Lysosomal and Proteasomal Degradation Play Distinct Roles in the Life Cycle of Cx43 in Gap Junctional Intercellular Communication-deficient and -competent Breast Tumor Cells

The present study was designed to determine the specific roles played by lysosomes and proteasomes in the degradation of Cx43 in both gap junctional intercellular communication-deficient MDA-MB-231 and -competent BICR-M1Rk cells. In MDA-MB-231 cells, immunolocalization and brefeldin A protein transport blocking studies revealed that there was a propensity for newly synthesized Cx43 to be transported to lysosomes. On the other hand, light and electron microscopic analysis of BICR-M1Rk cells showed that Cx43 gap junctions were prevalent with a subpopulation of intracellular Cx43 localized to lysosomes. In both cell types, Western blots revealed a notable increase in total cellular Cx43 in response to lysosome inhibitors. Interestingly, lactacystin inhibition of proteosomal degradation in MDA-MB-231 cells resulted in a marked increase in phosphorylated Cx43 at the expense of non-phosphorylated Cx43, and this change corresponded with an increase in “oversized” gap junction plaques. In BICR-M1Rk cells, lactacystin treatment partially prevented the BFA-induced loss of gap junctions. Together, our data suggests that lysosomes play a key role in not only degrading internalized gap junction in BICR-M1Rk cells but also in degrading Cx43 delivered from early secretory compartments to lysosomes in MDA-MB-231 cells. Overall proteasomal degradation regulates the stability of phosphorylated Cx43 and appears to promote the internalization of Cx43 from the cell surface. The present study was designed to determine the specific roles played by lysosomes and proteasomes in the degradation of Cx43 in both gap junctional intercellular communication-deficient MDA-MB-231 and -competent BICR-M1Rk cells. In MDA-MB-231 cells, immunolocalization and brefeldin A protein transport blocking studies revealed that there was a propensity for newly synthesized Cx43 to be transported to lysosomes. On the other hand, light and electron microscopic analysis of BICR-M1Rk cells showed that Cx43 gap junctions were prevalent with a subpopulation of intracellular Cx43 localized to lysosomes. In both cell types, Western blots revealed a notable increase in total cellular Cx43 in response to lysosome inhibitors. Interestingly, lactacystin inhibition of proteosomal degradation in MDA-MB-231 cells resulted in a marked increase in phosphorylated Cx43 at the expense of non-phosphorylated Cx43, and this change corresponded with an increase in “oversized” gap junction plaques. In BICR-M1Rk cells, lactacystin treatment partially prevented the BFA-induced loss of gap junctions. Together, our data suggests that lysosomes play a key role in not only degrading internalized gap junction in BICR-M1Rk cells but also in degrading Cx43 delivered from early secretory compartments to lysosomes in MDA-MB-231 cells. Overall proteasomal degradation regulates the stability of phosphorylated Cx43 and appears to promote the internalization of Cx43 from the cell surface. Gap junctions are the intercellular channels localized to the plasma membrane of cell-cell contact between adjacent cells. The existence of these channels allows an intercellular exchange of low molecular weight molecules including most second messengers like cAMP, calcium, and inositol 1,4,5-triphosphate (1Goodenough D.A. Goliger J.A. Paul D.L. Annu. Rev. Biochem. 1996; 65: 475-502Crossref PubMed Scopus (1094) Google Scholar, 2Nicholson B.J. Weber P.A. Cao F. Chang H. Lampe P. Goldberg G. Braz. J. Med. Biol. Res. 2000; 33: 369-378Crossref PubMed Scopus (108) Google Scholar). The building block of gap junctions is a transmembrane protein called a connexin. Six connexin molecules oligomerize into a hemichannel termed a connexon. After being transported to the plasma membrane, two hemichannels supplied by adjacent cells dock with each other to form a complete gap junction channel. The connexin family consists of at least 20 members (3Willecke K. Eiberger J. Degen J. Eckardt D. Romualdi A. Guldenagel M. Deutsch U. Sohl G. Biol. Chem. 2002; 383: 725-737Crossref PubMed Scopus (1010) Google Scholar), but Cx43 has attracted the most attention as it is widely expressed in many tissues and Cx43 gap junctions correlate with various physiological functions such as cardiac excitability (4Gehrmann J. Berul C.I. J. Cardiovasc. Electrophysiol. 