A Dileucine Motif Targets E-cadherin to the Basolateral Cell Surface in Madin-Darby Canine Kidney and LLC-PK1 Epithelial Cells

E-cadherin is a major adherens junction protein of epithelial cells, with a central role in cell-cell adhesion and cell polarity. Newly synthesized E-cadherin is targeted to the basolateral cell surface. We analyzed targeting information in the cytoplasmic tail of E-cadherin by utilizing chimeras of E-cadherin fused to the ectodomain of the interleukin-2α (IL-2α) receptor expressed in Madin-Darby canine kidney and LLC-PK1epithelial cells. Chimeras containing the full-length or membrane-proximal half of the E-cadherin cytoplasmic tail were correctly targeted to the basolateral domain. Sequence analysis of the membrane-proximal tail region revealed the presence of a highly conserved dileucine motif, which was analyzed as a putative targeting signal by mutagenesis. Elimination of this motif resulted in the loss of Tac/E-cadherin basolateral localization, pinpointing this dileucine signal as being both necessary and sufficient for basolateral targeting of E-cadherin. Truncation mutants unable to bind β-catenin were correctly targeted, showing, contrary to current understanding, that β-catenin is not required for basolateral trafficking. Our results also provide evidence that dileucine-mediated targeting is maintained in LLC-PK1 cells despite the altered polarity of basolateral proteins with tyrosine-based signals in this cell line. These results provide the first direct insights into how E-cadherin is targeted to the basolateral membrane. E-cadherin is a major adherens junction protein of epithelial cells, with a central role in cell-cell adhesion and cell polarity. Newly synthesized E-cadherin is targeted to the basolateral cell surface. We analyzed targeting information in the cytoplasmic tail of E-cadherin by utilizing chimeras of E-cadherin fused to the ectodomain of the interleukin-2α (IL-2α) receptor expressed in Madin-Darby canine kidney and LLC-PK1epithelial cells. Chimeras containing the full-length or membrane-proximal half of the E-cadherin cytoplasmic tail were correctly targeted to the basolateral domain. Sequence analysis of the membrane-proximal tail region revealed the presence of a highly conserved dileucine motif, which was analyzed as a putative targeting signal by mutagenesis. Elimination of this motif resulted in the loss of Tac/E-cadherin basolateral localization, pinpointing this dileucine signal as being both necessary and sufficient for basolateral targeting of E-cadherin. Truncation mutants unable to bind β-catenin were correctly targeted, showing, contrary to current understanding, that β-catenin is not required for basolateral trafficking. Our results also provide evidence that dileucine-mediated targeting is maintained in LLC-PK1 cells despite the altered polarity of basolateral proteins with tyrosine-based signals in this cell line. These results provide the first direct insights into how E-cadherin is targeted to the basolateral membrane. Madin-Darby canine kidney cells green fluorescence protein interleukin-2 receptor pig kidney proximal tubular epithelial cell line polyacrylamide gel electrophoresis phosphate-buffered saline polymerase chain reaction IL-2Rα chain radioimmune precipitation buffer base pair(s) cytomegalovirus E-cadherin is expressed on the lateral membranes of epithelial cells where it accumulates as a major component of the adherens junction. The cadherins in adherens junctions have central roles in establishing and maintaining cell-cell adhesion and cell polarity in epithelia and participate in morphogenesis during development (1Takeichi M. Curr. Opin. Cell Biol. 1995; 7: 619-627Crossref PubMed Scopus (1273) Google Scholar, 2Yap A.S. Brieher W.M. Gumbiner B.M. Annu. Rev. Cell Dev. Biol. 1997; 13: 119-146Crossref PubMed Scopus (690) Google Scholar, 3Gumbiner B.M. 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The cytoplasmic tail of E-cadherin is bound directly to β-catenin or plakoglobin, and thereby to α-catenin and actin (reviewed in Ref. 2Yap A.S. Brieher W.M. Gumbiner B.M. Annu. Rev. Cell Dev. Biol. 1997; 13: 119-146Crossref PubMed Scopus (690) Google Scholar). The binding site for β-catenin has been mapped by deletion mutagenesis to the distal 76 amino acids of the carboxyl terminus of E-cadherin (7Ozawa M. Ringwald M. Kemler R. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 4246-4250Crossref PubMed Scopus (682) Google Scholar), with critical residues found in the last 30 amino acid domain (8Stappert J. Kemler R. Cell Adhes. Commun. 1994; 2: 319-327Crossref PubMed Scopus (202) Google Scholar). 