Calreticulin and Dynamics of the Endoplasmic Reticulum Lumenal Environment

  • Marek Michalak
  • Kimitoshi Nakamura
  • Sylvia Papp
  • Michal Opas


It is widely accepted that Ca2+ is a universal signaling molecule in the cell (Pozzan et al., 1994). Due to the versatility of Ca2+ signaling both, Ca2+ storage and release must be tightly controlled in spatiotemporal manner (Petersen and Burdakov, 1999). While several organelles participate in control of Ca2+ homeostasis, the endoplasmic reticulum (ER) appears to be the most important organelle controlling many aspects of intracellular Ca2+ homeostasis (Pozzan et al., 1994; Meldolesi and Pozzan, 1998). Ca2+ is released from the ER by InsP3 receptor and/or RyR Ca2+ release channels and it is taken up by the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) (MacLennan et al., 1997 and Parys et al., this book). Alterations in the intracellular and ER lumenal Ca2+ concentration regulate a variety of diverse cellular functions including secretion, contraction-relaxation, cell motility, cytoplasmic and mitochondrial metabolism, protein synthesis, modification and folding, gene expression, cell cycle progression and apoptosis (Pozzan et al., 1994). The ER is a site of synthesis of membrane proteins, membrane lipids and secreted proteins. It contains the largest concentration of chaperones involved in protein folding, modification and assembly. The ER and its lumen contain a characteristic set of resident proteins that are involved in every aspect of the ER function. It is also likely that Ca2+ plays a role of signaling molecule in the ER lumen. The ER lumenal Ca2+ concentration ([Ca2+]ER) affect several processes in the ER lumen including modulation of chaperone-substrate and protein-protein interactions Corbett et al., 1999).


Mouse Embryonic Fibroblast Endoplasmic Reticulum Lumen Protein Disulphide Isomerase Endoplasmic Reticulum Function Amino Acid Signal Sequence 
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. Baksh, S., Burns, K., Andrin, C. and Michalak, M., 1995, Interaction of calreticulin with protein disulfide isomerase, J. Biol. Chem. 270, 31338–31344.PubMedCrossRefGoogle Scholar
  2. Barnes, J.A. and Smoak, I.W., 1997, Immunolocalization and heart levels of GRP94 in the mouse during post-implantation development, Anat. Embryol. 196, 335–341.PubMedCrossRefGoogle Scholar
  3. Barth, A.I., Nathke, I.S. and Nelson, W.J., 1997, Cadherins, catenins and APC protein: Interplay between cytoskeletal complexes and signaling pathways, Curr. Opin. Cell Biol. 9, 683–690.PubMedCrossRefGoogle Scholar
  4. Bastianutto, C., Clementi, E., Codazzi, F., Podini, P., De Giorgi, F., Rizzuto, R., Meldolesi, J. and Pozzan, T., 1995, Overexpression of calreticulin increases the Ca2+ capacity of rapidly exchanging Ca2+ stores and reveals aspects of their lumenal microenvironment and function, J. Cell Biol. 130, 847–855.PubMedCrossRefGoogle Scholar
  5. Bergeron, J.J., Brenner, M.B., Thomas, D.Y. and Williams, D.B., 1994, Calnexin: A membrane-bound chaperone of the endoplasmic reticulum, Trends Biochem. Sci. 19, 124–128.PubMedCrossRefGoogle Scholar
  6. Burns, K., Duggan, B., Atkinson, E.A., Famulski, K.S., Nemer, M., Bleackley, R.C. and Michalak, M., 1994, Modulation of gene expression by calreticulin binding to the glucocorticoid receptor, Nature 367, 476–480.PubMedCrossRefGoogle Scholar