2000; 11: 354-368Crossref PubMed Scopus (48) Google Scholar). As expected, Cx43 has been shown to co-translationally insert into endoplasmic reticulum (ER) 1The abbreviations used are: ER, endoplasmic reticulum; GJIC, gap junctional intercellular communication; BFA, brefeldin A; CHX, cycloheximide; GFP, green fluorescent protein. membranes followed by oligomerization during its transport from the ER to the Golgi apparatus (5Gaietta G. Deerinck T.J. Adams S.R. Bouwer J. Tour O. Laird D.W. Sosinsky G.E. Tsien R.Y. Ellisman M.H. Science. 2002; 296: 503-507Crossref PubMed Scopus (813) Google Scholar, 6Laird D.W. J. Bioenerg. Biomembr. 1996; 28: 311-318Crossref PubMed Scopus (156) Google Scholar, 7Laird D.W. Castillo M. Kasprzak L. J. Cell Biol. 1995; 131: 1193-1203Crossref PubMed Scopus (222) Google Scholar). Further maturation of newly synthesized Cx43 includes phosphorylation, a process that is closely related to gap junction assembly and turnover (8Musil L.S. Goodenough D.A. J. Cell Biol. 1991; 115: 1357-1374Crossref PubMed Scopus (619) Google Scholar). As analyzed by SDS-PAGE, Cx43 is normally reported as being represented by a faster migrating, non-phosphorylated species (Cx43-P0) and two more slower migrating, phosphorylated species (Cx43-P1 and Cx43-P2) that are both sensitive to phosphoserine-specific phosphatases (8Musil L.S. Goodenough D.A. J. Cell Biol. 1991; 115: 1357-1374Crossref PubMed Scopus (619) Google Scholar, 9Laird D.W. Puranam K.L. Revel J.P. Biochem. J. 1991; 273: 67-72Crossref PubMed Scopus (404) Google Scholar). Due to the lack of insight into the phosphorylation events that lead to these two Cx43 species, in the present study we refer to these species collectively as Cx43-P. The COOH-terminal portion of Cx43 contains 21 serines, and at least 5 protein kinases have been shown to phosphorylate Cx43, suggesting that this region of molecule contains a complex array of potential regulatory sites (10Lampe P.D. Lau A.F. Arch Biochem. Biophys. 2000; 384: 205-215Crossref PubMed Scopus (473) Google Scholar). Cx43 is a short-lived protein with a half-life of only 1–3 h in cultured cells and intact rat heart (9Laird D.W. Puranam K.L. Revel J.P. Biochem. J. 1991; 273: 67-72Crossref PubMed Scopus (404) Google Scholar, 11Beardslee M.A. Laing J.G. Beyer E.C. Saffitz J.E. Circ. Res. 1998; 83: 629-635Crossref PubMed Scopus (375) Google Scholar). Therefore, an efficient degradation mechanism is indispensable and is necessary to ensure the dynamic turnover of Cx43. In general, lysosomes are involved in the degradation of integral membrane proteins and receptor-mediated internalized proteins (12Hunziker W. Geuze H.J. Bioessays. 1996; 18: 379-389Crossref PubMed Scopus (240) Google Scholar). The proteasome, in addition to taking part in degrading most cytosolic and nuclear proteins (13Hochstrasser M. Annu. Rev. Genet. 1996; 30: 405-439Crossref PubMed Scopus (1468) Google Scholar, 14Rubin D.M. Finley D. Curr. Biol. 1995; 5: 854-858Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 15Ulrich H.D. Curr. Top. Microbiol. Immunol. 2002; 268: 137-174PubMed Google Scholar), plays a role in endoplasmic reticulum localized degradation of misfolded proteins. Interestingly, both lysosomes and proteasomes have been reported to be involved in the degradation of Cx43 (16Laing J.G. Beyer E.C. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, J.G. Beyer E.C. Cell Res. PubMed Scopus Google Scholar, L.S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). degradation of Cx43 was by the that Cx43 were with in cells D. B.J. Cell Res. PubMed Scopus Google Scholar). Laing and Beyer (16Laing J.G. Beyer E.C. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google showed that by cells with proteasomal and by cells with Cx43 by a the of the of in Cx43 degradation (16Laing J.G. Beyer E.C. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). revealed that of both proteasomes and lysosomes a half-life of Cx43 to a in rat cardiac the of these two for Cx43 degradation J.G. Beyer E.C. Cell Res. PubMed Scopus Google Scholar). that degradation of Cx43 gap junction assembly and intercellular and a mechanism gap junctional intercellular be at the of connexin turnover L.S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of Cx43 and that a of was to proteasomes by being into the in the of proteasomal L.S. J. Cell Biol. 2002; PubMed Scopus Google Scholar). Interestingly, data to that that that both lysosomes and proteasomes are involved in Cx43 it is to both are and for Cx43 is also not both Cx43 from cell gap junction as as Cx43 localized to the ER other compartments involved in the secretory it is that these degradation are in cells that are gap junctional intercellular as to cells that gap junction assembly and are In the that Cx43 is a for proteasomal degradation is present data revealed that Cx43 in MDA-MB-231 cells and internalized Cx43 in BICR-M1Rk cells were both to lysosomes for degradation suggesting that lysosomes play a Interestingly, a transport is to Cx43 from early secretory compartments to lysosomes for proteasomal degradation was to the phosphorylated species of Cx43 and gap junctions at the plasma Cell cells BICR-M1Rk cells, a rat cell D.W. Castillo M. Kasprzak L. J. Cell Biol. 1995; 131: 1193-1203Crossref PubMed Scopus (222) Google Scholar), were in and The cells were at with MDA-MB-231 cells have low of Cx43 we to Cx43. Cx43 Cx43 MDA-MB-231 cells, were into as reported A. F. G. J. Res. Google Scholar, J. D. J. Laird D.W. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, H. H. J. M.A. Laird D.W. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The were delivered into cells by to that was used to MDA-MB-231 cells. The cells were termed of of proteasomes and lysosomes and were from were with the at as of of of and of block protein 5 of brefeldin A 20 of was D.W. Castillo M. Kasprzak L. J. Cell Biol. 1995; 131: 1193-1203Crossref PubMed Scopus (222) Google Scholar, L.S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). these of cells were in with to with the various were for to proteins for Western of Cx43 Gap and MDA-MB-231 BICR-M1Rk cells were in at for 20 and as D.W. Castillo M. Kasprzak L. J. Cell Biol. 1995; 131: 1193-1203Crossref PubMed Scopus (222) Google Scholar). Cx43 protein was a of Cx43 In the cells with a Cx43 followed by with were with a of H. Laird D.W. Cell PubMed Scopus Google followed by to The were a as D.W. Castillo M. Kasprzak L. J. Cell Biol. 1995; 131: 1193-1203Crossref PubMed Scopus (222) Google Scholar). Gap junction in and BICR-M1Rk cells were the The were to the cell-cell that only the gap junction the cell-cell that were a of 5 were the that internalized gap junctions transport In and cells, we the total of gap junction 20 cell-cell that represented to The data was analyzed the and the of In cells, we gap junction that a in the and of were termed as of this were in cultured cells. In and BICR-M1Rk cells, we a cells and the total of gap junction the of these cells. The data was analyzed the and the of at least MDA-MB-231 cells were cultured was in complete to a of and at for were with for at After cells with to cells were to for and were both a cells were with and in at of were with in a of to and in as L. A. J. Cell Biol. PubMed Scopus Google Scholar). were and were for with in and for h with Cx43 of a of in After the were for h with with were with for followed by lead for were a electron Western BICR-M1Rk cells, were in and by were by in and and by was protein of protein were and by were to membranes that were with at a of for cells and for MDA-MB-231 cells COOH-terminal at a of The were by After being as H. H. J. M.A. Laird D.W. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), the membranes were with to ensure The of was The data was analyzed and the of Western blots Cx43 in and Cx43 in MDA-MB-231 to two cell to study the and degradation of the gap junction Cx43. BICR-M1Rk cells, a rat cell were to have Cx43 that into gap junction at cell-cell As these cells efficient intercellular of that Cx43 gap junction channels were the cells and BICR-M1Rk cells, cells of Cx43 H. H. J. M.A. Laird D.W. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google and the cells were to Cx43 and cells for Cx43 revealed an intracellular of Cx43, gap junction were at cell-cell the intracellular of connexin cells were for membrane and Cx43. analysis revealed that Cx43 were localized to lysosomes and a in of the of Cx43 was also revealed the of and with lysosomes and these data that the of Cx43 was transported to lysosomes MDA-MB-231 cells an role of lysosomes in Cx43 degradation in this cell and were to lysosomes in cells. were for Cx43 and the membrane protein and the revealed that a of Cx43 was with lysosomes of cells with revealed that Cx43 was delivered into lysosomes an the were MDA-MB-231 cells, Cx43 not lysosomes of BICR-M1Rk cells suggesting that lysosomes