Abstract
Wnt-1 induces morphological transformation of C57MG mammary epithelial cells and accumulation of cytosolic β-catenin whereas Wnt-5a has no effect. To identify regions within the 370 amino acid Wnt-1 protein required for these functions we tested eleven chimeric genes that contained variable amounts of Wnt-1 and Wnt-5a sequence. Transformation and β-catenin regulation in C57MG cells is controlled by amino acids that lie within 186 residues of the amino terminus of Wnt-1. Small substitutions between residues 186 and 292 reduced Wnt-1 activity. Replacement of the carboxy terminal 79 amino acids of Wnt-1 by Wnt-5a did not affect function. These results were supported by transient expression asssays in 293 cells wherein β-catenin accumulated in the cytoplasm in response to ectopic Wnt-1 expression. In 293 cells, a larger region of the amino-terminus of Wnt-1 was found to be required for β-catenin regulation. Nonfunctional chimeras that contained at least 99 amino terminal Wnt-1 residues inhibited Wnt-1 stimulation of 293 cells. One of these chimeras inhibited both Wnt-1 and Wnt-3 activity suggesting that Wnt-1 and Wnt-3 interact with a common signaling component.
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References
Bejsovec A and Wieschaus E. . 1995 Genetics 139: 309–320.
Bhanot P, Brink M, Samos CH, Hsieh J-C, Wang Y, Macke JP, Andrew D, Nathans J and Nusse R. . 1996 Nature 382: 225–230.
Binari RC, Staveley BE, Johnson WA, Godavarti R, Sasisekharan R and Manoukian AS. . 1997 Develop. 124: 2623–2632.
Blasband A, Schryver B and Papkoff J. . 1992 Oncogene 7: 153–161.
Bradbury JM, Niemeyer CC, Dale TC and Edwards PAW. . 1994 Oncogene 9: 2597–2603.
Bradley RS and Brown AM. . 1995 Mol. Cell. Biol. 15: 4616–4622.
Bradley RS and Brown AMC. . 1990 EMBO J. 9: 1569–1575.
Brown AMC and Dougherty JP. . 1995 In Retroviral vectors Glover DM and Hames BD (eds.).. Oxford University Press: Oxford Vol. 4.: pp. 113–142.
Brown AMC, Papkoff J, Fung YK, Shackleford GM and Varmus HE. . 1987 Mol. Cell. Biol. 7: 3971–3977.
Brown AMC, Wilden RS, Prendergast TJ and Varmus HE. . 1986 Cell 46: 1001–1009.
Burrus LW and McMahon AP. . 1995 Exp. Cell Res. 220: 363–373.
Cadigan KM and Nusse R. . 1997 Genes Dev. 11: 3286–3305.
Cumberledge S and Krasnow MA. . 1993 Nature 363: 549–552.
Dale TC. . 1998 Biochem. J. 329: 209–223.
Du SJ, Purcell SM, Christian JL, McGrew LL and Moon RT. . 1995 Mol. Cell. Biol. 15: 2625–2634.
Fagotto F, Guger K and Gumbiner BM. . 1997 Develop. 124: 453–460.
Finch PW, He X, Kelley MJ, Uren A, Schaudies RP, Popescu NC, Rudikoff S, Aaronson SA, Varmus HE and Rubin JS. . 1997 Proc. Natl. Acad. Sci. USA 94: 6770–6775.
Gavin BJ, McMahon JA and McMahon AP. . 1990 Genes Dev. 4: 2319–2332.
Haerry TE, Heslip TR, Marsh JL and O'Connor MB. . 1997 Develop. 124: 3055–3064.
He X, Saint-Jeannet JP, Wang Y, Nathans J, Dawid I and Varmus H. . 1997 Science 275: 1652–1654.
Heasman J, Crawford A, Goldstone K, Gamer-Hamrick P, Gumbiner B, McCrea P, Kintner C, Noro CY and Wylie C. . 1994 Cell 79: 791–803.
Hinck L, Nathke IS, Papkoff J and Nelson WJ. . 1994 Trends Biochem. Sci. 19: 538–542.
Hoang B, Moos M Jr, Vukicevic S and Luyten FP. . 1996 J. Biol. Chem. 271: 26131–26137.
Hoppler S, Brown JD and Moon RT. . 1996 Genes Dev. 10: 2805–2817.
Horton RM, Ho SN, Pullen JK, Hunt HD, Cai Z and Pease LR. . 1993 Methods Enzymol. 217: 270–279.
Hunter T. . 1997 Cell 88: 333–346.
Jasin M and Zalamea P. . 1992 Proc. Natl. Acad. Sci. USA 89: 10681–10685.
Jue SF, Bradley RS, Rudnicki JA, Varmus HE and Brown AMC. . 1992 Mol. Cell. Biol. 12: 321–328.
Kitajewski J, Mason JO and Varmus HE. . 1992 Mol. Cell. Biol. 12: 784–790.