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Cell Biol. 1992; PubMed Scopus Google in with and in and a conserved region of the cytoplasmic domain of human E-cadherin and β-catenin were was a and a the green fluorescence protein was also used for and and a human E-cadherin and the for were in the expression were to J. Scholar), from were by the transmembrane cytoplasmic domains the cytoplasmic tail or the half of the cytoplasmic tail of human E-cadherin were with specific E-cadherin to the protein as (6Rimm D.L. Morrow J.S. Biochem. Biophys. Res. Commun. 1994; 200: 1754-1761Crossref PubMed Scopus (41) Google Scholar). The of with the the into S.K. J. Cell Biol. 1992; PubMed Scopus Google the the and The Tac/E-cadherin were into the expression that also for the The were and the site was at the of the domain of the altered of the from to a The was by the E-cadherin into the and the full-length E-cadherin with the green fluorescence protein fused to the carboxyl terminus of the cytoplasmic domain. a site was at the carboxyl terminus of the full-length of E-cadherin. was by the of the E-cadherin specific M. S. C. M. Gumbiner P. EMBO J. 1999; PubMed Scopus Google as a The the site and a The was with and into the The of was by specific and as a The a site that the to be into the site into in the carboxyl terminus of E-cadherin. of the residues at and of human E-cadherin to was The was and to a that the for the dileucine The was with the and These a and a as as for residues The was For and expression of LLC-PK1 or cells were with in complex with to the For cells were and maintained in containing cells were for and at low density for of cells. cell were and by and to with of protein of cells on or on were in in for and in containing for LLC-PK1 cells were in for were with and containing as a were on in containing For cells were with which was to the for to to on were by and were with a of on were a on a and and were of and LLC-PK1 cells were in buffer containing on were with the for and with protein for a were by through of buffer and to in in cell and were on and to membranes and with to protein and protein were by in by with were and in the were of LLC-PK1 cells or on were in containing to the apical or of the for on were in cells were and in cell were with in for with were in of buffer and proteins bound to the and proteins in the were analyzed by and to the of E-cadherin is to the basolateral surface of polarized cells, where it a and specific The not E-cadherin in LLC-PK1 cells it cell surface of E-cadherin in and E-cadherin is expressed in both cell and is found in a polarized of human was expressed in cells, a basolateral surface with that is targeted in a to the protein was also expressed in epithelial where it was also targeted in a polarized to the basolateral membrane For targeting utilized chimeras of the ectodomain of fused to the cytoplasmic tail of E-cadherin expressed in epithelial cells proteins of the to the apical membrane in polarized cells J.S. M. G. A. J.S. Rodriguez-Boulan E. Biol. Cell. 1994; PubMed Scopus Google and a and basolateral signal in the E-cadherin cytoplasmic domain is to from apical to basolateral for or proteins were into and LLC-PK1 cells, and cell were were used to the proteins and by and of Tac/E-cadherin of or Tac/E-cadherin chimeras in cell the of in each of cells. and LLC-PK1 cells full-length on apical expressed in LLC-PK1 cells is on the basolateral membrane. The is also on the basolateral domains of LLC-PK1 cells and cells Chimeras containing the cytoplasmic tail of E-cadherin were expressed and found to to the basolateral domain in both and LLC-PK1 cells. Both and which the transmembrane domain of were by and by to the basolateral membranes of and the presence or of the E-cadherin transmembrane domain on These results that the Tac/E-cadherin chimeras are synthesized and to the cell surface and that the cytoplasmic tail of E-cadherin sorting of to a basolateral cells loss of E-cadherin on the basolateral surface that the sorting and targeting in cells has not been or by the the first in a analysis of the cytoplasmic tail of a was to the cytoplasmic the membrane-proximal of the tail fused to The was expressed in and LLC-PK1 cells and analysis that it was in a polarized was of apical membranes was to cells or cells, was of the basolateral membranes in LLC-PK1 and cells a and chimeras containing the full-length or the membrane-proximal are and have the polarized surface We in cells from was of in a in to basolateral surface was not in cell chimeras with full-length or LLC-PK1 cells were with to protein and and at of the was a loss of at by a of cell surface that of of the of at the basolateral surface. this it was that in cells a of newly synthesized in the pathway and that the membrane-proximal is to the basolateral membrane at a The targeting of was a surface to and its on the plasma membrane domains of polarized cells. Cell surface was on cell and of to the of the of the and proteins, whereas from the apical in results that a containing the membrane-proximal half of