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A comparative evaluation of β-catenin and plakoglobin signaling activity

Abstract

Vertebrates have two Armadillo-like proteins, β-catenin and plakoglobin. Mutant forms of β-catenin with oncogenic activity are found in many human tumors, but plakoglobin mutations are not commonly found. In fact, plakoglobin has been proposed to suppress tumorigenesis. To assess differences between β-catenin and plakoglobin, we compared several of their biochemical properties. After transient transfection of 293T cells with an expression vector encoding either of the two proteins, soluble wild type β-catenin does not significantly accumulate, whereas soluble wild type plakoglobin is readily detected. As anticipated, β-catenin is stabilized by the oncogenic mutation S37A; however, the analogous mutation in plakoglobin (S28A) does not alter its half-life. S37A-β-catenin activates a TCF/LEF-dependent reporter 20-fold more potently than wild type β-catenin, and 5-fold more potently than wild type or S28A plakoglobin. These differences may be attributable to an enhanced affinity of S37A β-catenin for LEF1 and TCF4, as observed here by immunoprecipitation assays. We show that the carboxyl-terminal domain is largely responsible for the difference in signaling and that the Armadillo repeats account for the remainder of the difference. The relatively weak signaling by plakoglobin and the failure of the S28A mutation to enhance its stability, may explain why plakoglobin mutations are infrequent in malignancies.

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References

  • Aberle H, Bierkamp C, Torchard D, Serova O, Wagner T, Natt E, Wirsching J, Heidkamper C, Montagna M, Lynch HT, Lenoir GM, Scherer G, Feunteun J and Kemler R. . 1995 Proc. Natl. Acad. Sci. USA 92: 6384–6388.

  • Aberle H, Schwartz H and Kemler R. . 1996 J. Cell. Biochem. 61: 514–523.

  • Barker N, Morin PJ and Clevers H. . 2000 Adv. Cancer Res. 77: 1–24.

  • Barth AI, Nathke IS and Nelson WJ. . 1997 Curr. Opin. Cell Biol. 9: 683–690.

  • Behrens J, Jerchow BA, Wurtele M, Grimm J, Asbrand C, Wirtz R, Kuhl M, Wedlich D and Birchmeier W. . 1998 Science 280: 596–599.

  • Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R and Birchmeier W. . 1996 Nature 382: 638–642.

  • Bierkamp C, Schwarz H, Huber O and Kemler R. . 1999 Development 126: 371–381.

  • Brannon M, Gomperts M, Sumoy L, Moon RT and Kimelman D. . 1997 Genes Dev. 11: 2359–2370.

  • Caca K, Kolliga FT, Ji X, Hayes M, Qian J, Yahanda A, Rimm DL, Costa J and Fearon E. . 1999 Cell. Growth Differ. 10: 369–376.

  • Carnac G, Kodjabachian L, Gurdon JB and Lemaire P. . 1996 Development 122: 3055–3065.

  • Chan EF, Gat U, McNiff JM and Fuchs E. . 1999 Nat. Genet. 21: 410–413.

  • Cook D, Fry MJ, Hughes K, Sumathipala R, Woodgett JR and Dale TC. . 1996 EMBO J. 15: 4526–4536.

  • Coso OA, Chiariello M, Yu JC, Teramoto H, Crespo P, Xu N, Miki T and Gutkind JS. . 1995 Cell. 81: 1137–1146.

  • Crawford HC, Fingleton BM, Rudolph-Owen LA, Goss KJ, Rubinfeld B, Polakis P and Matrisian LM. . 1999 Oncogene 18: 2883–2891.

  • Dale TC. . 1998 Biochem. J. 329: 209–232.

  • Denk C, Hulsken J and Schwarz E. . 1997 Cancer Lett. 120: 185–193.

  • Fagotto F, Gluck U and Gumbiner BM. . 1998 Curr. Biol. 8: 181–190.

  • Fagotto F, Jho E, Zeng L, Kurth T, Joos T, Kaufmann C and Costantini F. . 1999 J. Cell. Biol. 145: 741–756.

  • Fan MJ, Gruning W, Walz G and Sokol SY. . 1998 Proc. Natl. Acad. Sci. USA. 95: 5626–5631.

  • Farr III GH, Ferkey DM, Yost C, Pierce SB, Weaver C and Kimelman D. . 2000 J. Cell. Biol. 148: 691–702.

  • Gelderloos J, Witcher L, Cowin P and Klymkowsky MW. . 1997 Cytoskeletal-membrane interactions and signal transduction. Landes Bioscience, Austin, Texas pp. 13–30.

  • Gradl D, Kuhl M and Wedlich D. . 1999 Mol. Cell. Biol. 19: 5576–5587.

  • Haegel H, Larue L, Ohsugi M, Fedorov L, Herrenknecht K and Kemler R. . 1995 Development 121: 3529–3537.

  • Hart M, Concordet JP, Lassot I, Albert I, del los Santos R, Durand H, Perret C, Rubinfeld B, Margottin F, Benarous R and Polakis P. . 1999 Curr. Biol. 9: 207–210.