  7. Burridge, K. and Chrzanowska-Wodnicka, M., 1996, Focal adhesions, contractility, and signaling, Annu. Rev. Cell Dev. Biol. 12, 463–518.PubMedCrossRefGoogle Scholar
  8. Cala, S.E. and Jones, L.R., 1994, GRP94 resides within cardiac sarcoplasmic reticulum vesicles and is phosphorylated by casein kinase II, J. Biol. Chem. 269, 5926–5931.PubMedGoogle Scholar
  9. Cala, S.E., Ulbright, C, Kelley, J.S. and Jones, L.R., 1993, Purification of a 90-kDa protein (Band VII) from cardiac sarcoplasmic reticulum. Identification as calnexin and localization of casein kinase II phosphorylation sites, J. Biol. Chem. 268, 2969–2975.PubMedGoogle Scholar
  10. Camacho, P. and Lechleiter, J.D., 1995, Calreticulin inhibits repetitive intracellular Ca2+ waves, Cell 82, 765–771.PubMedCrossRefGoogle Scholar
  11. Coppolino, M.G., Woodside, M.J., Demaurex, N., Grinstein, S., St-Arnaud, R. and Dedhar, S., 1997, Calreticulin is essential for integrin-mediated calcium signalling and cell adhesion, Nature 386, 843–847.PubMedCrossRefGoogle Scholar
  12. Corbett, E.F. and Michalak, M., 2000, Calcium, a signaling molecule in the endoplasmic reticulum?, Trends Biochem. Sci. 25, 307–311.PubMedCrossRefGoogle Scholar
  13. Corbett, E.F., Oikawa, K., Francois, P., Tessier, D.C., Kay, C, Bergeron, J.J.M., Thomas, D.Y., Krause, K.H. and Michalak, M., 1999, Ca2+ regulation of interactions between endoplasmic reticulum chaperones, J. Biol. Chem. 274, 6203–6211.PubMedCrossRefGoogle Scholar
  14. Crabtree, G.R., 1999, Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NF-AT, Cell 96, 611–614.PubMedCrossRefGoogle Scholar
  15. Dedhar, S., Rennie, P.S., Shago, M., Hagesteijn, C.Y., Yang, H., Filmus, J., Hawley, R., Bruchovsky, N., Cheng, H., Matusik, R.J. and Giguere, V., 1994, Inhibition of nuclear hormone receptor activity by calreticulin, Nature 367, 480–483.PubMedCrossRefGoogle Scholar
  16. Eggleton, P. and Llewellyn, D.H., Autoimmune disease and calcium-binding proteins, this book.Google Scholar
  17. Eggleton, P., Reid, K.B., Kishore, U. and Sontheimer, R.D., 1997, Clinical relevance of calreticulin in systemic lupus erythematosus, Lupus 6, 564–571.PubMedCrossRefGoogle Scholar
  18. Ellgaard, L., Molinari, M. and Helenius, A., 1999, Setting the standards: Quality control in the secretory pathway, Science 286, 1882–1888.PubMedCrossRefGoogle Scholar
  19. Fadel, M.P., Dziak, E., Lo, CM., Ferrier, J., Mesaeli, N., Michalak, M. and Opas, M., 1999, Calreticulin affects focal contact-dependent but not close contact-dependent cell-substratum adhesion, J. Biol Chem. 274, 15085–15094.PubMedCrossRefGoogle Scholar
  20. Fliegel, L., Newton, E., Burns, K. and Michalak, M., 1990, Molecular cloning of cDNA encoding a 55-kDa multifunctional thyroid hormone binding protein of skeletal muscle sarcoplasmic reticulum, J. Biol. Chem. 265, 15496–15502.PubMedGoogle Scholar
  21. Ghosh, A. and Greenberg, M.E., 1995, Calcium signaling in neurons: Molecular mechanisms and cellular consequences, Science 268, 239–247.PubMedCrossRefGoogle Scholar
  22. Hanks, S.K. and Polte, T.R., 1997, Signaling through focal adhesion kinase, Bioessays 19, 137–145.PubMedCrossRefGoogle Scholar
  23. Hazan, R.B. and Norton, L., 1998, The epidermal growth factor receptor modulates the interaction of E-cadherin with the actin cytoskeleton, J. Biol. Chem. 273, 9078–9084.PubMedCrossRefGoogle Scholar
  24. Huttenlocher, A., Lakonishok, M., Kinder, M., Wu, S., Truong, T., Knudsen, K.A. and Horwitz, A.F., 1998, Integrin and cadherin synergy regulates contact inhibition of migration and motile activity, J. Cell Biol. 141, 515–526.PubMedCrossRefGoogle Scholar