the E-cadherin cytoplasmic has sufficient information to direct sorting and targeting to the basolateral cell at a with the full-length cytoplasmic surface to expression of and were with to apical or proteins were and analyzed by and to the of each from each of the cell in a expression of and were with to apical or proteins were and analyzed by and to the of each from each of the cell Sequence analysis of the membrane-proximal E-cadherin tail by the region in revealed the presence of putative targeting Sequence of of the of which E-cadherin is the and cadherins P. J. Biol. 2000; PubMed Scopus Google Scholar), revealed that a dileucine motif at is highly conserved and in of the this dileucine motif for targeting the at and were to in the chimeras the full-length tail and membrane-proximal The and were into LLC-PK1 and cells and by and were at the apical of LLC-PK1 and cells, in to the apical a and and distinct from the basolateral of the dileucine motif at from the E-cadherin cytoplasmic domain resulted in a loss of basolateral targeting We that this motif is a sorting signal for the basolateral membrane of E-cadherin and that it is necessary to direct The of of this dileucine motif the cadherins that it has a targeting signal of the is in the of tyrosine-based signal at was not and is not a for on from J. Cell Biol. 1999; PubMed Scopus Google and that the motif is not conserved in cadherins is to bind to the cytoplasmic tail of E-cadherin in the pathway and has been in to the cell surface J. Cell Biol. 1999; PubMed Scopus Google Scholar). Tac/E-cadherin chimeras were for to bind to The of E-cadherin in cells with β-catenin was by of the proteins E-cadherin was with the from of and LLC-PK1 cells, and β-catenin in the complex was by of both and LLC-PK1 cells, β-catenin was bound to that the full-length cytoplasmic tail in is correctly and in a to and surface The membrane-proximal is the β-catenin binding and as β-catenin was not with this protein E-cadherin and chimeras with full-length E-cadherin were to bind and β-catenin of the dileucine targeting signal on binding of which was with The basolateral targeting of in the of bound β-catenin that β-catenin is not for basolateral sorting and targeting in or The of β-catenin with newly synthesized E-cadherin may be required for other roles in or for the loss of β-catenin binding may for the and of the E-cadherin is of the polarized membrane proteins in is to the basolateral membrane and is in adherens junctions where it in cell-cell how E-cadherin is and targeted in polarized cells, of Tac/E-cadherin chimeras expressed in epithelial cell Our that chimeras containing full-length or cytoplasmic of E-cadherin were sorted and to the basolateral surface domain in and LLC-PK1 cells. this polarized targeting was deletion of a targeting motif in the proximal region of the from that a single dileucine motif at is to basolateral targeting information in Tac/E-cadherin chimeras and that this signal is necessary for basolateral that LLC-PK1 cells are to correctly and E-cadherin a in to proteins sorted by tyrosine-based signals that are in cells, and that β-catenin is not required for basolateral targeting and surface of E-cadherin. Chimeras containing the cytoplasmic tail of and were targeted and to the basolateral domain of and LLC-PK1 cells in a to that of E-cadherin or in cell line. The ectodomain not with the or in the full-length tail was evidence of membrane or the The transmembrane domain has been in lateral and of cadherins in the plasma membrane, surface Kemler R. D. J. Cell Sci. 1999; PubMed Google Scholar). acid transmembrane be involved in targeting as by the apical targeting signal in of the transmembrane of the of the L.A. P. J. Cell Biol. 2000; 148: PubMed Scopus Google Scholar). Our directly the E-cadherin transmembrane with the that this region of the protein has role in basolateral targeting in sorting or membrane of Tac/E-cadherin the results with the Tac/E-cadherin chimeras to the cytoplasmic tail of E-cadherin as basolateral sorting in with other membrane The basolateral targeting of the first that the membrane-proximal tail region is sufficient for membrane targeting and that distal of the tail are not required for targeting or surface mutants with the tail of were targeted, and to the basolateral cell at a with the cytoplasmic of in the as in LLC-PK1 cells, that it was the full-length of was in cells, although the tail mutants the cell surface. Our are in to of a in which a series of chimeras mutants of the E-cadherin tail fused to a were found to be J. Cell Biol. 1999; PubMed Scopus Google Scholar). of the proteins in that the surface of cells and were whereas the of the proteins were or in the pathway J. Cell Biol. 1999; PubMed Scopus Google Scholar). the of the targeting and of which tail to of the mutants in the that the and of chimeras