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Gene Review

HSP90B1  -  heat shock protein 90kDa beta (Grp94),...

Homo sapiens

Synonyms: 94 kDa glucose-regulated protein, ECGP, Endoplasmin, GP96, GRP-94, ...
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Disease relevance of HSP90B1


Psychiatry related information on HSP90B1

  • Our previous studies have demonstrated that a small number of genes exhibit increased expression in the cerebral cortex of the mouse and rat during recovery sleep after sleep deprivation: egr-3, fra-2, grp78, grp94, ngfi-b, and nr4a3 [6].

High impact information on HSP90B1


Chemical compound and disease context of HSP90B1


Biological context of HSP90B1

  • In vivo, inhibitors of caspases able to block etoposide-induced apoptosis can only partially protect GRP94 from proteolytic cleavage, whereas complete inhibition is observed with calpain inhibitor I but not with the proteasome inhibitor [12].
  • We further showed that reduction of GRP94 by antisense decreased cell viability in etoposide-treated Jurkat cells [12].
  • We report here that during apoptosis induced by the topoisomerase II inhibitor etoposide, a fraction of GRP94 associated with the endoplasmic reticulum membrane undergoes specific proteolytic cleavage, coinciding with the activation of the caspase CPP32 and initiation of DNA fragmentation [12].
  • The 94-kinase can be recovered from ER membrane fractions and is able to phosphorylate both the constitutive and stress-induced forms of GRP94, correlating with their induction kinetics [13].
  • Surface plasmon resonance analysis shows that the carboxy-terminal domain of Grp94 (Grp94-CT, residues 518-803) physically interacts with the catalytic subunit of protein kinase CK2 (CK2 alpha) under non-stressed conditions [14].

Anatomical context of HSP90B1

  • The endoplasmic reticulum chaperone glycoprotein GRP94 with Ca(2+)-binding and antiapoptotic properties is a novel proteolytic target of calpain during etoposide-induced apoptosis [12].
  • Together with the finding that GRP94 was found associated with sialylated apoB, we conclude that correct folding of apoB is dependent on the assistance of molecular chaperone, which play multiple roles in its maturation throughout the secretory pathway including distal compartments such as the trans-Golgi network [15].
  • Here we report that a 3- to 5-fold increase in the basal level of the GRP94 protein was observed in all five breast carcinoma cell lines examined [2].
  • In carcinoma cells deprived of glucose, mimicking the conditions in poorly vascularized solid tumors, up to 9-fold induction of GRP94 was observed relative to the basal level expressed in a normal breast epithelial cell line [2].
  • In contrast, aberrant activation of NFAT and ectopic expression of potential immunogenic proteins (tumor rejection antigen 1 and poliovirus receptor related protein 1) were found in the UC-diseased colon mucosa [16].

Associations of HSP90B1 with chemical compounds

  • GRP94 is a 94-kDa chaperone glycoprotein with Ca(2+)-binding properties [12].
  • In this report we show that highly purified GRP94 exhibits an active Mg2+-dependent serine kinase activity (termed 94-kinase) [13].
  • Regarding the colloidal insoluble multimerized Tg (m-Tg), which bears dityrosine bridges and is present in the follicular lumen, a mild oxidative system generated different soluble forms of Tg, more or less compacted by hydrophobic associations, and linked with Grp78 and Grp94 [17].
  • We found that valinomycin prevents UPR-induced protein expression, such as GRP78 and GRP94 [18].
  • Expression of GRP94 was found to be increased and HSP27 lowered by the highest concentrations of bifenthrin commercial formulations [19].

Physical interactions of HSP90B1

  • Membrane-associated p185erbB2 exists in a stable complex with GRP94 [20].
  • Competition experiments of HIF-1 DNA binding using specific probes containing each HRE sequence of the GRP94 promoter clearly evidenced that HIF-1 binds these sequences with high affinity [5].
  • Our results demonstrate that GRP94 interacts with FAC both in vitro and in vivo and regulates its intracellular level in a cell culture model [21].
  • However, the C-terminal 326 amino acids of GRP94 failed to form a complex with HSP90 alpha [22].

Co-localisations of HSP90B1


Regulatory relationships of HSP90B1

  • Decreased protein and mRNA expression of ER stress proteins GRP78 and GRP94 in HepG2 cells over-expressing CYP2E1 [24].
  • AIM: To investigate the expression and significance of heat shock protein 70 (HSP70) and glucose-regulated protein 94 (grp94) in human esophageal carcinoma and adjacent normal tissues [25].
  • In order explore possible consequences of GRP94 binding, we have studied recombinant nonmutant thyroglobulin expressed in control Chinese hamster ovary (CHO) cells in comparison to that produced in CHO cells genetically manipulated for selectively increased GRP94 expression [26].