  25. Ihara, Y, Cohen-Doyle, M.F., Saito, Y and Williams, D.B., 1999, Calnexin discriminates between protein conformational states and functions as a molecular chaperone in vitro, Molecular Cell 4, 331–341.PubMedCrossRefGoogle Scholar
  26. Ikeda, S., Kishida, S., Yamamoto, H., Murai, H., Koyama, S. and Kikuchi, A., 1998, Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin, EMBO J. 17, 1371–1384.PubMedCrossRefGoogle Scholar
  27. John, L.M., Lechleiter, J.D. and Camacho, P., 1998, Differential modulation of SERCA2 isoforms by calreticulin, J. Cell Biol. 142, 963–973.PubMedCrossRefGoogle Scholar
  28. Kaufman, R.J., 1999, Stress signaling from the lumen of the endoplasmic reticulum: Coordination of gene transcriptional and translational controls, Genes & Dev. 13, 1211–1233.CrossRefGoogle Scholar
  29. Krause, K.-H. and Michalak, M., 1997, Calreticulin, Cell 88, 439–443.PubMedCrossRefGoogle Scholar
  30. MacLennan, D.H., Rice, W.J. and Green, N.M., 1997, The mechanism of Ca2+ transport by sarco(endo)plasmic reticulum Ca2+-ATPases, J. Biol. Chem. 272, 28815–28818.PubMedCrossRefGoogle Scholar
  31. Meldolesi, J. and Pozzan, T, 1998, The endoplasmic reticulum Ca2+ store: A view from the lumen, Trends Biochem. Sci. 23, 10–14.PubMedCrossRefGoogle Scholar
  32. Mery, L., Mesaeli, N., Michalak, M., Opas, M., Lew, D.P. and Krause, K.-H., 1996, Overex-pression of calreticulin increases intracellular Ca2+ storage and decreases store-operated Ca2+ influx, J. Biol. Chem. 271, 9332–9339.PubMedCrossRefGoogle Scholar
  33. Mesaeli, N., Nakamura, K., Zvaritch, E., Dickie, P., Dziak, E., Krause, K.-H., Opas, M., MacLennan, D.H. and Michalak, M., 1999, Calreticulin is essential for cardiac development, J. Cell Biol. 144, 857–868.PubMedCrossRefGoogle Scholar
  34. Michalak, M., Burns, K., Andrin, C., Mesaeli, N., Jass, G.H., Busaan, J.L. and Opas, M., 1996, Endoplasmic reticulum form of calreticulin modulates glucocorticoid-sensitive gene expression, J Biol. Chem. 271, 29436–29445.PubMedCrossRefGoogle Scholar
  35. Michalak, M., Corbett, E.F., Mesaeli, N., Nakamura, K. and Opas, M., 1999, Calreticulin: one protein, one gene, many functions, Biochem. J. 344, 281–292.PubMedCrossRefGoogle Scholar
  36. Molinari, M. and Helenius, A., 1999, Glycoproteins form mixed disulphides with oxidoreductases during folding in living cells, Nature 402, 90–93.PubMedCrossRefGoogle Scholar
  37. Molkentin, J.D., Lu, J.R., Antos, C.L., Markham, B., Richardson, J., Robbins, J., Grant, S.R. and Olson, E.N., 1998, A calcineurin-dependent transcriptional pathway for cardiac hypertrophy, Cell 93, 215–228.PubMedCrossRefGoogle Scholar
  38. Nakhasi, H.L., Pogue, G.P, Duncan, R.C., Joshi, M., Atreya, CD., Lee, N.S. and Dwyer, D.M., 1998, Implications of calreticulin function in parasite biology, Parasitol. Today 14, 157–160.PubMedCrossRefGoogle Scholar
  39. Nigam, S.K., Goldberg, A.L., Ho, S., Rohde, M.F., Bush, K.T. and Sherman, M., 1994, A set of endoplasmic reticulum proteins possessing properties of molecular chaperones includes Ca2+-binding proteins and members of the thioredoxin superfamily, J. Biol. Chem. 269, 1744–1749.PubMedGoogle Scholar
  40. Oliver, J.D., Roderick, H.L., Llewellyn, D.H. and High, S., 1999, ERp57 Functions as a sub-unit of specific complexes formed with the ER lectins calreticulin and calnexin, Mol. Biol. Cell 10, 2573–2582.PubMedGoogle Scholar
