We are delighted to announce that Calreticulin Workshop,=20
devoted to the structure and function of calreticulin and=20
related proteins, will take place on March 31 - April 2,=20
1998 in Banff, Alberta, Canada. The Workshop will provide=20
unique opportunity to meet and interact with the scientists=20
interested in calreticulin research in spectacular=20
surroundings of Banff National Park in Canadian Rocky=20
Mountains. We are sure that the Banff Calreticulin Workshop=20
will be an important forum to share the latest findings and=20
to develop future interactions. Calreticulin has been=20
implicated to play a role in almost every aspect of cell=20
biology as outlined in a brief overview below. We hope that=20
the Workshop will be useful to sort out some of the latest=20
discoveries and controversies concerning calreticulin and=20
implication of this protein in a variety of biological=20
systems. On the behalf of the Organizing Committee we would=20
like to invite you to participate in the Workshop.=20
The Calreticulin Workshop is a satellite meeting to the 8th=20
Fisher Winternational Symposium on Cellular and Molecular=20
Biology which will be held April 2-5, 1998, also at the=20
Banff Conference Centre. The Winternational Symposium,=20
which is co-sponsored by our Society and Fisher Scientific,=20
is held annually, with a different focus each year. The=20
theme for the 1998 meeting is : "Membrane Proteins in Health=20
and Disease." Further information about the Fisher=20
Winternational or the satellite meetings can be obtained by=20
visiting the Society's web site at=20
or by contacting the Chair of the Scientific Program=20
Committee by E-mail: Carol Cass <carol.cass at ualberta.ca.>.
I hope you will participate in the Calreticulin Workshop. =20
If you would like to receive further information please send=20
a request (if possible, by e-mail) to Michal Opas at:
=09 m.opas at utoronto.ca =20
=09Department of Anatomy & Cell Biology
=09University of Toronto
=09Medical Sciences Building
=09Toronto, Ontario, M5S 1A8 Canada
=09 tel: (416) 978-8947
=09 fax: (416) 978-3954
I look forward to hearing from you in the near future.
For The Organizing Committee
Calreticulin, a multifunctional protein
Calreticulin, 60 kDa Ca-binding protein , is a major=20
component of the endoplasmic reticulum (ER) of non-muscle=20
cells [2-7]. The protein is of high physiological=20
importance as it knockout is embryonic lethal . Along=20
with a wide tissue distribution , calreticulin is present=20
in diverse animal and plant species . calreticulin is a=20
resident ER protein as demonstrated by a variety of=20
biochemical and immunological techniques [1,3,4,6,11]. The=20
protein is synthesized with an N-terminal signal sequence=20
and it terminates with the KDEL sequence [3,12] which is=20
responsible for retrieval of proteins to the lumen of the ER=20
=09Calreticulin functions in vivo as a Ca storage=20
protein [15,16]. It also has been well established that=20
calreticulin is a chaperone [17-21] and it shows similarity=20
in amino acid sequence to a part of calnexin, an ER membrane=20
chaperone . The Ca storage and chaperone functions of=20
calreticulin are consistent with both the ER localization of=20
calreticulin and its structure. Stable overexpression of=20
calreticulin increases both cell-substratum and cell-cell=20
adhesiveness with concomitant upregulation of=20
adhesion-specific cytoskeletal protein, vinculin . =20
Upregulation of calreticulin also affects adhesion-dependent=20
phenomena such as cell motility (which decreases) and cell=20
spreading (which increases). Downregulation of calreticulin=20
brings about inverse effects. In addition to the Ca=20
storage and chaperone function, calreticulin modulates gene=20
expression [24,25]. In vitro, calreticulin interaction with=20
the DNA binding domain of the glucocorticoid receptor=20
prevents the receptor from interacting with its=20
glucocorticoid response element . Transcriptional=20
activation by glucocorticoid and androgen receptors in vivo=20
is inhibited in cells overexpressing full length=20
calreticulin [24,25]. Calreticulin itself is=20
stress-regulated by heat and heavy metals [26-28]. =20
Calreticulin has antithrombotic activity . A host of=20
other putative calreticulin functions includes a role in=20
autoimmune diseases [30-34]. The protein affects=20
replication of the Rubella virus RNA [35,36]. In cytolytic=20
T lymphocytes it is found in the lytic granules where it may=20
play a role in killing of target cells . In human=20
neutrophils calreticulin may contribute to the process of=20
phagocytosis . In line with the reported functional=20
diversity, calreticulin was reported to be present in most=20
cellular compartments [10,11,37,39,40], including the outer=20
cell surface [41,42]. Recent hypotheses regarding=20
calreticulin function have been presented by Krause and=20
1. Ostwald TJ, MacLennan DH: Isolation of a high affinity=20
calcium binding protein from sarcoplasmic reticulum. J Biol=20
Chem 1974, 249:974-979.
2. Baksh S, Michalak M: Expression of calreticulin in=20
Escherichia coli and identification of its Ca2+ binding=20
domains. J Biol Chem 1991, 266:21458-21465.
