD44 and L-selectin (29.Kawashima H. Hirose M. Hirose J. Nagakubo D. Plaas A.H. Miyasaka M. J. Biol. Chem. 2000; 275: 35448-35456Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar). Binding of the G1 domain to hyaluronan affects cell adhesion (20.LeBaron R.G. Zimmermann D.R. Ruoslahti E. J. Biol. Chem. 1992; 267: 10003-10010Abstract Full Text PDF PubMed Google Scholar, 30.Ang L.C. Zhang Y. Cao L. Yang B.L. Young B. Kiani C. Lee V. Allan K. Yang B.B. J. Neuropathol. Exp. Neurol. 1999; 58: 597-605Crossref PubMed Scopus (79) Google Scholar). Our previous studies also demonstrated that PG-M/versican stimulates cell proliferation and migration and inhibits cell adhesion and differentiation (30.Ang L.C. Zhang Y. Cao L. Yang B.L. Young B. Kiani C. Lee V. Allan K. Yang B.B. J. Neuropathol. Exp. Neurol. 1999; 58: 597-605Crossref PubMed Scopus (79) Google Scholar, 31.Zhang Y. Cao L. Yang B.L. Yang B.B. J. Biol. Chem. 1998; 273: 21342-21352Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 32.Zhang Y. Cao L. Kiani C. Hu W. Yang B.B. J. Cell. Biochem. 1999; 73: 445-457Crossref PubMed Scopus (65) Google Scholar, 33.Zhang Y. Cao L. Yang B.L. Yang B.B. J. Biol. Chem. 1998; 273: 33054-33063Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 34.Yang B.L. Zhang Y. Cao L. Yang B.B. J. Cell. Biochem. 1999; 72: 210-220Crossref PubMed Scopus (92) Google Scholar, 35.Wu Y. Zhang Y. Cao L. Chen L. Lee V. Zheng P. Kiani C. Adams M.E. Ang L.C. Paiwand F. Yang B.B. J. Biol. Chem. 2001; 276: 14178-14186Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar), but the signaling pathway for this role is not known. Recently, we observed that a PG-M/versican mutant exerts a dominant-negative effect on cell proliferation by inhibiting secretion of endogenous PG-M/versican and can interact with intact astrocytoma cells (33.Zhang Y. Cao L. Yang B.L. Yang B.B. J. Biol. Chem. 1998; 273: 33054-33063Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). Our studies suggest that PG-M/versican functions through binding to cell-surface receptors. This study was designed to investigate whether PG-M/versican can act via an integrin-mediated pathway. We show here that PG-M/versican interacts with This interaction focal adhesion kinase cell and the cells from free radical-induced cell apoptosis. Dulbecco's modified Eagle's medium fetal bovine serum and were from The was from and all were from were from were by and cells were from the The cells were in with in a The cell was from the astrocytoma cell with the the G3 domain two contain a that to The and the cell was to for in a The was with native The were with and with The was with in protein for to and with The cell was in for protein interaction and by to in the The protein was with protein that with F. J. B. D.R. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar), by with the were in protein for by and with In the cell was with protein the as to were by and with were to native gel electrophoresis, and Cell were in and to on The were by and with were to on gel The system was were a in for in a The was in and for to binding on the The was with an the peptide of the which was in all with the in The were with and for with in as the bound were by G3 an were on as Y. Cao L. Yang B.L. Yang B.B. J. Biol. Chem. 1998; 273: 21342-21352Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). the G3 domain was by two and The was the and the an The G3 was expressed in expressed in was and were on an to the The protein was and in a and and cells by were with and and with for on in the of by with for on in the were Binding of to the cell was by cells were also with the medium from cells for with by for to binding of to and were in the system a of expressed was on and of cells were with in as a The cells were with and by as were with the medium from cells with were with cells with the and for The cell was in for and by with protein that with the were in protein for by and with to cells were on with the medium from cells and on the for as in the cells were by and the cells were was also used to The were with by with cells in for The were and cells were whether cell adhesion is to a of the from and cells were with saline to and