not in Cx43 degradation Cx43 is it the lysosomes. Cx43 BICR-M1Rk cells were by electron for of Cx43 lysosomes. gap junction that were for Cx43 were at the cell surface. Cx43 junction were a and that was of a In other electron that membrane was suggesting that this represented a gap junction that was in the of degradation the electron data that internalized gap junctions in the form of junctions K. Laird D.W. J. Cell PubMed Google were to the for be that lack of Cx43 at the cell in MDA-MB-231 cells was to the of gap junctions that were internalized into the cells. newly synthesized Cx43 be delivered to lysosomes to the plasma these we to block Cx43 transport the Golgi apparatus and the change in the of Cx43 between the two cell communication-deficient cells were with for h intracellular Cx43 and was localized to lysosomes the of Cx43 in the of the protein and this that was intact in cells, and Cx43 was transported to lysosomes in the of In BICR-M1Rk cells, the blocking of transport the phosphorylated species of Cx43 and with our studies D.W. Castillo M. Kasprzak L. J. Cell Biol. 1995; 131: 1193-1203Crossref PubMed Scopus (222) Google Scholar). As in cells, the cellular of Cx43 in BICR-M1Rk cells with the degradation of Cx43 during the inhibition of protein and Together, our data that there a newly synthesized Cx43 be to lysosomes in cells for the of Cx43 to be in the of of in the of Cx43, our data revealed that Cx43 was to lysosomes in both cell degradation of has been reported to both lysosomes and proteasomes J.G. Beyer E.C. Cell Res. PubMed Scopus Google Scholar). the specific roles of both in the of Cx43, we a of for both lysosomes and As expected, non-phosphorylated Cx43 (Cx43-P0) was in cells, the phosphorylated Cx43 species were with the that Cx43 was localized to gap junction plaques. was more in the cells with inhibition of lysosomes a increase in total cellular Cx43 by and the role of lysosomes in Cx43 degradation in cells. proteasomal by lactacystin at the expense of and the total cellular Cx43 and in cells both were inhibition of proteasomes not the of total cellular Cx43, but only at the expense of and proteosomal degradation the of to by in this was was of was also in MDA-MB-231 cells that of Cx43 the that Cx43 be to an degradation not of Cx43. Together, our that lysosomes are a for Cx43 degradation in MDA-MB-231 cells, proteasomes play a more role in by degrading proteins that to but with Gap in MDA-MB-231 phosphorylation is with the assembly of Cx43 into gap junctions (8Musil L.S. Goodenough D.A. J. Cell Biol. 1991; 115: 1357-1374Crossref PubMed Scopus (619) Google Scholar), we of correlate with an increase in the of gap junction plaques. cells gap junctions were the of gap junction in cells with lactacystin by A of the in cells was and in with the more gap junction and represented of the total Cx43 gap junction in cells In cells with Cx43 be and and gap junction were not from in cells and the of gap junction increase by and proteasomal degradation were and and suggesting that it was but not inhibition that was for the increase in of gap junction in cells. of the Cx43 in these cells were as with Western our studies that the increase in the phosphorylated species of Cx43 is with an increase in the of gap junction plaques. of for the of Gap in in the of studies cells that the inhibition of proteasomes allows for the maturation of and the of gap junctions at the cell surface. this mechanism was also involved in BICR-M1Rk cells that have a of gap junctions and microscopic revealed that Cx43 gap junction were at cell-cell in BICR-M1Rk cells with for h of gap but intracellular Cx43 was and with our studies D.W. Castillo M. Kasprzak L. J. Cell Biol. 1995; 131: 1193-1203Crossref PubMed Scopus (222) Google Scholar). with lactacystin an of and in the cells with gap junction were by with and there was an increase in intracellular Cx43, suggesting a role of lysosomes in degrading Cx43 in BICR-M1Rk cells and As expected, the cells were with and BFA, Cx43 in a but not at the plasma membrane in a loss of Cx43 was with treatment and Interestingly, cell treatment with lactacystin and the BFA-induced loss of Cx43 gap junctions with a of Cx43 as gap junction suggesting that proteasomal degradation plays role in Cx43 gap junction internalization and the lack of an increase in the of gap junction in BICR-M1Rk cells in the of lactacystin and to the that are with of phosphorylated Cx43, we the that