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Modulation of retinoid signalling through NGF-induced nuclear export of NGFI-B

Nature Cell Biology volume 2, pages 435–440 (2000)Cite this article

Abstract

The retinoid–X receptor (RXR) regulates multiple hormonal pathways through heterodimerization with nuclear receptors such as the all-trans retinoic acid receptor (RAR). The orphan nuclear receptor NGFI-B (also called Nur77) can heterodimerize with RXR. Here we show that nerve growth factor (NGF) induces the phosphorylation of Ser 105 of NGFI-B in PC12 phaeochromocytoma cells, resulting in translocation of the NGFI-B–RXR heterodimer complex out of the nucleus using nuclear export signals within NGFI-B. As a consequence of the redistribution of RXR, the transcriptional activity of RXR–RAR is reduced. NGFI-B-mediated nuclear export of receptors may serve as a mechanism for crosstalk between NGF and retinoid pathways.

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Figure 1: NGF induces transient translocation of GFP–RXR from the nucleus to the cytoplasm in PC12 cells.
Figure 2: Identification of nuclear localization signals (NLSs) on NGFI-B.
Figure 3: Identification of nuclear export signals (NESs) on NGFI-B.
Figure 4: NGF induces translocation of NGFI-B via phosphorylation through the TrkA/Ras/MAP kinase pathway.
Figure 5: NGFI-B alters the subcellular localization of RXR in PC12 cells.
Figure 6: NGFI-B regulates the function of RXR through altering its subcellular localization in PC12 cells.

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References

  1. Mangelsdorf, D. J. et al. The nuclear receptor superfamily: The second decade. Cell 83, 835–839 ( 1995).

    Article  CAS  Google Scholar 

  2. Mangelsdorf, D. J. & Evans, R. M. The RXR heterodimers and orphan receptors. Cell 83, 841– 850 (1995).

    Article  CAS  Google Scholar 

  3. Chambon, P. A decade of molecular biology of retinoic acid receptors. FASEB. J. 10, 940–954 ( 1996).

    Article  CAS  Google Scholar 

  4. Milbrandt, J. Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene. Neuron 1, 183–188 (1988).

    Article  CAS  Google Scholar 

  5. Hazel, T. G., Nathans, D. & Lau, L. F. A gene inducible by serum growth factors encodes a member of the steroid and thyroid hormone receptor superfamily. Proc. Natl Acad. Sci. USA 85, 8444–8448 (1988).

    Article  CAS  Google Scholar 

  6. Fahrner, T. J., Carroll, S. L. & Milbrandt, J. The NGFI-B protein, an inducible member of the thyroid/steroid receptor family, is rapidly modified posttranslationally. Mol. Cell. Biol. 10, 6454–6459 (1990).

    Article  CAS  Google Scholar 

  7. Hazel, T. G., Misra, R., Davis, I. J., Greenberg, M. E. & Lau, L. F. Nur77 is differentially modified in PC12 cells upon membrane depolarization and growth factor treatment. Mol. Cell. Biol. 11, 3239–3246 ( 1991).

    Article  CAS  Google Scholar 

  8. Wilson, T. E., Fahrner, T. J., Johnston, M. & Milbrandt, J. Identification of the DNA binding site for NGFI-B by genetic selection in yeast. Science 252, 1296– 1300 (1991).

    Article  CAS  Google Scholar 

  9. Philips, A. et al. Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells. Mol. Cell. Biol. 17, 5946– 5951 (1997).

    Article  CAS  Google Scholar 

  10. Forman, B. M., Umesono, K., Chen, J. & Evans, R. M. Unique response pathways are established by allosteric interactions among nuclear hormone receptors. Cell 81, 541– 550 (1995).

    Article  CAS  Google Scholar 

  11. Perlmann, T. & Jansson, L. A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1. Genes Dev. 9, 769–782 ( 1995).

    Article  CAS  Google Scholar 

  12. Katagiri, Y., Hirata, Y., Milbrandt, J. & Guroff, G. Differential regulation of the transcriptional activity of the orphan nuclear receptor NGFI-B by membrane depolarization and NGF. J. Biol. Chem. 272, 31278–31284 ( 1997).