  41. Olson, E.N. and Srivastava, D., 1996, Molecular pathways controlling heart development, Science 272, 671–676.PubMedCrossRefGoogle Scholar
  42. Opas, M., Szewczenko-Pawlikowski, M., Jass, G.K., Mesaeli, N. and Michalak, M., 1996, Calreticulin modulates cell adhesiveness via regulation of vinculin expression, J. Cell Biol. 135, 1913–1923.PubMedCrossRefGoogle Scholar
  43. Parys, J.B., Sienaert, I., Vanlingen, S., Callewaert, G., De Smet, P., Missiaen, L. and De Smedt, H., Regulation of inositol 1,4,5-trisphosphate-induced Ca2+ release by Ca2+, this book.Google Scholar
  44. Petersen, O.H. and Burdakov, D., 1999, Polarity in intracellular calcium signaling, Bioessays 21,851–860.PubMedCrossRefGoogle Scholar
  45. Pike, S.E., Yao, L., Jones, K.D., Cherney, B., Appella, E., Sakaguchi, K., Nakhasi, H., Teruya-Feldstein, J., Wirth, P., Gupta, G. and Tosato, G., 1998, Vasostatin, a calreticulin fragment, inhibits angiogenesis and suppresses tumor growth, J. Exp. Med. 188, 2349–2356.PubMedCrossRefGoogle Scholar
  46. Pozzan, T., Rizzuto, R., Volpe, P. and Meldolesi, J., 1994, Molecular and cellular physiology of intracellular calcium stores, Physiol. Rev. 74, 595–636.PubMedCrossRefGoogle Scholar
  47. Rao, A., Luo, C. and Hogan, P.G., 1997, Transcription factors of the NFAT family: Regulation and function, Annu. Rev. Immunol. 15, 707–747.PubMedCrossRefGoogle Scholar
  48. Rojiani, M.V., Finlay, B.B., Gray, V. and Dedhar, S., 1991, In vitro interaction of a polypeptide homologous to human Ro/SS-A antigen (calreticulin) with a highly conserved amino acid sequence in the cytoplasmic domain of integrin alpha subunits, Biochemistry 30, 9859–9866.PubMedCrossRefGoogle Scholar
  49. Saito, Y, Ihara, Y, Leach, M.R., Cohen-Doyle, M.F. and Williams, D.B., 1999, Calreticulin functions in vitro as a molecular chaperone for both glycosylated and non-glycosylated proteins, EMBO J. 18, 6718–6729.PubMedCrossRefGoogle Scholar
  50. Stehno-Bittel, L., Luckhoff, A. and Clapham, D.E., 1995, Calcium release from the nucleus by InsP3 receptor channels, Neuron 14, 163–167.PubMedCrossRefGoogle Scholar
  51. Urade, R., Takenaka, Y. and Kito, M., 1993, Protein degradation by ERp72 from rat and mouse liver endoplasmic reticulum, J. Biol. Chem. 268, 22004–22009.PubMedGoogle Scholar
  52. Verboomen, H., Wuytack, F., Van Den Bosch, L., Mertens, L. and Casteels, R., 1994, The functional importance of the extreme C-terminal tail of the gene 2 organellar Ca2+-transport ATPase (SERCA2a/b), Biochem. J. 303, 979–984.PubMedGoogle Scholar
  53. Vitadello, M., Colpo, P. and Gorza, L., 1998, Rabbit cardiac and skeletal interaction myocytes differ in constitutive and inducible expression of the glucose-regulated protein GRP94, Biochem. J. 332, 351–359.PubMedGoogle Scholar
  54. Zapun, A., Darby, N.J., Tessier, D.C., Michalak, M., Bergeron, J.J.M. and Thomas, D.Y., 1998, Enhanced catalysis of ribonuclease B folding by the of calnexin or calreticulin with ERp57, J. Biol. Chem. 273, 6009–6012.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2000

Authors and Affiliations

  • Marek Michalak
    • 1
  • Kimitoshi Nakamura
    • 1
  • Sylvia Papp
    • 2
  • Michal Opas
    • 2
  1. 1.Canadian Institutes of Health Research Group in Molecular Biology of Membranes and the Department of BiochemistryUniversity of AlbertaEdmontonCanada
  2. 2.Department of Anatomy and Cell BiologyUniversity of TorontoTorontoCanada

Personalised recommendations