  • Hart MJ, de los Santos R, Albert IN, Rubinfeld B and Polakis P. . 1998 Curr. Biol. 8: 573–581.

  • He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa L, Morin PJ, Vogelstein B and Kinzler KW. . 1998 Science 281: 1509–1512.

  • Hecht A, Litterst CM, Huber O and Kemler R. . 1999 J. Biol. Chem. 274: 18017–18025.

  • Hsu SC, Galceran L and Grosschedl R. . 1998 Mol. Cell. Biol. 18: 4807–4818.

  • Huang H, Fujii H, Sankila A, Mahler-Araujo BM, Matsuda M, Cathomas G and Ohgaki H. . 1999 Am. J. Pathol. 155: 1795–1801.

  • Huber AH, Nelson WJ and Weis WI. . 1997 Cell. 90: 871–882.

  • Huber O, Korn R, McLaughlin J, Ohsugi M, Herrmann BG and Kemler R. . 1996 Mech. Dev. 59: 3–10.

  • Huelsken J, Vogel R, Brinkmann V, Erdmann B, Birchmeier C and Birchmeier W. . 2000 J. Cell. Biol. 148: 567–578.

  • Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S and Kikuchi A. . 1998 EMBO J. 17: 1371–1384.

  • Jiang J and Struhl G. . 1998 Nature 391: 493–496.

  • Kessler DS. . 1997 Proc. Natl. Acad. Sci. USA 94: 13017–13022.

  • Kikuchi A. . 1999a Cytokine Growth Factor Rev. 10: 255–265.

  • Kikuchi A. . 1999b Cell. Signal 11: 777–788.

  • Kitagawa M, Hatakeyama S, Shirane M, Matsumoto M, Ishida N, Hattori K, Nakamichi I, Kikuchi A and Nakayama K. . 1999 EMBO J. 18: 2401–2410.

  • Klymkowsky MW, Williams BO, Barish GD, Varmus HE and Vourgourakis YE. . 1999 Mol. Biol. Cell. 10: 3151–3169.

  • Kodama S, Ikeda S, Asahara T, Kishida M and Kikuchi A. . 1999 J. Biol. Chem. 274: 27682–27688.

  • Kolligs FT, Kolligs B, Hajra KM, Hu G, Tani M, Cho KR and Fearon ER. . 2000 Genes Dev. 14: 1319–1331.

  • Kondo Y, Kanai Y, Sakamoto M, Genda T, Mizokami M, Ueda R and Hirohashi S. . 1999 Jpn. J. Cancer Res. 90: 1301–1309.

  • Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B and Clevers H. . 1997 Science 275: 1784–1787.

  • Kowalczyk AP, Bornslaeger EA, Norvell SM, Palka HL and Green KJ. . 1999 Int. Rev. Cytol. 185: 237–302.

  • Latres E, Chiaur DS and Pagano M. . 1999 Oncogene 18: 849–854.

  • Laurent MN, Blitz IL, Hashimoto C, Rothbacher U and Cho KW. . 1997 Development 124: 4905–4916.

  • Legoix P, Bluteau O, Bayer J, Perret C, Balabaud C, Belghiti J, Franco D, Thomas G, Laurent-Puig P and Zucman-Rossi J. . 1999 Oncogene 18: 4044–4046.

  • Liu C, Kato Y, Zhang Z, Do VM, Yankner BA and He X. . 1999 Proc. Natl. Acad. Sci. U S A 96: 6273–6278.

  • Margottin F, Bour SP, Durand H, Selig L, Benichou S, Richard V, Thomas D, Strebel K and Benarous R. . 1998 Mol. Cell. 1: 565–574.

  • Marikawa Y and Elinson RP. . 1998 Mech. Dev. 77: 75–80.

  • McKendry R, Hsu SC, Harland RM and Grosschedl R. . 1997 Dev. Biol. 192: 420–431.

  • Miller JR and Moon RT. . 1997 J. Cell. Biol. 139: 229–243.

  • Miyoshi Y, Iwao K, Nagasawa Y, Aihara T, Sasaki Y, Imaoka S, Murata M, Shimano T and Nakamura Y. . 1998 Cancer Res. 58: 2524–2527.

  • Molenaar M, van de Wetering M, Oosterwegel M, Peterson-Maduro J, Godsave S, Korinek V, Roose J, Destree O and Clevers H. . 1996 Cell. 86: 391–399.

  • Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B and Kinzler KW. . 1997 Science 275: 1787–1790.

  • Munemitsu S, Albert I, Rubinfeld B and Polakis P. . 1996 Mol. Cell. Biol. 16: 4088–4094.

  • Nhieu JT, Renard CA, Wei Y, Cherqui D, Zafrani ES and Buendia MA. . 1999 Am. J. Pathol. 155: 703–710.

  • Nusse R and Varmus HE. . 1992 Cell. 69: 1073–1087.

  • Ogawa K, Yamada Y, Kishibe K, Ishizaki K and Tokusashi Y. . 1999 Cancer Res. 59: 1830–1833.

  • Orsulic S and Peifer M. . 1996 J. Cell. Biol. 134: 1283–1300.