and used to tissue cells were on the in and for The medium was and the cells were with The cells on the were and The effect of the of and on the adhesion of cells was also The from and cells were used to tissue for of cells and cell were on the in and for The were and the cells were with The cells on were cells were in of in the of a of for The cells were on with and for cells were by The cells were and cell was by cell were with the cell bovine serum for by with bovine serum for the were with the medium from cells for to The medium was with cells for assays as cells were also with the medium from the in the of and for The cells were on tissue with and for cells were and cells were and cells in on in were with for for was used to were also to in the an to as C. S. J. E. Y. EMBO J. 2000; PubMed Scopus Google Scholar, C. C. A. D. R. L. A. A. L. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar). an was expressed in human astrocytoma cell The cell was native and with The was by and with The was used as a to and the cell from cells that to the was used as a The that β1-integrin was by the of the was confirmed by Our previous studies that cells interact with a mutant the and motifs expressed by cells and with the G3 domain expressed by (33.Zhang Y. Cao L. Yang B.L. Yang B.B. J. Biol. Chem. 1998; 273: 33054-33063Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 34.Yang B.L. Zhang Y. Cao L. Yang B.B. J. Cell. Biochem. 1999; 72: 210-220Crossref PubMed Scopus (92) Google Scholar). the of interaction the the cell from cells was to the pull-down as with that β1-integrin with and expressed in was and with intact cells for by pull-down The that bound to β1-integrin this was on the from cells and an the peptide of with the β1-integrin was with and was with As a the from cells was to native gel and and with detected with from to This that the of the interacts with β1-integrin native and that is an important in the integrin signaling does not contain the RGD consensus-binding sequence for integrins (14.Shinomura T. Nishida Y. Ito K. Kimata K. J. Biol. Chem. 1993; 268: 14461-14469Abstract Full Text PDF PubMed Google Scholar). binding of to the cell surface, and cells were by with demonstrated that cells with expressed and with this protein cells were with the medium from of bound were detected with from a system In the of binding of to the cell was the effect on and the effect on the binding as a of and not The binding was the for Binding of to the cell was also confirmed by with that bound to the of cells but was detected in cells investigate the effect of we effect on the in the integrin-mediated pathway (1.Hynes R.O. Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (8987) Google Scholar, S. Teramoto H. Coso O.A. Gutkind J.S. Burbelo P.D. Akiyama S.K. Yamada K.M. J. Cell Biol. 1995; 131: 791-805Crossref PubMed Scopus (1103) Google Scholar, 3.Gumbiner B.M. Cell. 1996; 84: 345-357Abstract Full Text Full Text PDF PubMed Scopus (2917) Google Scholar, 4.Palecek S.P. Loftus J.C. Ginsberg M.H. Lauffenburger D.A. Horwitz A.F. Nature. 1997; 385: 537-540Crossref PubMed Scopus (1184) Google Scholar, 5.Condic M.L. Letourneau P.C. Nature. 1997; 389: 852-856Crossref PubMed Scopus (159) Google Scholar, E.A. Brugge J.S. Science. 1995; 268: 233-239Crossref PubMed Scopus (2811) Google Scholar, 7.Zachary I. Rozengurt E. Cell. 1992; 71: 891-894Abstract Full Text PDF PubMed Scopus (387) Google Scholar). The cell from cells was with by and with cells a of with with that the of protein were of cells with also in enhanced of with is known that integrin-mediated cell adhesion in of (6.Clark E.A. Brugge J.S. Science. 1995; 268: 233-239Crossref PubMed Scopus (2811) Google Scholar, 7.Zachary I. Rozengurt E. Cell. 1992; 71: 891-894Abstract Full Text PDF PubMed Scopus (387) Google Scholar). investigate whether the observed is by in cell we and cells on tissue for assays. As cell with the cells were to and as cells and in that enhanced cell adhesion. this were with the medium and with in the medium enhanced cell with with the medium from cells We assays to in the to to the cell by We demonstrated that cells to to tissue and cells to to tissue with and of the to cell the function of and in the of cell we their on the of the cell and the cell The of and enhanced the of all of cells and the to the of but the to the of The by of the of fibroblasts is in In cells with were on with cell In cells were also with the medium the medium by the enhanced adhesion of the medium from the was with cells were on (24.Aspberg A. Binkert C. Ruoslahti E. