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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Identification of a Novel Human Lysophosphatidic Acid Acyltransferase, LPAAT-theta, Which Activates mTOR Pathway

  • Tang, Wenwen (State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University) ;
  • Yuan, Jian (State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University) ;
  • Chen, Xinya (State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University) ;
  • Gu, Xiuting (State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University) ;
  • Luo, Kuntian (State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University) ;
  • Li, Jie (State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University) ;
  • Wan, Bo (State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University) ;
  • Wang, Yingli (State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University) ;
  • Yu, Long (State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University)
  • Received : 2006.04.10
  • Accepted : 2006.06.13
  • Published : 2006.09.30
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Abstract

Lysophosphatidic acid acyltransferase (LPAAT) is an intrinsic membrane protein that catalyzes the synthesis of phosphatidic acid (PA) from lysophosphatidic acid (LPA). It is well known that LPAAT is involved in lipid biosynthesis, while its role in tumour progression has been of emerging interest in the last few years. To date, seven members of the LPAAT gene family have been found in human. Here we report a novel LPAAT member, designated as LPAAT-theta, which was 2728 base pairs in length and contained an open reading frame (ORF) encoding 434 amino acids. The LPAAT-theta gene consisted of 12 exons and 11 introns, and mapped to chromosome 4q21.23. LPAAT-theta was ubiquitously expressed in 18 human tissues by RT-PCR analysis. Subcellular localization of LPAAT-theta-EGFP fusion protein revealed that LPAAT-theta was distributed primarily in the endoplasmic reticulum (ER) of COS-7 cells. Furthermore, we found that the overexpression of LPAAT-theta can induce mTOR-dependent p70S6K phosphorylation on Thr389 and 4EBP1 phosphorylation on Ser65 in HEK293T cells.