3. Fliegel L, Burns K, Opas M, Michalak M: The=20
high-affinity calcium binding protein of sarcoplasmic=20
reticulum. Tissue distribution, and homology with=20
calregulin. Biochim Biophys Acta 1989, 982:1-8.
4. Opas M, Dziak E, Fliegel L, Michalak M: Regulation of=20
expression and intracellular distribution of calreticulin, a=20
major calcium binding protein of nonmuscle cells. J Cell=20
Physiol 1991, 149:160-171.
5. Milner RE, Baksh S, Shemanko C, Carpenter MR, Smillie L,=20
Vance JE, Opas M, Michalak M: Calreticulin, and not=20
calsequestrin, is the major calcium binding protein of=20
smooth muscle sarcoplasmic reticulum and liver endoplasmic=20
reticulum. J Biol Chem 1991, 266:7155-7165.
6. Michalak M, Baksh S, Opas M: Identification and=20
immunolocalization of calreticulin in pancreatic cells: no=20
evidence for "calciosomes". Exp Cell Res 1991, 197:91-99.
7. Michalak M, Milner RE, Burns K, Opas M: Calreticulin.=20
Biochem J 1992, 285:681-692.
8. Coppolino MG, Woodside MJ, Demaurex N, Grinstein S,=20
St-Arnaud R, Dedhar S: Calreticulin is essential for=20
integrin-mediated calcium signalling and cell adhesion.=20
Nature 1997, 386:843-847.
9. Tharin S, Dziak E, Michalak M, Opas M: Widespread tissue=20
distribution of rabbit calreticulin, a non-muscle functional=20
analogue of calsequestrin. Cell Tissue Res 1992, 269:29-37.
10. Opas M: The intracellular distribution and expression=20
of calreticulin. In Calreticulin, edited by Michalak M.=20
Georgetown: R.G. Landes; 1996:31-41.
11. Koch GLE: The endoplasmic reticulum and calcium=20
storage. BioEssays 1990, 12:527-531.
12. Fliegel L, Burns K, MacLennan DH, Reithmeier RAF,=20
Michalak M: Molecular cloning of the high affinity=20
calcium-binding protein (calreticulin) of skeletal muscle=20
sarcoplasmic reticulum. J Biol Chem 1989, 264:21522-21528.
13. Pelham HRB: Control of protein exit from the=20
endoplasmic reticulum. Annu Rev Cell Biol 1989, 5:1-23.
14. S=F6nnichsen B, F=FCllekrug J, Van PN, Diekmann W, Robinson=20
DG, Mieskes G: Retention and retrieval: Both mechanisms=20
cooperate to maintain calreticulin in the endoplasmic=20
reticulum. J Cell Sci 1994, 107:2705-2717.
15. Bastianutto C, Clementi E, Codazzi F, Podini P, De=20
Giorgi F, Rizzuto R, Meldolesi J, Pozzan T: Overexpression=20
of calreticulin increases the Ca2+ capacity of rapidly=20
exchanging Ca2+ stores and reveals aspects of their lumenal=20
microenvironment and function. J Cell Biol 1995,=20
16. Liu N, Fine RE, Simons E, Johnson RJ: Decreasing=20
calreticulin expression lowers the Ca2+ response to=20
bradykinin and increases sensitivity to ionomycin in=20
NG-108-15 cells. J Biol Chem 1994, 269:28635-28639.
17. Nauseef WM, McCormick SJ, Clark RA: Calreticulin=20
functions as a molecular chaperone in the biosynthesis of=20
myeloperoxidase. J Biol Chem 1995, 270:4741-4747.
18. Wada I, Imai S, Kai M, Sakane F, Kanoh H: Chaperone=20
function of calreticulin when expressed in the endoplasmic=20
reticulum as the membrane-anchored and soluble forms. J Biol=20
Chem 1995, 270:20298-20304.
19. Nigam SK, Goldberg AL, Ho S, Rhode MF, Bush KT, Sherman=20
MY: A set of endoplasmic reticulum proteins possessing=20
properties of molecular chaperones includes Ca2+-binding=20
proteins and members of the thioredoxin superfamily. J Biol=20
Chem 1994, 269:1744-1749.
20. Otteken A, Moss B: Calreticulin interacts with newly=20
synthesized human immunodeficiency virus type 1 envelope=20
glycoprotein, suggesting a chaperone function similar to=20
that of calnexin. J Biol Chem 1996, 271:97-103.
21. Hebert DN, Foellmer B, Helenius A: Calnexin and=20
calreticulin promote folding, delay oligomerization and=20
suppress degradation of influenza hemagglutinin in=20
microsomes. EMBO J 1996, 15:2961-2968.
22. Bergeron JJM, Brenner MB, Thomas DY, Williams DB:=20
Calnexin: a membrane-bound chaperone of the endoplasmic=20
reticulum. Trends Biochem Sci 1994, 19:124-128.