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10590-10594Crossref PubMed Scopus (123) Google Scholar), and the of free cell cells were also with the medium in the of free by with with free binding to the that an important role in enhanced cell adhesion through binding to integrin and of As integrin is with cell we whether cell adhesion affects integrin and cells were on tissue for and of integrin by that cells expressed of integrin cellular with cells detected of cell of cells were on the As integrin-mediated cell adhesion is for cell (1.Hynes R.O. Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (8987) Google Scholar, S. Teramoto H. Coso O.A. Gutkind J.S. Burbelo P.D. Akiyama S.K. Yamada K.M. J. Cell Biol. 1995; 131: 791-805Crossref PubMed Scopus (1103) Google Scholar, 3.Gumbiner B.M. Cell. 1996; 84: 345-357Abstract Full Text Full Text PDF PubMed Scopus (2917) Google Scholar, 4.Palecek S.P. Loftus J.C. Ginsberg M.H. Lauffenburger D.A. Horwitz A.F. Nature. 1997; 385: 537-540Crossref PubMed Scopus (1184) Google Scholar, 5.Condic M.L. Letourneau P.C. Nature. 1997; 389: 852-856Crossref PubMed Scopus (159) Google Scholar, E.A. Brugge J.S. Science. 1995; 268: 233-239Crossref PubMed Scopus (2811) Google Scholar, 7.Zachary I. Rozengurt E. Cell. 1992; 71: 891-894Abstract Full Text PDF PubMed Scopus (387) Google Scholar), we whether cell adhesion and integrin can cell We used the free to cell and the of was to and of and cells in was in cells as by cell and and by with C and We the effect of on integrin was to and cells and cell and the cell was by in but not in the with Our study for the that the chondroitin sulfate proteoglycan PG-M/versican to we observed that the the G3 and the G3 the two motifs all bound to the cell pull-down and assays that β1-integrin was in of and expressed in and the G3 domain in E. were bound to we were to Binding was confirmed by an the peptide of was to and β1-integrin was to the Integrins known to interact with ECM molecules as fibronectin, collagen, and and with as E. Pierschbacher M.D. Science. 1987; PubMed Scopus Google Scholar). Integrins also interact with cell-surface receptors as and P. J. EMBO J. 1994; PubMed Scopus (79) Google Scholar, M. A. C. M. R. F. J. Cell Biol. 1998; PubMed Scopus Google Scholar). The chondroitin sulfate proteoglycan PG-M/versican to interact with a number of ECM and cell-surface including fibronectin, and L-selectin (20.LeBaron R.G. Zimmermann D.R. Ruoslahti E. J. Biol. Chem. 1992; 267: 10003-10010Abstract Full Text PDF PubMed Google Scholar, A. Binkert C. Ruoslahti E. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10590-10594Crossref PubMed Scopus (123) Google Scholar, 25.Aspberg A. Miura R. Bourdoulous S. Shimonaka M. Heinegard D. Schachner M. Ruoslahti E. Yamaguchi Y. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 10116-10212Crossref PubMed Scopus (240) Google Scholar, A. Adam S. Kostka G. Timpl R. Heinegard D. J. Biol. Chem. 1999; 274: 20444-20449Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 27.Olin A.I. Morgelin M. Sasaki T. Timpl R. Heinegard D. Aspberg A. J. Biol. Chem. 2001; 276: 1253-1261Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, M. Yamada K.M. Yoneda M. Suzuki S. Kimata K. J. Biol. Chem. 1986; 261: 13526-13535Abstract Full Text PDF PubMed Google Scholar). the binding here represents the of interaction PG-M/versican and a known consensus-binding sequence for integrins is the RGD peptide (8.Ruoslahti E. Pierschbacher M.D. Cell. 1986; 44: 517-518Abstract Full Text PDF PubMed Scopus (1035) Google Scholar, 9.D'Souza S.E. Ginsberg M.H. Burke T.A. Lam S.C. Plow E.F. Science. 