Calreticulin-Mediated Nuclear Protein Export

  • Ben E. Black
  • Bryce M. Paschal
Part of the Molecular Biology Intelligence Unit book series (MBIU)


The role of calreticulin (CRT) as a molecular chaperone that functions in the endoplasmic reticulum (ER) is well established. This involves transient binding of CRT to hydrophobic residues and carbohydrate chains in polypeptides undergoing folding reactions in the lumen of the ER. The issue of CRT distribution and function outside of the ER, though controversial for several years, has now been addressed by rigorous biochemical fractionation and cell biological analysis. Cytosolic CRT, which refers to the non-ER form of the protein that shuttles between the cytoplasm and nucleus, can function as a receptor that mediates nuclear export of the glucocorticoid receptor (GR). The signal recognized by CRT is contained within the DNA binding domain (DBD) of GR. In this chapter, we introduce the topic of nuclear export and summarize the characterization of cytosolic CRT as an export receptor. We also review the evidence that the DBD functions as a signal for export of GR. The DBD is likely to function as the export signal for other members of the nuclear receptor (NR) superfamily, which is the largest family of transcription factors in higher eukaryotes. Our working model is that the non-ER form of CRT contributes to the regulation of multiple cellular pathways through a nuclear export-based mechanism.


Glucocorticoid Receptor Nuclear Export Nuclear Import Nuclear Pore Complex Nuclear Export Signal 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Gorlich D, Kutay U. Transport between the cell nucleus and the cytoplasm. Annu Rev Cell Dev Biol 1999; 15:607–660.PubMedCrossRefGoogle Scholar
  2. 2.
    Nakielny S, Dreyfuss G. Transport of proteins and RNAs in and out of the nucleus. Cell 1999; 99:677–690.PubMedCrossRefGoogle Scholar
  3. 3.
    Stoffler D, Fahrenkrog B, Aebi U. The nuclear pore complex: from molecular architecture to functional dynamics. Curr Opin Cell Biol 1999; 11:391–401.PubMedCrossRefGoogle Scholar
  4. 4.
    Wente SR. Gatekeepers of the nucleus. Science 2000; 288:1374–1377.PubMedCrossRefGoogle Scholar
  5. 5.
    Vasu SK, Forbes DJ. Nuclear pores and nuclear assembly. Curr Opin Cell Biol 2001; 13:363–375.PubMedCrossRefGoogle Scholar
  6. 6.
    Fischer U, Huber J, Boelens WC et al. The HIV-1 Rev activation domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs. Cell 1995; 82:475–83.PubMedCrossRefGoogle Scholar
  7. 7.
    Wen W, Meinkoth JL, Tsien RY et al. Identification of a signal for rapid export of proteins from the nucleus. Cell 1995; 82:463–473.PubMedCrossRefGoogle Scholar
  8. 8.
    Fornerod M, van Deursen J, van Baal S et al. The human homologue of yeast CRM1 is in a dynamic subcomplex with CAN/Nup214 and a novel nuclear pore component Nup88. EMBO J 1997; 16:807–816.Google Scholar
  9. 9.
    Pemberton LF, Blobel G, Rosenblum JS. Transport routes through the nuclear pore complex. Curr Opin Cell Biol 1998; 10:392–399.PubMedCrossRefGoogle Scholar
  10. 10.
    Fornerod M, Ohno M, Yoshida M et al. CRM1 is an export receptor for leucine-rich nuclear export signals. Cell 1997; 90:1051–60.PubMedCrossRefGoogle Scholar
  11. 11.
    Stade K, Ford CS, Guthrie C et al. Exportin 1 (Crmlp) is an essential nuclear export factor. Cell 1997; 90:1041–1050.PubMedCrossRefGoogle Scholar
  12. 12.
