Prototypical Type I E-cadherin and Type II Cadherin-7 Mediate Very Distinct Adhesiveness through Their Extracellular Domains

Abstract

Using a dual pipette assay that measures the force required to separate adherent cell doublets, we have quantitatively compared intercellular adhesiveness mediated by Type I (E- or N-cadherin) or Type II (cadherin-7 or -11) cadherins. At similar cadherin expression levels, cells expressing Type I cadherins adhered much more rapidly and strongly than cells expressing Type II cadherins. Using chimeric cadherins, we found that the extracellular domain exerts by far the dominant effect on cell adhesivity, that of E-cadherin conferring high adhesivity, and that of cadherin-7 conferring low adhesivity. Type I cadherins were incorporated to a greater extent into detergent-insoluble cytoskeletal complexes, and their cytoplasmic tails were much more effective in disrupting strong adherent junctions, suggesting that Type II cadherins form less stable complexes with β-catenin. The present study demonstrates compellingly, for the first time, that cadherins are dramatically different in their ability to promote intercellular adhesiveness, a finding that has profound implications for the regulation of tissue morphogenesis. Using a dual pipette assay that measures the force required to separate adherent cell doublets, we have quantitatively compared intercellular adhesiveness mediated by Type I (E- or N-cadherin) or Type II (cadherin-7 or -11) cadherins. At similar cadherin expression levels, cells expressing Type I cadherins adhered much more rapidly and strongly than cells expressing Type II cadherins. Using chimeric cadherins, we found that the extracellular domain exerts by far the dominant effect on cell adhesivity, that of E-cadherin conferring high adhesivity, and that of cadherin-7 conferring low adhesivity. Type I cadherins were incorporated to a greater extent into detergent-insoluble cytoskeletal complexes, and their cytoplasmic tails were much more effective in disrupting strong adherent junctions, suggesting that Type II cadherins form less stable complexes with β-catenin. The present study demonstrates compellingly, for the first time, that cadherins are dramatically different in their ability to promote intercellular adhesiveness, a finding that has profound implications for the regulation of tissue morphogenesis. Adhesive interactions, so essential to multicellular life, are mediated by a diversity of cell surface receptors. Prominent among them are the cadherins, calcium-dependent adhesion molecules central to tissue development and morphogenesis (1Takeichi M. Curr. Opin. Cell Biol. 1995; 7: 619-627Crossref PubMed Scopus (1262) Google Scholar, 2Tepass U. Curr. Opin. Cell Biol. 1999; 11: 540-548Crossref PubMed Scopus (78) Google Scholar, 3Wheelock M.J. Johnson K.R. Annu. Rev. Cell Dev. Biol. 2003; 19: 207-235Crossref PubMed Scopus (535) Google Scholar). The growing superfamily of cadherins is subdivided into five families: classical Type I cadherins, atypical Type II cadherins, desmosomal cadherins, protocadherins, and seven-pass transmembrane cadherins (4Yagi T. Takeichi M. Genes Dev. 2000; 14: 1169-1180PubMed Google Scholar, 5Nollet F. Kools P. van Roy F. J. Mol. Biol. 2000; 299: 551-572Crossref PubMed Scopus (591) Google Scholar). Classical Type I and desmosomal cadherins are found primarily in tissues where a high degree of cell cohesion is required for tissue integrity. Other types of cadherins are expressed in situations where cells are more motile, and intercellular interactions are more transitory (6Dufour S. Beauvais-Jouneau A. Delouvée A. Thiery J.P. J. Cell Biol. 1999; 146: 501-516Crossref PubMed Scopus (60) Google Scholar, 7Pishavaian M.J. Feltes C.M. Thompson P. Bussemakers M.J. Schalken J.A. Byers S.W. 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Cell Biol. 2001; 153: 1049-1060Crossref PubMed Scopus (462) Google Scholar, 15Stockinger A. Eger A. Wolf J. Beug H. Foisner R. J. Cell Biol. 2001; 154: 1185-1196Crossref PubMed Scopus (277) Google Scholar, 16Price S.R. de Marco Garcia N.V. Ranscht B. Jessell T.M. Cell. 2002; 109: 205-216Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar, 17Conacci-Sorrell M. Simcha I. Ben-Yedidia T. Blechman J. Savagner P. BenZe'ev A. J. Cell Biol. 2003; 163: 847-857Crossref PubMed Scopus (409) Google Scholar). Predictably, the pattern of cadherin expression during development is complex. For example, development of the neural crest involves epithelial to mesenchymal transitions, cell migration, cell aggregation, and cell differentiation (18Le Douarin N.M. Kalcheim C. The Neural Crest. 