Caveolin-1 Regulates Matrix Metalloproteinases-1 Induction and CD147/EMMPRIN Cell Surface Clustering
CD147, a regulator of matrix metalloproteinase (MMP) production, showed highly specific association with caveolin-1 on the surface of multiple cell types. CD147-caveolin-1 complex formation was temperature and cholesterol dependent, reminiscent of associations seen within caveolae/lipid rafts. However, the subset of caveolin-1 associated with CD147 appeared exclusively within intermediate density sucrose gradient fractions, rather than in the low density fractions containing the bulk of caveolin-1. Mutagenesis experiments revealed that CD147 Ig domain 2 was required for caveolin-1 association. In contrast to CD147-caveolin-1 complexes, CD147-α3 integrin association was not disrupted upon cholesterol depletion, occurred in high density sucrose fractions, and did not involve CD147 Ig domain 2. Overexpression of caveolin-1 caused a specific decrease in clustering of cell surface CD147, as detected by “cluster specific” mAb M6/13. Conversely, a mutant CD147 deficient in caveolin-1 association showed enhanced spontaneous cell surface clustering (detected by mAb M6/13), and did not show decreased clustering in response to caveolin-1 overexpression. Furthermore, the same CD147 mutant yielded an elevated induction of MMP-1. In conclusion, caveolin-1 associates with CD147, in a complex distinct from CD147-α3 integrin complexes, thereby diminishing both CD147 clustering and CD147-dependent MMP-1-inducing activity. CD147, a regulator of matrix metalloproteinase (MMP) production, showed highly specific association with caveolin-1 on the surface of multiple cell types. CD147-caveolin-1 complex formation was temperature and cholesterol dependent, reminiscent of associations seen within caveolae/lipid rafts. However, the subset of caveolin-1 associated with CD147 appeared exclusively within intermediate density sucrose gradient fractions, rather than in the low density fractions containing the bulk of caveolin-1. Mutagenesis experiments revealed that CD147 Ig domain 2 was required for caveolin-1 association. In contrast to CD147-caveolin-1 complexes, CD147-α3 integrin association was not disrupted upon cholesterol depletion, occurred in high density sucrose fractions, and did not involve CD147 Ig domain 2. Overexpression of caveolin-1 caused a specific decrease in clustering of cell surface CD147, as detected by “cluster specific” mAb M6/13. Conversely, a mutant CD147 deficient in caveolin-1 association showed enhanced spontaneous cell surface clustering (detected by mAb M6/13), and did not show decreased clustering in response to caveolin-1 overexpression. Furthermore, the same CD147 mutant yielded an elevated induction of MMP-1. In conclusion, caveolin-1 associates with CD147, in a complex distinct from CD147-α3 integrin complexes, thereby diminishing both CD147 clustering and CD147-dependent MMP-1-inducing activity. Stromal fibroblasts secrete multiple matrix metalloproteinases (MMP) 1The abbreviations used are: MMP, matrix metalloproteinase; mAb, monoclonal antibody; GFP, green fluorescent protein; Mes, 4-morpho-lineethanesulfonic acid. 1The abbreviations used are: MMP, matrix metalloproteinase; mAb, monoclonal antibody; GFP, green fluorescent protein; Mes, 4-morpho-lineethanesulfonic acid. that can promote tumor cell growth, survival, invasion, angiogenesis, and metastasis (1MacDougall J.R. Matrisian L.M. Cancer Metast. Rev. 1995; 14: 351-362Crossref PubMed Scopus (400) Google Scholar, 2Chang C. Werb Z. Trends Cell Biol. 2001; 11: S37-S43Abstract Full Text Full Text PDF PubMed Scopus (620) Google Scholar, 3Egeblad M. Werb Z. Nat. Rev. Cancer. 2002; 2: 161-174Crossref PubMed Scopus (5031) Google Scholar). A search for MMP-inducing tumor cell factors led to discovery and characterization of CD147/EMMPRIN (4Ellis S.M. Nabeshima K. Biswas C. Cancer Res. 1989; 49: 3385-3391PubMed Google Scholar, 5Kataoka H. DeCastro R. Zucker S. Biswas C. Cancer Res. 1993; 53: 3154-3158PubMed Google Scholar). This molecule, on the surface of carcinoma cells or in recombinant soluble form, stimulates production of MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), and MMP-3 (stromelysin) but not TIMP-1 (4Ellis S.M. Nabeshima K. Biswas C. Cancer Res. 1989; 49: 3385-3391PubMed Google Scholar, 5Kataoka H. DeCastro R. Zucker S. Biswas C. Cancer Res. 1993; 53: 3154-3158PubMed Google Scholar, 6Guo H. Zucker S. Gordon M.K. Toole B.P. Biswas C. J. Biol. Chem. 1997; 272: 24-27Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar, 7Taylor P.M. Woodfield R.J. Hodgkin M.N. Pettitt T.R. Martin A. Kerr D.J. Wakelam M.J. Oncogene. 