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Activation of Src in human breast tumor cell lines: elevated levels of phosphotyrosine phosphatase activity that preferentially recognizes the Src carboxy terminal negative regulatory tyrosine 530

Oncogene volume 18, pages 1227–1237 (1999)Cite this article

Abstract

Elevated levels of Src kinase activity have been reported in a number of human cancers, including colon and breast cancer. We have analysed four human breast tumor cell lines that exhibit high levels of Src kinase activity, and have determined that these cell lines also exhibit a high level of a phosphotyrosine phosphatase activity that recognizes the Src carboxy-terminal P-Tyr530 negative regulatory site. Total Src kinase activity in these cell lines is elevated as much as 30-fold over activity in normal control cells and specific activity is elevated as much as 5.6-fold. When the breast tumor cells were grown in the presence of the tyrosine phosphatase inhibitor vanadate, Src kinase activity was reduced in all four breast tumor cell lines, suggesting that Src was being activated by a phosphatase which could recognize the Tyr530 negative regulatory site. In fractionated cell extracts from the breast tumor cells, we found elevated levels of a membrane associated tyrosine phosphatase activity that preferentially dephosphorylated a Src family carboxy-terminal phosphopeptide containing the regulatory tyrosine 530 site. Src was hypophosphorylated in vivo at tyrosine 530 in at least two of the tumor cell lines, further suggesting that Src was being activated by a phosphatase in these cells. In preliminary immunoprecipitation and antibody depletion experiments, we were unable to correlate the major portion of this phosphatase activity with several known phosphatases.

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References

  • Berger MS, Locher GW, Saurer S, Gullick WJ, Waterfield MD, Groner B and Hynes NE. . 1988 Cancer Res. 48: 1238–1243.

  • Bjorge JD, Bellagamba C, Cheng HC, Tanakab A, Wang JH and Fujita DJ. . 1995 J Br. Cancer 270: 24222–24228.

  • Cartwright CA, Eckhart W, Simon S and Kaplan PL. . 1987 Cell 49: 83–91.

  • Cartwright CA, Kamps MP, Meisler AI, Pipas JM and Eckhart W. . 1989 J. Clin. Invest. 83: 2025–2033.

  • Cartwright CA, Meisler AI and Eckhart W. . 1990 Proc. Natl. Acad. Sci. USA 87: 558–562.

  • Charbonneau H and Tonks NK. . 1992 Ann. Rev. Cell Biol. 8: 463–493.

  • den Hertog J, Pals CE, Peppelenbosch MP, Tertoolen LG, de Laat SW and Kruijer W. . 1993 EMBO J. 12: 3789–3798.

  • Elson A and Leder P. . 1995 J Br. Cancer 270: 26116–26122.

  • Galaktionov K, Lee AK, Eckstein J, Draetta G, Meckler J, Loda M and Beach D. . 1995 Science 269: 1575–1577.

  • Guy CT, Muthuswamy SK, Cardiff RD, Soriano P and Muller WJ. . 1994 Genes & Dev. 8: 23–32.

  • Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD and Muller WJ. . 1992 Proc. Natl. Acad. Sci. USA 89: 10578–10582.

  • Jacobs C and Rubsamen H. . 1983 Cancer Res. 43: 1696–1702.

  • Janes PW, Daly RJ, deFazio A and Sutherland RL. . 1994 Oncogene 9: 3601–3608.

  • Jove R, Kornbluth S and Hanafusa H. . 1987 Cell 50: 937–943.

  • Kmiecik TE and Shalloway D. . 1987 Cell 49: 65–73.

  • Kraus MH, Fedi P, Starks V, Muraro R and Aaronson SA. . 1993 Proc. Natl. Acad. Sci. USA 90: 2900–2904.

  • Kraus MH, Popescu NC, Amsbaugh SC and King CR. . 1987 EMBO J. 6: 605–610.

  • Litwin CM, Cheng HC and Wang JH. . 1991 J. Biol. Chem 266: 2557–2566.

  • Luttrell DK, Lee A, Lansing TJ, Crosby RM, Jung KD, Willard D, Luther M, Rodriguez M, Berman J and Gilmer TM. . 1994 Proc. Natl. Acad. Sci. USA 91: 83–87.

  • Luttrell DK, Luttrell LM and Parsons SJ. . 1988 Mol. Cell. Biol. 8: 497–501.

  • Maa MC, Leu TH, McCarley DJ, Schatzman RC and Parsons SJ. . 1995 Proc. Natl. Acad. Sci. USA 92: 6981–6985.

  • Muthuswamy SK and Muller WJ. . 1995 Oncogene 11: 271–279.

  • Muthuswamy SK, Siegel PM, Dankort DL, Webster MA and Muller WJ. . 1994 Mol. Cell. Biol. 14: 735–743.

  • O'Connor TJ, Bjorge JD, Cheng HC, Wang JH and Fujita DJ. . 1995 Cell Growth Differ. 6: 123–130.