    Steggerda SM, Paschal BP. Regulation of nuclear import and export by the GTPase Ran. Int Rev Cytol 2002; 217:41–91.PubMedCrossRefGoogle Scholar
  13. 13.
    Klemm JD, Beals CR, Crabtree GR. Rapid targeting of nuclear proteins to the cytoplasm. Curr Biol 1997; 7:638–644.PubMedCrossRefGoogle Scholar
  14. 14.
    Kehlenbach RH, Dickmanns A, Gerace L. Nucleocytoplasmic shuttling factors including Ran and Crml mediate nuclear export of NFAT in vitro. J Cell Biol 1998; 141:863–874.PubMedCrossRefGoogle Scholar
  15. 15.
    Roth J, Dobbelstein M, Freedman DA et al. Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein. EMBO J 1998; 17:554–564.PubMedCrossRefGoogle Scholar
  16. 16.
    Stommel JM, Marchenko ND, Jimenez GS et al. A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking. EMBO J 1999; 18:1660–1672.PubMedCrossRefGoogle Scholar
  17. 17.
    Wolff B, Sanglier JJ, Wang Y. Leptomycin B is an inhibitor of nuclear export: inhibition of nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 (HIV-1) Rev protein and Rev-dependent mRNA. Chem Biol 1997; 4:139–147.PubMedCrossRefGoogle Scholar
  18. 18.
    Holaska JM, Paschal BM. A cytosolic activity distinct from Crml mediates nuclear export of protein kinase inhibitor in permeabilized cells. Proc Natl Acad Sci USA 1998; 95:14739–14744.PubMedCrossRefGoogle Scholar
  19. 19.
    Adam SA, Sterne-Marr RE, Gerace L. Nuclear protein import in permeabilized mammalian cells requires soluble cytoplasmic factors. J Cell Biol 1990; 111:807–816.PubMedCrossRefGoogle Scholar
  20. 20.
    Holaska JM, Black BE, Love DC et al. Calreticulin is a receptor for nuclear export. J Cell Biol 2001; 152:127–140.PubMedCrossRefGoogle Scholar
  21. 21.
    Osrwald TJ, MacLennan DH. Isolation of a high affinity calcium-binding protein from sarcoplasmic reticulum. J Biol Chem 1974; 249:974–979.Google Scholar
  22. 22.
    Michalak M, Burns K, Andrin C et al. Endoplasmic reticulum form of calreticulin modulates glucocorticoid-sensitive gene expression. J Biol Chem 1996; 271:29436–29445.PubMedCrossRefGoogle Scholar
  23. 23.
    Jethmalani SM, Henle KJ, Gazitt Y et al. Intracellular distribution of heat-induced stress glycoproteins. J Cell Biochem 1997; 66:98–111.PubMedCrossRefGoogle Scholar
  24. 24.
    Roderick HL, Campbell AK, Llewellyn DH. Nuclear localisation of calreticulin in vivo is enhanced by its interaction with glucocorticoid receptors. FEBS Lett 1997; 405:181–185.PubMedCrossRefGoogle Scholar
  25. 25.
    Burns K, Duggan B, Atkinson EA et al. Modulation of gene expression by calreticulin binding to the glucocorticoid receptor. Nature 1994; 367:476–480.PubMedCrossRefGoogle Scholar
  26. 26.
    Dedhar S, Rennie PS, Shago M et al. Inhibition of nuclear hormone receptor activity by calreticulin. Nature 1994; 367:480–483.PubMedCrossRefGoogle Scholar
  27. 27.
    Wheeler DG, Horsford J, Michalak M et al. Calreticulin inhibits vitamin D3 signal transduction. Nucleic Acids Res 1995; 23:3268–3274.PubMedCrossRefGoogle Scholar
  28. 28.
    Büchner J. Hsp90 & Co.-a holding for folding. Trends Biochem Sci 1999; 24:136–141.PubMedCrossRefGoogle Scholar
  29. 29.
    Mesaeli N, Nakamura K, Zvaritch E et al. Calreticulin is essential for cardiac development. J Cell Biol 1999; 144:857–868.PubMedCrossRefGoogle Scholar
  30. 30.
    Black BE, Holaska JM, Rastinejad F et al. DNA binding domains in diverse nuclear receptors function as nuclear export signals. Curr Biol 2001; 11:1749–1758.PubMedCrossRefGoogle Scholar
  31. 31.