2nd Ed. Cambridge University Press, Cambridge1999Crossref Google Scholar), each of which is associated with tightly regulated, differential expression of Type I and II cadherins. Premigratory cells of the avian neural crest express first N-cadherin, and then they down-regulate N-cadherin and express Type II cadherin-6B, but later down-regulate it and induce expression of the Type II cadherin-7 as they migrate throughout the embryo (19Duband J.-L. Volberg T. Sabanay I. Thiery J.P. Geiger B. Development. 1988; 103: 325-344PubMed Google Scholar, 20Nakagawa S. Takeichi M. Development. 1995; 121: 1321-1332Crossref PubMed Google Scholar). Another Type II cadherin, cadherin-11, is similarly induced in migrating neural crest cells of rat and Xenopus embryos (21Simonneau L. Kitagawa M. Suzuki S. Thiery J.P. Cell Adhes. Comm. 1995; 3: 115-130Crossref PubMed Scopus (124) Google Scholar, 22Vallin J. Thiery J.P. Broders F. Mech. Dev. 1998; 75: 183-186Crossref Scopus (70) Google Scholar, 23Borchers A. David R. Wedlich D. Development. 2001; 128: 3049-3060PubMed Google Scholar). Cell grafting experiments in vivo verify that expression of cadherin-7 correlates with cell dispersion and migration along migratory pathways, whereas that of N-cadherin fosters strong intercellular cohesivity and failure to migrate (6Dufour S. Beauvais-Jouneau A. Delouvée A. Thiery J.P. J. Cell Biol. 1999; 146: 501-516Crossref PubMed Scopus (60) Google Scholar). Regulation of cellular adhesion can be achieved in a variety of ways (for review see Ref. 24Gumbiner B.M. J. Cell Biol. 2000; 148: 399-403Crossref PubMed Scopus (690) Google Scholar). The simplest, altering the number of cadherins on the cell surface, has been clearly shown to dictate the pattern of cell sorting in vitro (25Steinberg M.S. Takeichi M. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 206-209Crossref PubMed Scopus (491) Google Scholar, 26Friedlander D.R. Mege R.-M. Cunningham B.A. Edelman G.M. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 7043-7047Crossref PubMed Scopus (196) Google Scholar, 27Duguay D. Foty R.A. Steinberg M.S. Dev. Biol. 2003; 253: 309-323Crossref PubMed Scopus (288) Google Scholar). Changes in the cadherins expressed on cells during morphogenesis and under pathological conditions are also well documented (1Takeichi M. Curr. Opin. Cell Biol. 1995; 7: 619-627Crossref PubMed Scopus (1262) Google Scholar, 2Tepass U. Curr. Opin. Cell Biol. 1999; 11: 540-548Crossref PubMed Scopus (78) Google Scholar, 3Wheelock M.J. Johnson K.R. Annu. Rev. Cell Dev. Biol. 2003; 19: 207-235Crossref PubMed Scopus (535) Google Scholar). Such differential expression would be even more effective if each cadherin promoted intercellular adhesion that is qualitatively or quantitatively unique. To test this possibility, we developed a dual pipette assay that quantifies precisely and reproducibly the force required to separate pairs of adherent cells (28Chu Y.S. Thomas W.A. Eder O. Pincet F. Perez E. Thiery J.P. Dufour S. J. Cell Biol. 2004; 167: 1183-1194Crossref PubMed Scopus (325) Google Scholar, 29Chu Y.S. Dufour S. Thiery J.P. Perez E. Pincet F. Phys. Rev. Lett. 2005; 94: 028102Crossref PubMed Scopus (160) Google Scholar). In earlier work we focused on E-cadherin that mediates rapid initial adhesion subsequently strengthened by cytoskeletal remodeling and nectin modulation (28Chu Y.S. Thomas W.A. Eder O. Pincet F. Perez E. Thiery J.P. Dufour S. J. Cell Biol. 2004; 167: 1183-1194Crossref PubMed Scopus (325) Google Scholar, 30Martinez-Rico C. Pincet F. Perez E. Thiery J.P. Shimizu K. Takai Y. Dufour S. J. Biol. Chem. 2005; 280: 4753-4760Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). Here we compare four different cadherins. The results indicate that Type I cadherins (E and N) promote much stronger adhesiveness than Type II cadherins (7 and 11), the difference being attributable primarily to the extracellular domain of the and and cell were a M. Takeichi and S. The to and E-cadherin and the were and and were E-cadherin or were and to were to and were Cell and and are expressing E-cadherin and N-cadherin, and were (6Dufour S. Beauvais-Jouneau A. Delouvée A. Thiery J.P. J. Cell Biol. 1999; 146: 501-516Crossref PubMed Scopus (60) Google Scholar, 26Friedlander D.R. Mege R.-M. Cunningham B.A. Edelman G.M. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 7043-7047Crossref PubMed Scopus (196) Google Scholar). The and to their of E-cadherin were by (28Chu Y.S. Thomas W.A. Eder O. Pincet F. Perez E. Thiery J.P. Dufour S. J. Cell Biol. 2004; 167: 1183-1194Crossref PubMed Scopus (325) Google Scholar). with different of cadherin-7 or were by stable of cells with or S. Takeichi M. Development. 