  • Ottenhoff-Kalff AE, Rijksen G, van Beurden EA, Hennipman A, Michels AA and Staal GE. . 1992 Cancer Res. 52: 4773–4778.

  • Oude Weernink PA, Ottenhoff-Kalff AE, Vendrig MP, van Beurden EA, Staal GE and Rijksen G. . 1994 FEBS Letts 352: 296–300.

  • Pallen CJ. . 1993 Sem. Cell Biol. 4: 403–408.

  • Peng ZY and Cartwright CA. . 1995 Oncogene 11: 1955–1962.

  • Roche S, Koegl M, Barone MV, Roussel MF and Courtneidge SA. . 1995 Mol. Cell. Biol. 15: 1102–1109.

  • Rosen N, Bolen JB, Schwartz AM, Cohen P, DeSeau V and Israel MA. . 1986 J Br. Cancer 261: 13754–13759.

  • Shen SH, Bastien L, Posner BI and Chretien P. . 1991 Nature 352: 736–739.

  • Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A and McGuire WL. . 1987 Science 235: 177–182.

  • Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A and Press MF. . 1989 Science 244: 707–712.

  • Somani A-K, Bignon JS, Mills GB, Siminovitch KA and Branch DR. . 1997 J Br. Cancer 272: 21113–21119.

  • Songyang Z, Carraway KL, Eck MJ, Harrison SC, Feldman RA, Mohammadi M, Schlessinger J, Hubbard SR, Smith DP, Eng C, Lorenzo MJ, Ponder BAJ, Mayer BJ and Cantley LC. . 1995 Nature 373: 536–539.

  • Stover DR, Becker M, Liebetanz J and Lydon NB. . 1995 J Br. Cancer 270: 15591–15597.

  • Talamonti MS, Roh MS, Curley SA and Gallick GE. . 1993 J. Clin. Invest. 91: 53–60.

  • Tanaka A, Salem M, Eckroade RJ and Fujita DJ. . 1990 Oncogene Res. 5: 305–322.

  • Tomic S, Greiser U, Lammers R, Kharitonenkov A, Imyanitov E, Ullrich A and Bohmer FD. . 1995 J. Br. Cancer 270: 21277–21284.

  • Uckun FM, Tuel-Ahlgren L, Waddick KG, Jun X, Jin J, Myers DE, Rowley RB, Burkhardt AL and Bolen JB. . 1996 J. Br. Cancer 271: 6389–6397.

  • Varley JM, Swallow JE, Brammar WJ, Whittaker JL and Walker RA. . 1987 Oncogene 1: 423–430.

  • Webster MA, Cardiff RD and Muller WJ. . 1995 Proc. Natl. Acad. Sci. USA 92: 7849–7853.

  • Wilson LK, Luttrell DK, Parsons JT and Parsons SJ. . 1989 Mol. Cell. Biol. 9: 1536–1544.

  • Yuan ZM, Kharbanda S and Kufe D. . 1995 Biochemistry 34: 1058–1063.

  • Zhai YF, Beittenmiller H, Wang B, Gould MN, Oakley C, Esselman WJ and Welsch CW. . 1993 Cancer Res. 53, (Suppl): 2272–2278.

  • Zheng XM, Wang Y and Pallen CJ. . 1992 Nature 359: 336–339.

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Acknowledgements

We are grateful to Joan Brugge for Mab327, David Morgan for a baculovirus vector expressing CSK, Jeff Bjorge and Zhong Qi for helpful discussions and reagents, Yamini Achari and Jing Wang for sharing unpublished information, and Shelly Lloyd for excellent technical assistance. This work was supported by grants from the National Cancer Institute of Canada/Canadian Breast Cancer Research Initiative (DJF), and the Medical Research Council of Canada (DJF, JHW). DJF is a Scientist of the Alberta Heritage Foundation for Medical Research (AHFMR), and JHW is the recipient of an AHFMR international travel award.

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  1. Heung-Chin Cheng

    Present address: Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria, 3052, Australia

Authors and Affiliations

  1. Department of Medical Biochemistry, Cell Regulation Group, University of Calgary Medical Centre, Calgary, T2N 4N1, Alberta, Canada

    Cay Egan, Andrew Pang, Denise Durda, Heung-Chin Cheng, Jerry H Wang & Donald J Fujita

  2. Department of Medical Biochemistry, Cancer Biology Research Group, University of Calgary Medical Centre, Calgary, T2N 4N1, Alberta, Canada

    Cay Egan, Andrew Pang & Donald J Fujita

  3. Department of Biochemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong

    Jerry H Wang

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Egan, C., Pang, A., Durda, D. et al. Activation of Src in human breast tumor cell lines: elevated levels of phosphotyrosine phosphatase activity that preferentially recognizes the Src carboxy terminal negative regulatory tyrosine 530. Oncogene 18, 1227–1237 (1999). https://doi.org/10.1038/sj.onc.1202233

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