Klingensmith J and Nusse R. . 1994 Dev. Biol. 166: 396–414.
Klymkowsky MW. . 1997 BioEssays 19: 537–539.
Leyns L, Bouwmeester T, Kim SH, Piccolo S and De Robertis EM. . 1997 Cell 88: 747–756.
Lin K, Wang S, Julius MA, Kitajewski J, Moos Jr M and Luyten FP. . 1997 Proc. Natl. Acad. Sci. USA 94: 11196–11200.
Mason JO, Kitajewski J and Varmus HE. . 1992 Mol. Biol. Cell. 3: 521–533.
McMahon AP and Moon RT. . 1989 Cell 58: 1075–1084.
Miller JR and Moon RT. . 1996 Genes Dev. 10: 2527–2539.
Moon RT, Campbell RM, Christian JL, McGrew LL, Shih J and Fraser S. . 1993 Develop. 119: 97–111.
Nusse R and Varmus HE. . 1992 Cell 69: 1073–1087.
Papkoff J, Brown AMC and Varmus HE. . 1987 Mol. Cell. Biol. 7: 3978–3984.
Papkoff J, Rubinfeld B, Schryver B and Polakis P. . 1996 Mol. Cell. Biol. 16: 2128–2134.
Papkoff J and Schryver B. . 1990 Mol. Cell. Biol. 10: 2723–2730.
Parkin N, Kitajewski J and Varmus HE. . 1993 Genes Dev. 7: 2181–2193.
Parr BA and McMahon AP. . 1994 Curr. Opin. Genet. Dev. 4: 523–528.
Pear WS, Nolan GP, Scott ML and Baltimore D. . 1993 Proc. Natl. Acad. Sci. USA 90: 8392–8396.
Peifer M, Sweeton D, Casey M and Wieschaus E. . 1994 Develop. 120: 369–380.
Peifer M and Wieschaus E. . 1990 Cell 63: 1167–1178.
Rattner A, Hsieh JC, Smallwood PM, Gilbert DJ, Copeland NG, Jenkins NA and Nathans J. . 1997 Proc. Natl. Acad. Sci. USA 94: 2859–2863.
Rijsewijk F, Deemter L, Wagenaar E, Sonneberg A and Nusse R. . 1987 EMBO J. 6: 127–131.
Schryver B, Hinck L and Papkoff J. . 1996 Oncogene 13: 333–342.
Shimizu H, Julius MA, Giarre M, Zheng Z, Brown AMC and Kitajewski J. . 1997 Cell Growth & Differ. 8: 1349–1358.
Smolich BD, McMahon JA, McMahon AP and Papkoff J. . 1993 Mol. Biol. Cell. 4: 1267–1275.
Vaidya AB, Lasfargues EY, Sheffield JB and Coutinho WG. . 1978 Virology 90: 12–22.
van den Heuvel M, Nusse R, Johnson P and Lawrence PA. . 1989 Cell 59: 739–749.
van Leeuwen F, Samos CH and Nusse R. . 1994 Nature 368: 342–344.
Wang S, Krinks M, Lin K, Luyten FP and Moos Jr M. . 1997 Cell 88: 757–766.
Wang Y, Macke JP, Abella BS, Andreasson K, Worley P, Gilbert DJ, Copeland NG, Jenkins NA and Nathans J. . 1996 J. Biol. Chem. 271: 4468–4476.
Wieschaus E and Riggleman R. . 1987 Cell 49: 177–184.
Wong GT, Gavin BJ and McMahon AP. . 1994 Mol. Cell. Biol. 14: 6278–6286.
Yost C, Torres M, Miller JR, Huang E, Kimelman D and Moon R. . 1996 Genes Dev. 10: 1443–1454.
Young CS, Kitamura M, Hardy S and Kitajewski J. . 1998 Mol. Cell. Biol. 18: 2474–2485.
Zecca M, Basler K and Struhl G. . 1996 Cell 87: 833–844.
Acknowledgements
The authors wish to thank Rita Yeretsian for technical support; Eve Vagg and Rachel Yarmolinsky for graphics arts assistance; Drs Marielba Zerlin and James Goldman for their assistance and making available their photomicrography equipment and Drs David Cobrinik, John Krolewski and Hendrik Uyttendaele for providing comments on the manuscript. This work was supported by an American Cancer Society Grant DB-81, a US Army Medical Research and Material Command Grant DAMD17-94-J-4069, and the Marilyn Bokemeier Sperry Fund (to JK). SDR was supported by a Student Undergraduate Research Fellowship from Columbia University.
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Julius, M., Rai, S. & Kitajewski, J. Chimeric Wnt proteins define the amino-terminus of Wnt-1 as a transformation-specific determinant. Oncogene 18, 149–156 (1999). https://doi.org/10.1038/sj.onc.1202268
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DOI: https://doi.org/10.1038/sj.onc.1202268
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