1995; 121: 1321-1332Crossref PubMed Google Scholar, Y. H. Inoue T. K. T. T. Takeichi M. Dev. Biol. 1995; PubMed Scopus Google Scholar), with as (28Chu Y.S. Thomas W.A. Eder O. Pincet F. Perez E. Thiery J.P. Dufour S. J. Cell Biol. 2004; 167: 1183-1194Crossref PubMed Scopus (325) Google Scholar). of cells with the cytoplasmic tails of cadherins were of and of to and were a M. The and were by B. Dufour S. Thiery J.P. Cell Res. PubMed Scopus Google Scholar). for chimeric and cadherins in which the and cytoplasmic of E-cadherin and cadherin-7 were as in for in with the cytoplasmic tails of N-cadherin and cadherin-7 and were as The of is shown in The cytoplasmic domain of N-cadherin by and of the cadherin-7 cytoplasmic domain and The were with and or and and into The of each by of the Cell and cells were in with and were by with in For force and cell cell in S. Takeichi M. Development. 1995; 121: 1321-1332Crossref PubMed Google Scholar). to the cells were in with and by the to cell were to for in the assay to be that they were were as (6Dufour S. Beauvais-Jouneau A. Delouvée A. Thiery J.P. J. Cell Biol. 1999; 146: 501-516Crossref PubMed Scopus (60) Google Scholar). of Cell and of cell and were as (6Dufour S. Beauvais-Jouneau A. Delouvée A. Thiery J.P. J. Cell Biol. 1999; 146: 501-516Crossref PubMed Scopus (60) Google with a of and or cadherin, by by the on a The to for the of each The of and E-cadherin of cells were as the for with other For of the cell were in the of of cadherin the and as by A. H. R. J. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). the cell were to the and of the and were to as with of cells by of with of vivo of with cadherins were as M. R. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). the on a the results The into to the for each of cadherins in cells as (6Dufour S. Beauvais-Jouneau A. Delouvée A. Thiery J.P. J. Cell Biol. 1999; 146: 501-516Crossref PubMed Scopus (60) Google Scholar). The cells were by a and a were by a work expression by as (28Chu Y.S. Thomas W.A. Eder O. Pincet F. Perez E. Thiery J.P. Dufour S. J. Cell Biol. 2004; 167: 1183-1194Crossref PubMed Scopus (325) Google Scholar). of in by (28Chu Y.S. Thomas W.A. Eder O. Pincet F. Perez E. Thiery J.P. Dufour S. J. Cell Biol. 2004; 167: 1183-1194Crossref PubMed Scopus (325) Google Scholar, 29Chu Y.S. Dufour S. Thiery J.P. Perez E. Pincet F. Phys. Rev. Lett. 2005; 94: 028102Crossref PubMed Scopus (160) Google Scholar). were on the of a with a or by a work cells were on the of each and were into for a of the of At the of the time, the were in to the adherent cells the pipette to the of that where the then The with in the of which were with a the in the pipette to the for each of the in the and were to the for each the to this where is the of The results for were to the for a in The is to as the in the and in cells express of cadherins or and adhesion in tissue (6Dufour S. Beauvais-Jouneau A. Delouvée A. Thiery J.P. J. Cell Biol. 1999; 146: 501-516Crossref PubMed Scopus (60) Google Scholar, 26Friedlander D.R. Mege R.-M. Cunningham B.A. Edelman G.M. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 7043-7047Crossref PubMed Scopus (196) Google Scholar). cells to express E-cadherin N-cadherin or cadherin-7 intercellular in tissue with the cadherin and expressing of E-cadherin I and cadherin-7 and or and were compared for their cadherin and The for and cadherin-7 and were for and to as and The cell were by a in cadherin cytoplasmic cells and E-cadherin and (28Chu Y.S. Thomas W.A. Eder O. Pincet F. Perez E. Thiery J.P. Dufour S. J. Cell Biol. 2004; 167: 1183-1194Crossref PubMed Scopus (325) Google Scholar), expressed and of the and Type II cadherins be with this of a of the the of expression to that of cadherin in the and N-cadherin, and cadherin-7 a with and expression to the cadherin in Type I and Type II and N-cadherin and cadherin-7 are the cell surface by and as shown by I and and The of of the surface of and in that cadherin-11, the other cadherins, is present and that and cells expressed high of cadherin their The for the were and for and and cells expressed similar of cadherin their surface, and cells expressed of the as the results with the of cadherin the of cell were also in with the that cadherins are the of cell as shown in of the for dual pipette we first the of for cells expressing the four different cadherins. that cells rapidly and then their adhesion with of Y.S. Thomas W.A. Eder O. Pincet F. Perez E. Thiery J.P. Dufour S. J. Cell Biol. 2004; 167: 1183-1194Crossref PubMed Scopus (325) Google and cells but with adhesivity. and of we a of and for compared with and for cells expressing Type II cadherins much