2002; 21: 5765-5772Crossref PubMed Scopus (130) Google Scholar). The name “EMMPRIN” reflects the extracellular matrix metalloproteinase inducer activity of CD147. CD147 expression is often elevated on human tumor cells (4Ellis S.M. Nabeshima K. Biswas C. Cancer Res. 1989; 49: 3385-3391PubMed Google Scholar, 8Polette M. Gilles C. Marchand V. Lorenzato M. Toole B. Tournier J.M. Zucker S. Birembaut P. J. Histochem. Cytochem. 1997; 45: 703-709Crossref PubMed Scopus (130) Google Scholar, 9Muraoka K. Nabeshima K. Murayama T. Biswas C. Koono M. Int. J. Cancer. 1993; 55: 19-26Crossref PubMed Scopus (97) Google Scholar) and correlates with glioma tumor progression (10Sameshima T. Nabeshima K. Toole B.P. Yokogami K. Okada Y. Goya T. Koono M. Wakisaka S. Int. J. Cancer. 2000; 88: 21-27Crossref PubMed Scopus (135) Google Scholar), hepatoma metastasis (11Jiang J.L. Zhou Q. Yu M.K. Ho L.S. Chen Z.N. Chan H.C. J. Biol. Chem. 2001; 276: 46870-46877Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar), and squamous cell carcinoma invasion, MMP-2 production, and extracellular matrix degradation (12Bordador L.C. Li X. Toole B. Chen B. Regezi J. Zardi L. Hu Y. Ramos D.M. Int. J. Cancer. 2000; 85: 347-352Crossref PubMed Scopus (136) Google Scholar). On melanoma cells, elevated CD147 promotes MMP-1, MMP-2, and MMP-3 production, and invasion through basement membrane (13van den Oord J.J. Paemen L. Opdenakker G. de Wolf-Peeters C. Am. J. Pathol. 1997; 151: 665-670PubMed Google Scholar, 14Kanekura T. Chen X. Kanzaki T. Int. J. Cancer. 2002; 99: 520-528Crossref PubMed Scopus (284) Google Scholar), whereas overexpression of CD147 in a breast cancer cell line stimulated MMP-2 and MMP-9 production, and tumor growth and metastasis in nude mice (15Zucker S. Hymowitz M. Rollo E.E. Mann R. Conner C.E. Cao J. Foda H.D. Tompkins D.C. Toole B.P. Am. J. Pathol. 2001; 158: 1921-1928Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar). In summary, CD147 on tumor cells stimulates MMP production by stromal cells and/or other tumor cells, thereby leading to extracellular matrix degradation, and elevated tumor growth and metastasis. The MMP-inducing functions of CD147 at least partly involve CD147 acting as a counter-receptor for itself (16Sun J. Hemler M.E. Cancer Res. 2001; 61: 2276-2281PubMed Google Scholar). Also, CD147 stimulates production of MMP-1 and MMP-3 in rheumatoid synovial tissue (17Tomita T. Nakase T. Kaneko M. Shi K. Takahi K. Ochi T. Yoshikawa H. Arthritis Rheum. 2002; 46: 373-378Crossref PubMed Scopus (72) Google Scholar), and may facilitate erythrocyte circulation (18Coste I. Gauchat J.F. Wilson A. Izui S. Jeannin P. Delneste Y. MacDonald H.R. Bonnefoy J.Y. Renno T. Blood. 2001; 97: 3984-3988Crossref PubMed Scopus (52) Google Scholar), and development of the thymus (19Renno T. Wilson A. Dunkel C. Coste I. Maisnier-Patin K. Benoit D.C. Aubry J.P. Lees R.K. Bonnefoy J.Y. MacDonald H.R. Gauchat J.F. J. Immunol. 2002; 168: 4946-4950Crossref PubMed Scopus (59) Google Scholar) and retina (20Hori K. Katayama N. Kachi S. Kondo M. Kadomatsu K. Usukura J. Muramatsu T. Mori S. Miyake Y. Investig. Ophthalmol. Vis. Sci. 2000; 41: 3128-3133PubMed Google Scholar). Mice lacking the gene for CD147/EMMPRIN (called basigin in mice) showed defects in spermatogenesis and female fertilization (21Igakura T. Kadomatsu K. Kaname T. Muramatsu H. Fan Q.W. Miyauchi T. Toyama Y. Kuno N. Yuasa S. Takahashi M. Senda T. Taguchi O. Yamamura K. Arimura K. Muramatsu T. Dev. Biol. 1998; 194: 152-165Crossref PubMed Scopus (245) Google Scholar, 22Kuno N. Kadomatsu K. Fan Q.W. Hagihara M. Senda T. Mizutani S. Muramatsu T. FEBS Lett. 1998; 425: 191-194Crossref PubMed Scopus (101) Google Scholar), an altered mixed lymphocyte reaction, and loss of an aversive response to a strong odor (23Igakura T. Kadomatsu K. Taguchi O. Muramatsu H. Kaname T. Miyauchi T. Yamamura K. Arimura K. Muramatsu T. Biochem. Biophys. Res. Commun. 