    Evans RM. The steroid and thyroid hormone receptor superfamily. Science 1988; 240:889–895.PubMedCrossRefGoogle Scholar
  32. 32.
    Luisi BF, Xu WX, Orwinowski Z et al. Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA. Nature 1991; 352:497–505.PubMedCrossRefGoogle Scholar
  33. 33.
    Madan AP, DeFranco DB. Bidirectional transport of glucocorticoid receptors across the nuclear envelope. Proc Natl Acad Sci USA 1993; 90:3588–3592.PubMedCrossRefGoogle Scholar
  34. 34.
    Michael WM, Choi M, Dreyfuss G. A nuclear export signal in hnRNP Al: a signal-mediated, temperature-dependent nuclear protein export pathway. Cell 1995; 83:415–422.PubMedCrossRefGoogle Scholar
  35. 35.
    Singh NK, Atreya CD, Nakhasi HL. Identification of calreticulin as a rubella virus RNA binding protein. Proc Natl Acad Sci USA 1994; 91:12770–12774.PubMedCrossRefGoogle Scholar
  36. 36.
    Holaska JM, Black BE, Rastinejad FR et al. Ca2+-dependent nuclear export mediated by calreticulin. Mol Cell Biol 2002; 22:6286–6297.PubMedCrossRefGoogle Scholar
  37. 37.
    Vassilakos A, Michalak M, Lehrman MA et al. Oligosaccharide binding characteristics of the molecular chaperones calnexin and calreticulin. Biochemistry 1998; 37:3480–3490.PubMedCrossRefGoogle Scholar
  38. 38.
    Komeili A, O’Shea EK. Nuclear transport and transcription. Curr Opin Cell Biol 2000; 12:355–360.PubMedCrossRefGoogle Scholar
  39. 39.
    Gottlicher M, Heck S, Herrlich P. Transcriptional cross-talk, the second mode of steroid hormone action. J Mol Med 1998; 76:480–489.PubMedCrossRefGoogle Scholar
  40. 40.
    Karin M, Chang L. AP-1/glucocorticoid receptor crosstalk taken to a higher level. J Endocrinol 2001; 169:447–451.PubMedCrossRefGoogle Scholar
  41. 41.
    Liu J, DeFranco DB. Protracted nuclear export of glucocorticoid receptor limits its turnover and does not require the exportin 1/CRM 1-directed nuclear export pathway. Mol Endocrinol 2000; 14:40–51.PubMedCrossRefGoogle Scholar
  42. 42.
    Freedman DA, Levine AJ. Nuclear export is required for degradation of endogenous p53 by MDM2 and human papillomavirus E6. Mol Cell Biol 1998; 18:7288–7293.PubMedGoogle Scholar
  43. 43.
    Rodriguez MS, Thompson J, Hay RT et al. Nuclear retention of IkB-a protects it from signal-induced degradation and inhibits nuclear factor kB transcriptional activation. J Biol Chem 1999; 274:9108–9115.PubMedCrossRefGoogle Scholar
  44. 44.
    Falkenstein E, Tillmann HC, Christ M et al. Multiple actions of steroid hormones-a focus on rapid, nongenomic effects. Pharmacol Rev 2000; 52:513–555.PubMedGoogle Scholar
  45. 45.
    Manolagas SC, Kousteni S. Perspective: nonreproductive sites of action of reproductive hormones. Endo 2001; 142:2200–2204.CrossRefGoogle Scholar
  46. 46.
    Migliaccio A, Castoria G, Di Domenico M et al. Steroid-induced androgen receptor-oestradiol receptor b-Src complex triggers prostate cancer cell progression. EMBO J 2000; 19:5406–5417.PubMedCrossRefGoogle Scholar
  47. 47.
    Simoncini T, Hafezi-Moghadam A, Brazil DP et al. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 2000; 407:538–541.PubMedCrossRefGoogle Scholar
  48. 48.
    Kousteni S, Bellido T, Plotkin LI et al. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 2001; 104:719–730.PubMedGoogle Scholar
  49. 49.
    DeFranco DB. DNA-binding domains find a surprising partner. Curr Biol 2001; 11:R1036–R1037.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Ben E. Black
  • Bryce M. Paschal

There are no affiliations available

Personalised recommendations