1988; 242: 91-93Crossref PubMed Scopus (291) Google Scholar). The PG-M/versican G3 domain does not contain an RGD the binding observed in this study a novel mechanism of integrin The binding of PG-M/versican are via hyaluronan to the of the and interactions the glycosaminoglycan of and tenascin and fibulin-1 bind to the motif of PG-M/versican. The sequence in all here is and was to the motif in that interacts with we not binding with the in the of and was the interaction with β1-integrin that the binding the of and to the for binding to whether can interact with we used assays. We of β1-integrin for the but was that the binding a modification of β1-integrin that can in The binding also the of the of the α We and to the α chain the binding we not the that the interaction of PG-M/versican with integrin in for their that cell to G3 suggest a interaction β1-integrin and the cell from cells with the was to native gel and β1-integrin detected with This that two molecules are important with and comigrated gel This not the that β1-integrin and also interact with integrins with ECM in that not the with that of the that with the cell surface, a of binding to all by and E. cells with the binding The cell with the for binding as by The cells expressing for binding the G3 domain the by cells was the to the for β1-integrin by cells with in the medium was to integrins on the cell The G3 domain by E. not the with that expressed by and binding for the cell binding are in with the of the cell and assays. with the E. expressed G3 domain cell with with the and the E. G3 cells from free radical-induced cell that the G3 with enhanced cell and of cells to free the of and enhanced the of cell including and the of This to the in the of which interacts with the G3 domain of the is not known which α chain of the integrins is to with the chain and is that α chain is in this is also not of cells in binding to the G3 CD44 to bind (29.Kawashima H. Hirose M. Hirose J. Nagakubo D. Plaas A.H. Miyasaka M. J. Biol. Chem. 2000; 275: 35448-35456Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar), does not bind to the G3 was to that the of β1-integrin in cells free the that β1-integrin an important role in the cells from free radical-induced apoptosis. the not the that the were to an in protein a in protein we in the medium by acid and by We not a in the of β1-integrin not that in the of free integrin was of the protein was not In all of the of the of β1-integrin in to and this the cells from free radical-induced apoptosis. This was demonstrated by the with the G3 which cell in to free In study demonstrated that interacts with β1-integrin and to the cell interactions are with enhanced cell and of cells from free radical-induced apoptosis. The mechanism of this binding and are for that PG-M/versican also to hyaluronan through the G1 domain and cell adhesion (20.LeBaron R.G. Zimmermann D.R. Ruoslahti E. J. Biol. Chem. 1992; 267: 10003-10010Abstract Full Text PDF PubMed Google Scholar, 30.Ang L.C. Zhang Y. Cao L. Yang B.L. Young B. Kiani C. Lee V. Allan K. Yang B.B. J. Neuropathol. Exp. Neurol. 1999; 58: 597-605Crossref PubMed Scopus (79) Google Scholar, 34.Yang B.L. Zhang Y. Cao L. Yang B.B. J. Cell. Biochem. 1999; 72: 210-220Crossref PubMed Scopus (92) Google Scholar), a role to that of the G1 domain L. Zhang Y. Yang B.B. Biol. 1998; PubMed Scopus Google Scholar). This an new for of cell adhesion in the interaction the G1 domain) the of the G3 the G1 domain is not the interaction cell adhesion and cell of the G1 and G3 also in the of and W. L. Zheng J. M.L. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, C. Lee V. Cao L. Chen L. Y. Zhang Y. Adams M.E. Yang B.B. Biochem. J. 2001; PubMed Scopus Google Scholar, J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, B.L. Cao L. Kiani C. Lee V. Zhang Y. Adams M.E. Yang B.B. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, L. Y. Lee V. Kiani C. Adams M.E. Y. Yang B.B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, C. Chen L. Y. Yang B.B. Cell PubMed Scopus Google Scholar). to the G1 and G3 the functions of chondroitin sulfate of is the that the binding here represents an entirely new mechanism for integrin binding does not contain an RGD the consensus-binding sequence for of the sequence in the interaction We Y. T. M. and W. Y. for

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