more and were adhesion similar to of Type I cadherins, but on with different of developed of with for cells and cells developed and of The results for cells were even more they for of less than The were so to that were The of and and were far even for of in by the In the for than that for of For cells expressing Type I cadherins, the for were much more similar than of for expressing Type II cadherins (cadherin-7 or were much than of Type I cadherins and were of of cells cadherins. of for of cells expressing different cadherins results The for much greater than that for even cadherin expression in the that in the results were with a N-cadherin expressing the for expressing different cadherin in a The difference Type I and Type II cadherins even more and cells expressed cadherin and of the they of and were with or less than for the expressing the of Type I of into the of cadherins by and of and cadherins were found in but their the with the of and of the and N-cadherin, but of cadherin found in the detergent-insoluble of the cell The results for were similar to for cadherin-7 of cells with that of cells were much more to than of The of in cells and whereas in cells and results that Type II cadherin-7 is incorporated much less than Type I or N-cadherin into the detergent-insoluble complex. N-cadherin and cadherin-7 with and of is to cadherin J. T. H. S. J. J. Cell Biol. PubMed Scopus Google Scholar, S. S. J. Garcia de A. M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), but and cells similar of suggesting that the adhesiveness of cells in the of β-catenin. expression of Type I cadherin cytoplasmic tails can adherent in cells and with I. C. E. M. Geiger B. M. A. Mol. Biol. Cell. 2001; 12: PubMed Scopus Google Scholar). have compared the ability of the cytoplasmic domain of the different cadherins to intercellular to the cytoplasmic tails of each cadherin were expressed in and their effect on the of and of a Type I cadherin (E- or in cytoplasmic of and a in the of and and Ref. I. C. E. M. Geiger B. M. A. Mol. Biol. Cell. 2001; 12: PubMed Scopus Google Scholar). the cells more than of in the and much for expression of the Type II cadherin-7 cytoplasmic in more than of the cells and of them of in the on Cell expression for chimeric cadherins where the transmembrane or cytoplasmic domain were E-cadherin Type I and cadherin-7 Type II cadherins were they the difference in in cells expressing or chimeric cadherins and were and compared with E-cadherin different or cadherin-7 of expressing and chimeric cadherins and of their of and chimeric cadherins in which the extracellular were E-cadherin and of cadherin and in cell of and expressing with a the cytoplasmic domain of and with the extracellular domain of chimeric cadherins. The by and expressed a of cadherin similar to that of the and were for of the chimeric cadherins intercellular of cadherins the cell surface of and expressed a similar of cadherin their on expressing and and and that and expressed cadherin than and cells expressed cadherin similar to cells and chimeric cadherins the cadherin and were on of cells expressing each of the chimeric cadherins and and of and cells of and than that of cells cells expressed of cadherin than of The of for and strong initial that in with similar to by cells expressing the for and doublets, were under the of of and the of and as compared with the for and expressing the cadherin-7 transmembrane domain and than the and and expressing the E-cadherin transmembrane in the and regulation of intercellular adhesion (28Chu Y.S. Thomas W.A. Eder O. Pincet F. Perez E. Thiery J.P. Dufour S. J. Cell Biol. 2004; 167: 1183-1194Crossref PubMed Scopus (325) Google Scholar, 30Martinez-Rico C. Pincet F. Perez E. Thiery J.P. 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M. 1998; 19: PubMed Scopus Google Scholar, 2002; PubMed Scopus Google Scholar, M.J. Res. 2005; PubMed Scopus Google Scholar). In the present we that the for adherent cells cadherin Type and of a to for the differential interactions to cell migration in to in the which are to In the results of this study for the first time, that Type I cadherins (E- and are different Type II cadherins and -11) in the intercellular they the which they and the in which they are Type I cadherins stronger more whereas Type II cadherins form much and more in the that Type I cadherins are primarily in of whereas Type II cadherins are expressed on the surface of migrating results also into the regulation of as The E-cadherin developed under the of the of and by the of of the University of D. and D. for with and are to M. Takeichi and S. for the of and and also to M. J. and P. for with