Keywords

References

  1. Aguado, B. and Campbell, R. D. (1998) Characterization of a human lysophosphatidic acid acyltransferase that is encodedby a gene located in the class III region of the human major histocompativility complex. J. Biol. Chem. 273, 4096-4105. https://doi.org/10.1074/jbc.273.7.4096
  2. Agarwal, A. K. and Garg, A. (2003) Congenital generalized lipodystrophy: significance of triglyceride biosynthetic pathways. Trends Endocrinol. Metab. 14, 214-221. https://doi.org/10.1016/S1043-2760(03)00078-X
  3. Avila-Flores, A., Santos, T., Rincon, E. and Merida, I. (2005) Modulation of the mammalian target of rapamycin pathway by diacylglycerol kinase-produced phosphatidic acid. J. Biol. Chem. 280, 10091-10099. https://doi.org/10.1074/jbc.M412296200
  4. Bonham, L., Leung, D. W., White, T., Hollenback, D., Klein, P., Tulinsky, J., Coon, M., de Vries, P. and Singer, J. W. (2003) Lysophosphatidic acid acyltransferase-beta: a novel target for induction of tumour cell apoptosis. Expert Opin. Ther. Targets 7, 643-661. https://doi.org/10.1517/14728222.7.5.643
  5. Eberhardt, C., Gray, P. W. and Tjoelker, L. W. (1997) Human lysophophstidic acid acyltransferase. cDNA cloning, expression, and localization of chromosome 9q34.3. J. Biol. Chem. 272, 20299-20305. https://doi.org/10.1074/jbc.272.32.20299
  6. English, D., Cui, Y. and Siddiqui, R. A. (1996) Messenger functions of phosphatidic acid. Chem. Phys. Lipids 80, 117-132. https://doi.org/10.1016/0009-3084(96)02549-2
  7. Fang, Y., Park, I. H., Wu, A. L., Du, G., Huang, P., Frohman, M. A., Walker, S. J., Brown, H. A. and Chen, J. (2003) PLD1 regulates mTOR signaling and mediates Cdc42 activation of S6K1. Curr. Biol. 13, 2037-2044. https://doi.org/10.1016/j.cub.2003.11.021
  8. Fang, Y., Vilella-Bach, M., Bachmann, R., Flanigan, A. and Chen, J. (2001) Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science 294, 1942-1945. https://doi.org/10.1126/science.1066015
  9. Fingar, D. C. and Blenis, J. (2004) Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 23, 3151-3171. https://doi.org/10.1038/sj.onc.1207542
  10. Flores, I., Casaseca, T., Martinez-A, C., Kanoh, H. and Merida, I. (1996) Phosphatidic acid generation through interleukin 2 (IL-2)-induced alpha-diacylglycerol kinase activation is an essential step in IL-2-mediated lymphocyte proliferation. J. Biol. Chem. 271, 10334-10340. https://doi.org/10.1074/jbc.271.17.10334
  11. Huang, S. and Houghton, P. J. (2003) Targeting mTOR signaling of cancer therapy. Curr. Opin. Pharmacol. 3, 371-377. https://doi.org/10.1016/S1471-4892(03)00071-7
  12. Keith, C. T. and Schreiber, S. L. (1995) PIK-related kinases: DNA repair, recombination, and cell cycle checkpoints. Science 270, 50-51. https://doi.org/10.1126/science.270.5233.50
  13. Kent, C. (1995) Eukaryotic phospholipids biosynthesis. Annu. Rev. Biochem. 64, 315-343. https://doi.org/10.1146/annurev.bi.64.070195.001531
  14. Kume, K. and Shimizu, T. (1997) cDNA cloning and expression of murine 1-acyl-sn-glycerol-3- phosphate acyltransferase. Biochem. Biophys. Res. Commun. 237, 663-666. https://doi.org/10.1006/bbrc.1997.7214
  15. Leung, D. W. (2001) The structure and functions of human lysophosphatidic acid acyltransferases. Front Biosci. 6, 944-953. https://doi.org/10.2741/Leung
  16. Lewin, T. M., Wang, P. and Coleman, R. A. (1999) Analysis of amino acid motifs diagnostic for the sn-glycerol-3-phosphate acyltransferase reaction. Biochemistry 38, 5764-5771. https://doi.org/10.1021/bi982805d
  17. Li, D., Yu, L., Wu, H., Shan, Y., Guo, J., Dang, Y., Wei, Y. and Zhao, S. (2003) Cloning and identification of the human LPAAT-zeta gene, a novel member of the lysophosphatidic acid acyltransferase family. J. Hum. Genet. 48, 438-442. https://doi.org/10.1007/s10038-003-0045-z
  18. Shamji, A. F., Nghiem, P. and Schreiber, S. L. (2003) Integration of growth factor and nutrient signaling: Implications for cancer biology. Mol. Cell 12, 271-280. https://doi.org/10.1016/j.molcel.2003.08.016
  19. Shapiro, M. B. and Senapathy, P. (1987) RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 15, 7155-7174. https://doi.org/10.1093/nar/15.17.7155
  20. Stamps, A. C., Elmore, M. A., Hill, M. E., Kelly, K., Makda, A. A. and Finnen, M. J. (1997) A human cDNA sequence with homology to non-mammalian lysophosphatidic acid acyltransferases. Biochem. J. 326, 455-461. https://doi.org/10.1042/bj3260455
  21. Thompson, J. D., Gibson, T. J., Plewniak, F., Jeanmougin, F. and Higgins, D. G. (1997) Clustal X windows interface: Flexible strategies for multiple sequences alignment aided by quality analysis tools. Nucleic Acids Res. 24, 4876-4882.
  22. Vivanco, I. and Sawyers, C. L. (2002) The phosphatidylinositol 3-Kniase AKT pathway in human cancer. Nat. Rev. Cancer 2, 489-501. https://doi.org/10.1038/nrc839
  23. West, J., Tompkins, C. K., Balantac, N., Nudelman, E., Meengs, B., White, T., Bursten, S., Coleman, J., Kumar, A., Singer, J. W. and Leung, D. W. (1997) Cloning and expression of two human lysophosphatidic acid acyltransferase cDNAs that enhance cytokine-induced signaling responses in cells. DNA Cell Biol. 16, 691-701.
  24. Ye, G. M., Chen, C., Huang, S., Han, D. D., Guo, J. H., Wan, B. and Yu, L. (2005) Cloning and characterization a novel human 1-acyl-sn-glycerol-3-phosphate acyltransferase gene AGPAT7. DNA Seq. 16, 386-390. https://doi.org/10.1080/10425170500213712

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