1996; 224: 33-36Crossref PubMed Scopus (111) Google Scholar). A cytotoxic antibody to CD147 has shown promising results in the treatment of graft versus host disease, presumably by selectively targeting activated B and T lymphocytes (24Deeg H.J. Blazar B.R. Bolwell B.J. Long G.D. Schuening F. Cunningham J. Rifkin R.M. Abhyankar S. Briggs A.D. Burt R. Lipani J. Roskos L.K. White J.M. Havrilla N. Schwab G. Heslop H.E. Blood. 2001; 98: 2052-2058Crossref PubMed Scopus (89) Google Scholar). These diverse results emphasize the significance of CD147 and underscore the need for detailed understanding of its mechanism of action. The variably glycosylated CD147 protein (32–60 kDa) contains two extracellular immunoglobulin domains, a transmembrane domain, and a 39-amino acid cytoplasmic domain (25Biswas C. Zhang Y. DeCastro R. Guo H. Nakamura T. Kataoka H. Nabeshima K. Cancer Res. 1995; 55: 434-439PubMed Google Scholar). The homophilic counter-receptor binding activity of CD147 requires the first Ig domain (16Sun J. Hemler M.E. Cancer Res. 2001; 61: 2276-2281PubMed Google Scholar). Inhibitors of CD147 homophilic interactions (bivalent CD147-Fc protein, monoclonal antibody) also inhibited MMP production and MMP-dependent invasion through Matrigel basement membrane (16Sun J. Hemler M.E. Cancer Res. 2001; 61: 2276-2281PubMed Google Scholar). A monoclonal antibody screen for α3β1 integrin-associated proteins revealed a robust and possibly direct association of the structurally similar α3β1 and α6β1 integrins (but not α5β1 or α2β1 integrins) with CD147/EMMPRIN (26Berditchevski F. Chang S. Bodorova J. Hemler M.E. J. Biol. Chem. 1997; 272: 29174-29180Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar). However, at present, there is no evidence to suggest that CD147 alters integrin function. CD147 also associates with the monocarboxylate transporters MCT1 and MCT4 (27Kirk P. Wilson M.C. Heddle C. Brown M.H. Barclay A.N. Halestrap A.P. EMBO J. 2000; 19: 3896-3904Crossref PubMed Scopus (504) Google Scholar), and facilitates their targeting to plasma membrane, where they act as lactic acid transporters. Studies using CD147 chimeras indicated that the cytoplasmic tail and/or transmembrane regions of CD147 may be particularly important for association with MCT1 (a protein that itself spans the membrane 12 times) (27Kirk P. Wilson M.C. Heddle C. Brown M.H. Barclay A.N. Halestrap A.P. EMBO J. 2000; 19: 3896-3904Crossref PubMed Scopus (504) Google Scholar). Here we show that a population of CD147 (distinct from the integrin-associated population) co-immunoprecipitates with caveolin-1, with a resulting negative effect on CD147 cell surface clustering and function. The association of caveolin-1 with Ig superfamily proteins has generally not been observed. Instead, caveolin-1 is known primarily as an integral membrane protein, which oligomerizes and plays a central role in the formation of flask-shaped membrane structures known as caveolae (28Liu P. Rudick M. Anderson R.G. J. Biol. Chem. 2002; 277: 41295-41298Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar). Caveolin-1 can associate either directly or indirectly with a variety of signaling molecules (growth factor receptors, G proteins, Src family kinases, etc.), sometimes resulting in down-regulation of signaling function (28Liu P. Rudick M. Anderson R.G. J. Biol. Chem. 2002; 277: 41295-41298Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar, 29Okamoto T. Schlegel A. Scherer P.E. Lisanti M.P. J. Biol. Chem. 1998; 273: 5419-5422Abstract Full Text Full Text PDF PubMed Scopus (1336) Google Scholar). This down-regulation of critical signaling pathways is consistent with the oncosuppressive effects of caveolin-1 (29Okamoto T. Schlegel A. Scherer P.E. Lisanti M.P. J. Biol. Chem. 1998; 273: 5419-5422Abstract Full Text Full Text PDF PubMed Scopus (1336) Google Scholar). In this regard, caveolin-1 can suppress cell proliferation, while being generally elevated on normal cells, but or on tumor cells B. Lisanti M.P. J. Investig. 