  • Pantel K, Passlick B, Vogt J, Stosiek P, Angstwurn M, Seen-Hibler R, Haussinger K, Thetter O, Izbicki JR and Riethmuller G. . 1998 J. Clin. Oncol. 16: 1407–1413.

  • Papkoff J, Rubinfeld B, Schryver B and Polakis P. . 1996 Mol. Cell. Biol. 16: 2128–2134.

  • Polakis P. . 1999 Curr. Opin. Genet. Dev. 9: 15–21.

  • Porfiri E, Rubinfeld B, Albert I, Hovanes K, Waterman M and Polakis P. . 1997 Oncogene 15: 2833–2839.

  • Rubenstein A, Merriam J and Klymkowsky MW. . 1997 Dev. Genet. 20: 91–102.

  • Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E and Polakis P. . 1997 Science 275: 1790–1792.

  • Rubinfeld B, Souza B, Albert I, Muller O, Chamberlain SH, Masiarz FR, Munemitsu S and Polakis P. . 1993 Science 262: 1731–1734.

  • Sadot E, Simcha I, Iwai K, Ciechanover A, Geiger B and Ben-Ze'ev A. . 2000 Oncogene 19: 1992–2001.

  • Sakanaka C, Weiss JB and Williams LT. . 1998 Proc. Natl. Acad. Sci. USA 95: 3020–3023.

  • Simcha I, Geiger B, Yehuda-Levenberg S, Salomon D and Ben-Ze'ev A. . 1996 J. Cell. Biol. 133: 199–209.

  • Simcha I, Shtutman M, Salomom D, Zhurinsky J, Sadot E, Geiger B and Ben-Ze'ev A. . 1998 J. Cell Biol. 141: 1433–1448.

  • Smalley MJ, Sara E, Paterson H, Naylor S, Cook D, Jayatilake H, Fryer LG, Hutchinson L, Fry MJ and Dale TC. . 1999 EMBO J 18: 2823–2835.

  • Sparks AB, Morin PJ, Vogelstein B and Kinzler KW. . 1998 Cancer Res. 58: 1130–1134.

  • Su LK, Vogelstein B and Kinzler KW. . 1993 Science 262: 1734–1737.

  • Tao YS, Edwards RA, Tubb B, Wang S, Bryant J and McCrea PD. . 1996 J. Cell. Biol. 134: 1271–1281.

  • Tetsu O and McCormick F. . 1999 Nature 398: 422–426.

  • van de Wetering M, Cavallo R, Dooijes D, van Beest M, van Es J, Loureiro J, Ypma A, Hursh D, Jones T, Bejsovec A, Peifer M, Mortin M and Clevers H. . 1997 Cell 88: 789–799.

  • Wahl J, Sacco P, McGranahan ST, Sauppe L, Wheelock M and Johnson K. . 1996 J. Cell. Sci. 109: 1143–1154.

  • White P, Aberle H and Vincent JP. . 1998 J. Cell. Biol. 140: 183–195.

  • Winston JT, Strack P, Beer RP, Chu CY, Elledge SJ and Harper JW. . 1999 Genes Dev. 13: 270–283.

  • Witcher LL, Collins R, Puttagunta S, Mechanic SE, Munson M, Gumbiner B and Cowin P. . 1996 J. Biol. Chem. 271: 10904–10909.

  • Yamamoto H, Kishida S, Uochi T, Ikeda S, Koyama S, Asashima M and Kikuchi A. . 1998 Mol. Cell. Biol. 18: 2867–2875.

  • Yokoya F, Imamoto N, Tachibana T and Yoneda Y. . 1999 Mol. Biol. Cell. 10: 1119–1131.

  • Yost C, Torres M, Miller JR, Huang E, Kimelman D and Moon RT. . 1996 Genes Dev 10: 1443–1454.

  • Zeng L, Fagotto F, Zhang T, Hsu W, Vasicek TJ, Perry III WL, Lee JJ, Tilghman SM, Gumbiner BM and Costantini F. . 1997 Cell 90: 181–192.

  • Zhurinsky J, Shtutman M and Ben Ze'ev A. . 2000 Mol. Cell Biol. in press.

  • Zorn AM, Barish GD, Williams BO, Lavender P, Klymkowsky MW and Varmus HE. . 1999 Mol. Cell. 4: 487–498.

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Acknowledgements

We would like to thank Mario Chamorro for advice on the pulse/chase analysis and other members of the Varmus laboratory for helpful discussions. BO Williams was a post-doctoral fellow of the Damon Runyon-Walter Winchell Cancer Research Fund. GD Barish was a Howard Hughes Medical Institute-NIH Research Scholar. MW Klymkowsky was supported by NIH grant GM54001.

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Williams, B., Barish, G., Klymkowsky, M. et al. A comparative evaluation of β-catenin and plakoglobin signaling activity. Oncogene 19, 5720–5728 (2000). https://doi.org/10.1038/sj.onc.1203921

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Keywords

  • β-catenin
  • plakoglobin
  • Wnt
  • LEF/TCF

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