may have been to the of the ectodomain being a function of E-cadherin or proteins The membrane-proximal tail region of E-cadherin has been in a of and were to be by in the membrane-proximal region of the tail A.S. Gumbiner B.M. J. Cell Biol. 1998; PubMed Scopus Google Scholar). of the protein has also been to in this region A.S. Gumbiner B.M. J. Cell Biol. 1998; PubMed Scopus Google Scholar, M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), and of the amino acid mapped by as being involved in the binding of J. Cell Biol. 2000; 148: PubMed Scopus Google Scholar), with the dileucine targeting signal in this is that this membrane-proximal region of the tail is involved in protein interactions that are for E-cadherin and for function at the cell surface. sorting by the membrane-proximal tail to on putative sorting signals in this The dileucine motif at was as a targeting being in the region of the revealed that the dileucine motif is highly conserved cadherins of or P. J. Biol. 2000; PubMed Scopus Google Scholar). We that this dileucine function to target transmembrane cadherins to basolateral domains of polarized epithelial cells. in which the are not conserved cadherins and The as not have a dileucine motif J. E. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). 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J. C. J. Cell Biol. 1997; PubMed Scopus Google Scholar). the dileucine signal has a or in the that this motif also function as endocytosis are motifs with targeting signals in the E-cadherin at the being in the membrane-proximal region and at the carboxyl were in a and found to have role in targeting of E-cadherin J. Cell Biol. 1999; PubMed Scopus Google Scholar). is a and dileucine motif in to the motif, which has been to be for basolateral targeting of the receptor in cells E. K. A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). is also a motif to the with a at the Both of signals are adjacent or the β-catenin binding domain and are to be E-cadherin is to The that of signals be during protein interactions and act as targeting signals during of surface E-cadherin. or of signals for target E-cadherin to for endocytosis and A.S. Stow J.L. J. Cell Biol. 1999; 146: PubMed Scopus Google it the basolateral plasma membrane. analysis of targeting motifs to a dileucine signal tyrosine-based signals being for the polarized sorting and basolateral of E-cadherin. Both and LLC-PK1 cell polarized epithelial in that basolateral and of Stow J.L. J. Physiol. Google Scholar, J.L. L. J. Cell Biol. PubMed Scopus Google Scholar). to the polarity of LLC-PK1 D.L. Naim H.Y. Roth M.G. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, J.S. Mellman I. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), it was of to also E-cadherin in cells. Our that E-cadherin is correctly to the basolateral surface of the LLC-PK1 cells, and that this as in cells, is by a dileucine evidence to that basolateral targeting via correctly in LLC-PK1 cells. The targeting of and that sorting is sufficient to direct basolateral in cells. LLC-PK1 cells are in targeting of tyrosine-based motifs to the of the chain J.S. Mellman I. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). the sorting of dileucine motifs occurs through with the of the complex I. P. EMBO J. 1998; PubMed Scopus Google Scholar), sorting of proteins as cell receptor Fc and E-cadherin. The targeting of E-cadherin and in LLC-PK1 cells as evidence that this targeting in on dileucine The of the or that required for of E-cadherin in LLC-PK1 or epithelial cells have to be the current also insights into the role of β-catenin in E-cadherin trafficking. is a cytoplasmic protein with for the cytoplasmic tail of it to E-cadherin in the a complex that is to the cell surface L. I.S. J. J. Cell Biol. 1994; PubMed Scopus Google Scholar). and J. Cell Biol. 1999; PubMed Scopus Google that β-catenin is required for the and of on a deletion of residues or the β-catenin binding domain and loss of surface in chimeras and other current results a We that full-length tail chimeras β-catenin in to that in the which not bind found it was correctly targeted and to the cell that β-catenin is not required for sorting or may have a role in or the or of newly synthesized E-cadherin. of factors to the and of that in the of and that β-catenin binding also to the E-cadherin tail from A.H. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus (215) Google Scholar). Our that β-catenin is not required for basolateral targeting or surface on β-catenin as a role in not trafficking. The polarized targeting of E-cadherin is of to the of epithelial polarity and signals and the basolateral of newly synthesized E-cadherin and of and E-cadherin for its into adherens this basolateral sorting via a dileucine specific roles for signals and for of the proteins in We for providing and and for