    Article  CAS  Google Scholar 

  13. Wilson, T. E., Paulsen, R. E., Padgett, K. A. & Milbrandt, J. Participation of non-zinc finger residues in DNA binding by two nuclear orphan receptors. Science 256, 107– 110 (1992).

    Article  CAS  Google Scholar 

  14. Wen, W., Meinkoth, J. L., Tsien, R. Y. & Taylor, S. S. Identification of a signal for rapid export of proteins from the nucleus. Cell 82, 463–473 ( 1995).

    Article  CAS  Google Scholar 

  15. Fischer, U., Huber, J., Boelens, W. C., Mattaj, I. W. & Luhrmann, R. The HIV-1 Rev activation domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs. Cell 82, 475– 483 (1995).

    Article  CAS  Google Scholar 

  16. Fukuda, M., Gotoh, I., Adachi, M., Gotoh, Y. & Nishida, E. A novel regulatory mechanism in the mitogen-activated protein (MAP) kinase cascade. Role of nuclear export signal of MAP kinase kinase. J. Biol. Chem. 272, 32642– 32648 (1997).

    Article  CAS  Google Scholar 

  17. Nishi, K. et al. Leptomycin B targets a regulatory cascade of crm1, a fission yeast nuclear protein, involved in control of higher order chromosome structure and gene expression. J. Biol. Chem. 269, 6320–6324 (1994).

    CAS  PubMed  Google Scholar 

  18. Greene, L. A. & Kaplan, D. R. Early events in neurotrophin signalling via Trk and p75 receptors. Curr. Opin. Neurobiol. 5 , 579–587 (1995).

    Article  CAS  Google Scholar 

  19. Koizumi, S. et al. K-252 a: a specific inhibitor of the action of nerve growth factor on PC 12 cells. J. Neurosci. 8, 715 –721 (1988).

    Article  CAS  Google Scholar 

  20. Thomas, S. M., DeMarco, M., D’Arcangelo, G., Halegoua, S. & Brugge, J. S. Ras is essential for nerve growth factor-and phorbol ester-induced tyrosine phosphorylation of MAP kinases. Cell 68, 1031–1040 (1992).

    Article  CAS  Google Scholar 

  21. Wu, Q. et al. Modulation of retinoic acid sensitivity in lung cancer cells through dynamic balance of orphan receptors nur77 and COUP-TF and their heterodimerization . EMBO J. 16, 1656–1669 (1997).

    Article  CAS  Google Scholar 

  22. Nigg, E. A. Nucleocytoplasmic transport: signals, mechanisms and regulation. Nature 386, 779–787 ( 1997).

    Article  CAS  Google Scholar 

  23. Jans, D. A. & Hubner, S. Regulation of protein transport to the nucleus: central role of phosphorylation. Physiol. Rev. 76, 651–685 (1996).

    Article  CAS  Google Scholar 

  24. Kaffman, A., Rank, N. M., O’Neill, E. M., Huang, L. S. & O’Shea, E. K. The receptor Msn5 exports the phosphorylated transcription factor Pho4 out of the nucleus . Nature 396, 482–486 (1998).

    Article  CAS  Google Scholar 

  25. Ben-Levy, R., Hooper, S., Wilson, R., Paterson, H. F. & Marshall, C. J. Nuclear export of the stress–activated protein kinase p38 mediated by its substrate MAPKAP kinase-2. Curr. Biol. 8, 1049–1057 ( 1998).

    Article  CAS  Google Scholar 

  26. Torchia, J., Glass, C. & Rosenfeld, M. G. Co-activators and co-repressors in the integration of transcriptional responses. Curr. Opin. Cell Biol. 10, 373–383 (1998).