23. Opas M, Szewczenko-Pawlikowski M, Jass GK, Mesaeli N,=20
Michalak M: Calreticulin modulates cell adhesiveness via=20
regulation of vinculin expression. J Cell Biol 1996,=20
24. Burns K, Duggan B, Atkinson EA, Famulski KS, Nemer M,=20
Bleackley RC, Michalak M: Modulation of gene expression by=20
calreticulin binding to the glucocorticoid receptor. Nature=20
25. Dedhar S, Rennie PS, Shago M, Leung-Hagesteijn C-Y,=20
Yang H, Filmus J, Hawley RG, Bruchovsky N, Cheng H, Matusik=20
RJ, Gigu=E8re V: Inhibition of nuclear hormone receptor=20
activity by calreticulin. Nature 1994, 367:480-483.
26. Nguyen TQ, Capra JD, Sontheimer RD: Calreticulin is=20
transcriptionally upregulated by heat shock, calcium and=20
heavy metals. Mol Immunol 1996, 33:379-386.
27. Dreher D, Vargas JR, Hochstrasser DF, Junod AF: Effects=20
of oxidative stress and Ca2+ agonists on molecular=20
chaperones in human umbilical vein endothelial cells.=20
Electrophoresis 1995, 16:1205-1214.
28. Conway EM, Liu L, Nowakowski B, Steiner-Mosonyi M,=20
Ribeiro SP, Michalak M: Heat shock-sensitive expression of=20
calreticulin. In vitro and in vivo up-regulation. J Biol=20
Chem 1995, 270:17011-17016.
29. Kuwabara K, Pinsky DJ, Schmidt AM, Benedict C, Brett J,=20
Ogawa S, Broekman MJ, Marcus AJ, Sciacca RR, Michalak M,=20
Wang F, Pan YC, Grunfeld S, Patton S, Malinski T, Stern DM,=20
Ryan J: Calreticulin, an antithrombotic agent which binds to=20
vitamin K-dependent coagulation factors, stimulates=20
endothelial nitric oxide production, and limits thrombosis=20
in canine coronary arteries. J Biol Chem 1995,=20
30. Karska K, Tuckova L, Steiner L, Tlaskalova-Hogenova H,=20
Michalak M: Calreticulin--the potential autoantigen in=20
celiac disease. Biochem Biophys Res Commun 1995,=20
31. Boehm J, Orth T, Van Nguyen P, S=F6ling H-D: Systemic=20
lupus erythematosus is associated with increased=20
auto-antibody titers against calreticulin and grp94, but=20
calreticulin is not the Ro/SS-A antigen. Eur J Clin Invest=20
32. Zhu J, Newkirk MM: Viral induction of the human=20
autoantigen calreticulin. Clin Invest Med 1994, 17:196-205.
33. Ben-Chetrit E: The molecular basis of the SSA/Ro=20
antigens and the clinical significance of their=20
autoantibodies. Br J Rheumatol 1993, 32:396-402.
34. McCauliffe DP, Sontheimer RD: Molecular=20
characterization of the Ro/SS-A autoantigens. J Invest=20
Dermatol 1993, 100:73S-79S.
35. Atreya CD, Singh NK, Nakhasi HL: The rubella virus RNA=20
binding activity of human calreticulin is localized to the=20
N-terminal domain. J Virol 1995, 69:3848-3851.
36. Singh NK, Atreya CD, Nakhasi HL: Identification of=20
calreticulin as a rubella virus RNA binding protein. Proc=20
Natl Acad Sci USA 1994, 91:12770-12774.
37. Dupuis M, Schaerer E, Krause K-H, Tschopp J: The=20
calcium-binding protein calreticulin is a major constituent=20
of lytic granules in cytolytic T lymphocytes. J Exp Med=20
38. Stendahl O, Krause K-H, Krischer J, Jerstrom P, Theler=20
JM, Clark RA, Carpentier JL, Lew DP: Redistribution of=20
intracellular Ca2+ stores during phagocytosis in human=20
neutrophils. Science 1994, 265:1439-1441.
39. Nakamura M, Moriya M, Baba T, Michikawa Y, Yamanobe T,=20
Arai K, Okinaga S, Kobayashi T: An endoplasmic reticulum=20
protein, calreticulin, is transported into the acrosome of=20
rat sperm. Exp Cell Res 1993, 205:101-110.
40. Dedhar S: Novel functions for calreticulin: =20
Interaction with integrins and modulation of gene=20
expression. Trends Biochem Sci 1994, 19:269-271.
41. White TK, Zhu Q, Tanzer ML: Cell surface calreticulin=20
is a putative mannoside lectin which triggers mouse melanoma=20
cell spreading. J Biol Chem 1995, 270:15926-15929.
42. Gray AJ, Park PW, Broekelmann TJ, Laurent GJ, Reeves=20
JT, Stenmark KR, Mecham RP: The mitogenic effects of the B =20
chain of fibrinogen are mediated through cell surface=20
calreticulin. J Biol Chem 1995, 270:26602-26606.
43. Krause K-H, Michalak M: Calreticulin. Cell 1997,=20
Dr. Michal Opas
Department of Anatomy & Cell Biology
University of Toronto
1 King's College Circle
Medical Sciences Building
Toronto, Ontario, M5S 1A8 Canada
phone: (416) 978-8947
fax: (416) 978-3954
e-mail: m.opas at utoronto.ca
www homepage: http://www.utoronto.ca/anatomy/opas/start.htm=20