2001; PubMed Scopus Google Scholar). Caveolin-1 also can tumor cell invasion, growth, and MMP production G. R. M. Oncogene. 2002; 21: PubMed Scopus Google Scholar). suggest that caveolin-1 down-regulation of CD147 functions at least in to the oncosuppressive effects of caveolin-1, and to caveolin-1 effects on MMP and Cell to CD147 and mAb (16Sun J. Hemler M.E. Cancer Res. 2001; 61: 2276-2281PubMed Google Scholar, F. Chang S. Bodorova J. Hemler M.E. J. Biol. Chem. 1997; 272: 29174-29180Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar), and mAb and C. G. R. I. J. P. O. V. H. Int. Immunol. 11: PubMed Scopus Google Scholar, I. T. H. J. Immunol. Google Scholar). was from mAb was from and was from to integrins and and to and X. C. Chen Z. Hemler M.E. Biol. 2002; PubMed Scopus Google Scholar). cell from carcinoma and and in with and and cell in with cell line was from and cells, with high caveolin-1 used for cells, with low used for caveolin-1 cells, with low of CD147, for of and mutant CD147. recombinant CD147 and caveolin-1 to and and CD147 was to and in of 2 for at with protein to binding with antibody for and at by with from with by and to with containing for for 2 or with antibody in the same as with and with detected using an and on the Cell we evidence that CD147 associate with caveolin-1. we caveolin-1 not from cell of carcinoma cells and from caveolin-1 and but also from CD147 and and and integrin and integrin at high we did not caveolin-1 with molecules and we did not caveolin-1 from of other highly cell surface molecules or from other transmembrane Ig superfamily proteins In a using cells with and of CD147 yielded caveolin-1 and of caveolin-1 yielded CD147 association can be cells in of CD147-caveolin-1 association was not we that CD147-caveolin-1 on the cell The cell surface subset of CD147 was on cells, using mAb of revealed an of associated caveolin-1 of cell surface CD147 complexes, CD147 in the was with caveolin-1 associated at In a cell surface was on cells, using an an of associated caveolin-1 was In the of CD147 caveolin-1 In of cells with Ig did not associated caveolin-1 from the Also, of CD147 from of the cell surface yielded a of associated caveolin-1 seen from the CD147 was at similar from surface and fractions, and at a from These results that caveolin-1 is associated with cell surface CD147 in multiple cell and that caveolin-1 is to cells to In of caveolin-1 from of cells yielded cell surface CD147 the cell surface of CD147-caveolin-1 CD147 with a of in a and proteins associate indirectly with caveolin-1 in the of membrane that associations at and on cholesterol (29Okamoto T. Schlegel A. Scherer P.E. Lisanti M.P. J. Biol. Chem. 1998; 273: 5419-5422Abstract Full Text Full Text PDF PubMed Scopus (1336) Google Scholar, M.H. PubMed Scopus Google Scholar, J. Cell Biol. PubMed Scopus Google Scholar, O. I. Biol. 2001; 11: Full Text Full Text PDF PubMed Scopus Google Scholar). association of CD147 with caveolin-1 was CD147 at of of caveolin-1 was by temperature and and no was associated with negative integrin a and In association of CD147 with caveolin-1 was upon of cells with of the CD147 association with caveolin-1 was upon cholesterol and CD147 association with integrin was not and of from cell was was associated with either or integrins and containing caveolin-1 in the fractions of sucrose C. Hemler M.E. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). from of cells, the bulk of caveolin-1 appeared in fractions containing low density sucrose In CD147 was associated with a subset of caveolin-1 that was to intermediate density fractions and CD147-caveolin-1 from the of other protein complexes, which in membrane fractions (28Liu P. Rudick M. Anderson R.G. J. Biol. Chem. 2002; 277: 41295-41298Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar). of cholesterol with CD147 from intermediate fractions the fractions in sucrose In a of cell surface proteins, was to the fractions In a CD147 was and associated integrin was shown to be in the fractions and with integrin than with CD147 shown in and the that association is and on while in the of an CD147 Ig 2 a in Caveolin-1 the in CD147 required for caveolin-1 association we CD147 chimeras in which the first Ig domain, Ig domain, or cytoplasmic either or by from protein (called Hemler M.E. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google of and cells to CD147 Ig domain 2 as being critical for caveolin-1 association of indicated of Ig domain 2 with the transmembrane domain and cytoplasmic domain in loss of caveolin-1 association In of the cytoplasmic domain or cytoplasmic transmembrane regions or of Ig domain caveolin-1 association. These results that Ig domain 2 plays a critical role in the association. the of CD147 Ig domain was either with Ig domain from or with Ig domain 2 from and in both caveolin-1 association was In experiments in of CD147 Ig domain 2 with Ig domain from also caveolin-1 association. of CD147 Ig domain 2 or Ig and 2 caveolin-1 whereas of the cytoplasmic tail did or of CD147 domain 2 no effect on association with α3β1 integrin and of Caveolin-1 to the of CD147-caveolin-1 we caveolin-1 in cells and its effect on cell surface clustering of CD147, using “cluster specific” monoclonal antibody C. G. R. I. J. P. O. V. H. Int. Immunol. 11: PubMed Scopus Google Scholar). of the on CD147 was whereas by mAb was The from was by In of protein by caveolin-1 overexpression. that caveolin-1 association to decreased by decreased loss of caveolin-1 association to enhanced the was selectively enhanced upon expression of the mutant caveolin-1 with CD147 in cells In mutant and CD147 yielded similar of the using mAb The from than to In antibody binding to integrin and binding by the CD147 from and that caveolin-1 overexpression effect on with CD147. was in cells caveolin-1 or not caveolin-1, the was the same In CD147 did show a decrease in the to of the caveolin-1 CD147 association with caveolin-1 correlates with CD147 cells with or mutant and as in the to that antibody was to the effects of caveolin-1 on mutant and CD147 in cells not caveolin-1 with either or and of cells for mAb or binding by as in and in cells not caveolin-1 with either or and of cells for mAb or binding by as in and in cells not caveolin-1 with either or and of cells for mAb or binding by as in and in cells not caveolin-1 with either or and of cells for mAb or binding by as in and in a we for the effects of altered caveolin-1 association and clustering on the MMP-1 activity of CD147. and mutant CD147 on cells at similar either or than CD147. of cells with human MMP-1 activity was enhanced that seen with either cell in both the of MMP-1 activity was was These results suggest that loss of caveolin-1 association not CD147 but also to elevated MMP activity. of the we an association an Ig superfamily protein, CD147, and caveolin-1, on in cell and The was as to and integrins and and other cell surface proteins and did not caveolin-1 Also, other Ig superfamily proteins and did not show caveolin-1 association. The CD147-caveolin-1 complex appeared on the cell as seen in both cell surface antibody binding and cell surface CD147-caveolin-1 association was and consistent with associations with other proteins (29Okamoto T. Schlegel A. Scherer P.E. Lisanti M.P. J. Biol. Chem. 1998; 273: 5419-5422Abstract Full Text Full Text PDF PubMed Scopus (1336) Google Scholar, M.H. PubMed Scopus Google Scholar, J. Cell Biol. PubMed Scopus Google Scholar, O. I. Biol. 2001; 11: Full Text Full Text PDF PubMed Scopus Google Scholar). However, the CD147-caveolin-1 complex is for two the CD147-caveolin-1 complex was in but and disrupted in whereas the of cell surface to the subset of caveolin-1 associated with CD147 is not with the bulk of caveolin-1 in the membrane fractions of sucrose but in intermediate density in and other caveolin-1 in the and of of their of other proteins in and has been N. A. K. S. R. EMBO J. PubMed Scopus Google Scholar). was that the proteins in highly by cholesterol and whereas other proteins may in domains, possibly at the of the highly N. A. K. S. R. EMBO J. PubMed Scopus Google Scholar). has not been CD147-caveolin-1 at the of the bulk of plasma is to the of can caveolin-1 to a soluble A. M. K. S. Biochem. Biophys. Res. Commun. 