proteasomal not increase the of in BICR-M1Rk cells. were with of proteasomes lysosomes in with and to Western blots to both the and of Cx43. with our that the maturation of Cx43 to the most phosphorylated species, our data showed that treatment by an increase in the of Cx43 that the cells with and revealed a In both by Interestingly, was used in with there was a of that in to treatment only in with to a increase in that proteosomal plays roles in gap junction cells, BICR-M1Rk cells both and A and the Together, our data that proteasomes play an role in the internalization and of gap junctions. The an to the of Cx43 was used in these studies suggests that of Cx43 was by In the cells with both Cx43 species were to a increase in total Cx43 by there was more of that the A and of the most of is In cultured cardiac and intact the half-life of Cx43 was to be 1–3 h (9Laird D.W. Puranam K.L. Revel J.P. Biochem. J. 1991; 273: 67-72Crossref PubMed Scopus (404) Google Scholar, 11Beardslee M.A. Laing J.G. Beyer E.C. Saffitz J.E. Circ. Res. 1998; 83: 629-635Crossref PubMed Scopus (375) Google Scholar). a dynamic an efficient degradation mechanism to the intracellular of Cx43. As transmembrane were and to be in lysosome J.G. Beyer E.C. Cell Res. PubMed Scopus Google Scholar, L.S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, D. B.J. Cell Res. PubMed Scopus Google Scholar, G. J. Biol. Chem. 268: Full Text PDF PubMed Google Scholar). was by the that the turnover of Cx43 in cell types, suggesting that proteasomes play a role in connexin degradation (16Laing J.G. Beyer E.C. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, J.G. Beyer E.C. Cell Res. PubMed Scopus Google Scholar, L.S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, Beyer E.C. 2000; Scopus Google Scholar). proteasomes are normally involved in degrading cytosolic misfolded it is to the role of proteasomal degradation in the of that oligomerize into hemichannels and into of of studies by and L.S. J. Cell Biol. 2002; PubMed Scopus Google revealed a of Cx43 in the that to have from ER membranes in the of a proteasomal degradation L.S. J. Cell Biol. 2002; PubMed Scopus Google Scholar). it was not this cytosolic of Cx43 was it that proteasomal degradation be the of this of Cx43. the degradation of in cell are into gap is the degradation of in cells, cells H. H. J. M.A. Laird D.W. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, H. Laird D.W. Cell PubMed Scopus Google Scholar, L.S. Biol. 2000; 11: PubMed Scopus Google Scholar, W. M. H. F. K. M. M. J. Genet. PubMed Scopus Google Scholar). is in cells that to is the involved in connexin and assembly in cells H. H. J. M.A. Laird D.W. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). in cells that be to the of at the plasma membrane in the secretory involved in to the cell for gap junction In the present study we used MDA-MB-231 cells and Cx43 degradation in this cell with that in a cell BICR-M1Rk rat cells. data that lysosomes Cx43 in BICR-M1Rk cells, proteasomes play a role in the internalization of gap junctions. lysosomes Cx43 in but a mechanism appears to newly synthesized Cx43 be to lysosomes for the other hand, by the maturation stability of Cx43 gap junctions. our studies are with proteasomes the and turnover of Cx43 Cx43 being a for proteasomal In BICR-M1Rk cells, Cx43 gap junction were present at cell-cell with a intracellular of Cx43, from Cx43. key of that Cx43 is lysosomes of these cells. electron revealed and Cx43 membrane localized to membrane with lysosomes. that lysosomes are the for junctions that were shown to be internalized gap junctions K. Laird D.W. J. Cell PubMed Google Scholar). Western blots revealed that of degradation total cellular Cx43. is by a study by M.A. M. O. J. Cell PubMed Scopus Google lysosomes were to be involved in Cx43 degradation in and these that a the COOH-terminal degradation of Cx43 M.A. M. O. J. Cell PubMed Scopus Google Scholar). In and Western in the of in MDA-MB-231 cells revealed that Cx43 was also to lysosomes for the for degradation of Cx43 in MDA-MB-231 cells was the as to Cx43 was delivered to lysosomes. be that gap junction in MDA-MB-231 cells be and internalized for Western blots blocking protein with revealed change in the of Cx43, inhibition of protein for the of a in total Cx43. our data a newly synthesized Cx43 is to lysosomes being transported to the plasma membrane and to lysosomes. in part the in cell to be synthesized but gap junctions are H. H. J. M.A. Laird D.W. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, D.W. P. G. L. M.A. Res. Google Scholar). In we reported that misfolded Cx43 also lysosomes in cells, Cx43 was into gap junctions H. Laird D.W. Cell PubMed Scopus Google Scholar). to in a of the have an intracellular L.S. Biol. 2000; 11: PubMed Scopus Google Scholar, W. M. H. F. K. M. M. J. Genet. PubMed Scopus Google Scholar). cell that with are to be into gap a mechanism that to misfolded it is that lysosomes play an role in degrading Cx43 in both cell used in this a key as to the role of proteasomes are involved in the degradation of and misfolded integral membrane proteins have been reported to proteasomal degradation D.M. Finley D. Curr. Biol. 1995; 5: 854-858Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 15Ulrich H.D. Curr. Top. Microbiol. Immunol. 2002; 268: 137-174PubMed Google Scholar). The proteasomes with connexin degradation the that proteasomal the turnover of (16Laing J.G. Beyer E.C. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, L.S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, L.S. Biol. 2000; 11: PubMed Scopus Google Scholar). we that inhibition a of Cx43 in BICR-M1Rk cells but total Cx43 in cells. proteasomal with BICR-M1Rk cells that proteasomes to the internalization of Cx43 gap the Cx43 half-life as reported by Laing and Beyer (16Laing J.G. Beyer E.C. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). Interestingly, the of integral membrane and the are also to be by P. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the mechanism is not the inhibition of the turnover of and gap junctions at the plasma The of this more proteins that Cx43 is is to with Cx43 Curr. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google at that cell but the of this Interestingly, regulates the of the phosphorylated species of Cx43 in cells. data these cells revealed that proteasomal not the of total Cx43 and it lysosome of intracellular Cx43. and Western analysis showed that Cx43 more and more gap junction were proteasomes were suggesting that the maturation stability of Cx43. are with L.S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google the inhibition of proteasomes gap junction and cell-cell in gap junction cells, suggesting that the and of gap junctions be at the of connexin turnover L.S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). Together, our data revealed that the of Cx43 at intracellular that the of Cx43 in not be a for proteasomal but its turnover is by proteasomal degradation of other for this is the of and gap junctions into the of a from the membrane, and the of Cx43 gap junctions in is with proteasomal the of Cx43 are not our data are with proteasomes a of Cx43 to to lysosomes for that a of Cx43 is (16Laing J.G. Beyer E.C. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar), and Cx43 to be to proteasomes a to our has not been reported for integral membrane protein. it is that of Cx43 this is to Cx43 are data revealed that sensitive only non-phosphorylated and phosphorylated Cx43 species with of In a a of Cx43 was be into the the that this of Cx43 in and to proteasomes for degradation L.S. J. Cell Biol. 2002; PubMed Scopus Google Scholar). proteins be by proteasomes proteasomal degradation has only been reported for intracellular proteins such as and W. M. H. A. Biol. 2002; PubMed Scopus Google Scholar, G. J. L. U. A. 2002; PubMed Scopus Google Scholar, P. Goldberg 83: 311-318Crossref PubMed Scopus Google Scholar, J. Biochem. 2002; PubMed Scopus Google Scholar, J. 11: PubMed Scopus Google Scholar). we an role of proteasomes in the turnover of we the that degradation for Cx43 various cell and L.S. J. Cell Biol. 2002; PubMed Scopus Google have a role for proteasomes in the degradation of membrane and it is that expressed in with is also that Cx43 has but in cell and cells in with in and membrane including lysosomes the two cell used in this the Golgi apparatus D.W. Castillo M. Kasprzak L. J. Cell Biol. 1995; 131: 1193-1203Crossref PubMed Scopus (222) Google Scholar, K. M. M. A. Lampe P.D. Laird D.W. Biol. PubMed Scopus Google and junctions K. Laird D.W. J. Cell PubMed Google Scholar). is that these in of Cx43 in Cx43 but in Cx43 transport and In our study revealed that lysosomes and proteasomes play roles in the of Cx43, and it to be as to the by proteasomes that gap junctions and

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