    Article  CAS  Google Scholar 

  27. Blanco, J. C. et al. The histone acetylase PCAF is a nuclear receptor coactivator . Genes Dev. 12, 1638–1651 (1998).

    Article  CAS  Google Scholar 

  28. Blumberg, B. & Evans, R. M. Orphan nuclear receptors-new ligands and new possibilities. Genes Dev. 12, 3149 –3155 (1998).

    Article  CAS  Google Scholar 

  29. Chan, F. K., Zhang, J., Cheng, L., Shapiro, D. N. & Winoto, A. Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16 ink4. Mol. Cell Biol. 15, 2682–2688 (1995).

    Article  CAS  Google Scholar 

  30. Jehn, B. M., Bielke, W., Pear, W. S. & Osborne, B. A. Protective effects of notch-1 on TCR-induced apoptosis. J. Immunol. 162, 635–638 (1999).

    CAS  PubMed  Google Scholar 

  31. Rivest, S. & Rivier, C. Stress and interleukin-1 beta-induced activation of c-fos, NGFI-B and CRF gene expression in the hypothalamic PVN: comparison between Sprague-Dawley, Fisher-344 and Lewis rats. J. Neuroendocrinol. 6, 101–117 (1994).

    Article  CAS  Google Scholar 

  32. Honkaniemi, J., Kononen, J., Kainu, T., Pyykonen, I. & Pelto-Huikko, M. Induction of multiple immediate early genes in rat hypothalamic paraventricular nucleus after stress. Brain Res. Mol. Brain Res. 25, 234–241 ( 1994).

    Article  CAS  Google Scholar 

  33. Zetterstrom, R. H., Williams, R., Perlmann, T. & Olson, L. Cellular expression of the immediate early transcription factors Nurr1 and NGFI-B suggests a gene regulatory role in several brain regions including the nigrostriatal dopamine system. Brain Res. Mol. Brain Res. 41, 111–120 (1996).

    Article  CAS  Google Scholar 

  34. Hamada, K. et al. H-2 RIIBP, a member of the nuclear hormone receptor superfamily that binds to both the regulatory element of major histocompatibility class I genes and the estrogen response element. Proc. Natl Acad. Sci. USA 86, 8289–8293 ( 1989).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank S. S. Simons (NIDDK, NIH), Y. Hirata (RIKEN, Japan), X. W. Liu (NICHD, NIH), and K. Ingham (American Red Cross) for helpful discussion and support. We are grateful to J. Milbrandt (Washington University, St Louis) for NGFI–B plasmid and monoclonal antibody, and to M. Yoshida (University of Tokyo, Japan) for leptomycin B. We also thank E. Mills and D. Balasundaram (NICHD, NIH) for critical comments for this manuscript.

This article is dedicated to G. Guroff, who died on 9 July 1999 as the result of an automobile accident.

Correspondence should be addressed to Y.K.

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Author notes

  1. Yasuhiro Katagiri

    Present address: American Red Cross, Holland Laboratory, Biochemistry Department, 15601 Crabbs Branch Way, Rockville, Maryland, 20892, USA

Authors and Affiliations

  1. Section on Growth Factors, NICHD, National Institutes of Health, 9000 Rockville Pike, Bethesda, 20892, Maryland, USA

    Yasuhiro Katagiri & Gordon Guroff

  2. Pathology Section, NHLBI, National Institutes of Health, 9000 Rockville Pike, Bethesda, 20892, Maryland, USA

    Kazuyo Takeda, Zu-Xi Yu & Victor J. Ferrans

  3. Laboratory of Molecular Growth Regulation, NICHD, National Institutes of Health, 9000 Rockville Pike, Bethesda, 20892, Maryland, USA

    Keiko Ozato

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Correspondence to Yasuhiro Katagiri.

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Katagiri, Y., Takeda, K., Yu, ZX. et al. Modulation of retinoid signalling through NGF-induced nuclear export of NGFI-B. Nat Cell Biol 2, 435–440 (2000). https://doi.org/10.1038/35017072

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