2000; 273: PubMed Scopus Google Scholar, P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). to be CD147-caveolin-1 for to the of caveolin-1 that is associated with CD147. of CD147 CD147 experiments that Ig domain 2 was required for caveolin-1 whereas other domains, Ig domain and the cytoplasmic tail CD147 Ig domain 2 contains two not caveolin-1 association was not is not known specific of CD147 Ig domain 2 from the Ig of and which not caveolin-1 association. the extracellular Ig domain 2 of CD147 to caveolin-1, an integral membrane is monocarboxylate transporters MCT1 and MCT4 (27Kirk P. Wilson M.C. Heddle C. Brown M.H. Barclay A.N. Halestrap A.P. EMBO J. 2000; 19: 3896-3904Crossref PubMed Scopus (504) Google Scholar, C. Muramatsu T. Investig. Ophthalmol. Vis. Sci. PubMed Scopus Google Scholar). However, of the CD147 transmembrane domain be to association of loss of a required acid M.C. Halestrap A.P. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar), but of the CD147 transmembrane domain did not caveolin-1 association. we that Ig domain 2 of CD147 may an caveolae/lipid targeting In this regard, transmembrane protein, its membrane extracellular domain for targeting to containing regions of the cell M. Anderson R.G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). Also, protein of H. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar) and the F. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) proteins to rafts. there is for cell surface proteins using for targeting to but the for not CD147 association with caveolin-1 required Ig domain was and and occurred within intermediate density fractions of a sucrose density In CD147 association with α3β1 integrin did not involve caveolin-1 and was by Ig domain 2 of or of temperature to and occurred within distinct fractions of a sucrose The required CD147 Ig domain of domain 2. distinct from CD147-caveolin-1 complexes, that α3β1 a CD147 and or to integrin and associated proteins we to from cells or other cell either in or results and B. Hemler M.E. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google In other of caveolin-1 with integrins from cells and other cells F. E.E. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, A. C. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. X. Q. J. Cell Biol. PubMed Scopus Google Scholar). that of integrins with F. E.E. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, A. C. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar) is to than we using soluble to cell Also, we that of a low can integrin-associated proteins caveolin-1 of Caveolin-1 caveolin-1 expression led to decreased CD147 clustering in cells, expression of mutant that caveolin-1 association showed spontaneous clustering with in Furthermore, did not show clustering in response to caveolin-1 expression in caveolin-1 association and CD147 clustering clustering we of mAb C. G. R. I. J. P. O. V. H. Int. Immunol. 11: PubMed Scopus Google Scholar). These low for CD147 and on which is CD147 is C. G. R. I. J. P. O. V. H. Int. Immunol. 11: PubMed Scopus Google Scholar). we suggest that negative of CD147 clustering by caveolin-1 to decreased CD147-dependent MMP mutant that caveolin-1 association and showed clustering also showed MMP-1 overexpression of caveolin-1 in cells not caused decreased clustering but also decreased MMP-1 production by in a with human fibroblasts we that results to caveolin-1 multiple other effects on MMP mAb C. G. R. I. J. P. O. V. H. Int. Immunol. 11: PubMed Scopus Google Scholar) inhibited MMP production in cell (16Sun J. Hemler M.E. Cancer Res. 2001; 61: 2276-2281PubMed Google Scholar), clustering to MMP evidence and M. that highly glycosylated CD147 not associate with but MMP production, and is to consistent with and M. that of caveolin-1 by to a in CD147 its highly for cell surface in clustering is associated with In conclusion, cell surface protein CD147 the of association with caveolin-1, in a complex with and density Furthermore, evidence a in which MMP induction is by CD147, with caveolin-1 a negative role on both clustering and MMP a mechanism may at least tumor effects of caveolin-1. and for