Other interactions of HSP90B1

  • This sequence is homologous with previously determined regulatory sequences of the human GRP78 and GRP94 promoters [27].
  • The 5'-flanking region of the human calreticulin gene shares homology with the human GRP78, GRP94, and protein disulfide isomerase promoters [27].
  • In vitro, GRP94 is not a substrate for CPP32; rather, it can be completely cleaved by calpain, a Ca(2+)-regulated protease [12].
  • GA binding to GRP94 disrupts this complex, leading to degradation of pre-existing p185erbB2 protein, and resulting in an altered subcellular distribution of newly synthesized p185erbB2 [20].
  • There is no relationship between expression of HSP70, grp94 and cell cycle [28].

Analytical, diagnostic and therapeutic context of HSP90B1


  1. Activation of the grp78 and grp94 promoters by hepatitis C virus E2 envelope protein. Liberman, E., Fong, Y.L., Selby, M.J., Choo, Q.L., Cousens, L., Houghton, M., Yen, T.S. J. Virol. (1999) [Pubmed]
  2. De-regulation of GRP stress protein expression in human breast cancer cell lines. Gazit, G., Lu, J., Lee, A.S. Breast Cancer Res. Treat. (1999) [Pubmed]
  3. Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs. Jones, D.T., Addison, E., North, J.M., Lowdell, M.W., Hoffbrand, A.V., Mehta, A.B., Ganeshaguru, K., Folarin, N.I., Wickremasinghe, R.G. Blood (2004) [Pubmed]
  4. Cloning and expression of the Escherichia coli K1 outer membrane protein A receptor, a gp96 homologue. Prasadarao, N.V., Srivastava, P.K., Rudrabhatla, R.S., Kim, K.S., Huang, S.H., Sukumaran, S.K. Infect. Immun. (2003) [Pubmed]
  5. Up-regulation of 94-kDa glucose-regulated protein by hypoxia-inducible factor-1 in human endothelial cells in response to hypoxia. Paris, S., Denis, H., Delaive, E., Dieu, M., Dumont, V., Ninane, N., Raes, M., Michiels, C. FEBS Lett. (2005) [Pubmed]
  6. Gene expression in the rat cerebral cortex: comparison of recovery sleep and hypnotic-induced sleep. Wisor, J.P., Morairty, S.R., Huynh, N.T., Steininger, T.L., Kilduff, T.S. Neuroscience (2006) [Pubmed]
  7. Sequential interaction of the chaperones BiP and GRP94 with immunoglobulin chains in the endoplasmic reticulum. Melnick, J., Dul, J.L., Argon, Y. Nature (1994) [Pubmed]
  8. HLA-DR associates with specific stress proteins and is retained in the endoplasmic reticulum in invariant chain negative cells. Schaiff, W.T., Hruska, K.A., McCourt, D.W., Green, M., Schwartz, B.D. J. Exp. Med. (1992) [Pubmed]
  9. Biochemical, cell biological and immunological issues surrounding the endoplasmic reticulum chaperone GRP94/gp96. Nicchitta, C.V. Curr. Opin. Immunol. (1998) [Pubmed]
  10. Scavenger receptor-A mediates gp96/GRP94 and calreticulin internalization by antigen-presenting cells. Berwin, B., Hart, J.P., Rice, S., Gass, C., Pizzo, S.V., Post, S.R., Nicchitta, C.V. EMBO J. (2003) [Pubmed]
  11. GRP94 reduces cell death in SH-SY5Y cells perturbated calcium homeostasis. Bando, Y., Katayama, T., Aleshin, A.N., Manabe, T., Tohyama, M. Apoptosis (2004) [Pubmed]
  12. The endoplasmic reticulum chaperone glycoprotein GRP94 with Ca(2+)-binding and antiapoptotic properties is a novel proteolytic target of calpain during etoposide-induced apoptosis. Reddy, R.K., Lu, J., Lee, A.S. J. Biol. Chem. (1999) [Pubmed]
  13. Endoplasmic reticulum stress-inducible protein GRP94 is associated with an Mg2+-dependent serine kinase activity modulated by Ca2+ and GRP78/BiP. Ramakrishnan, M., Schönthal, A.H., Lee, A.S. J. Cell. Physiol. (1997) [Pubmed]
  14. The carboxy-terminal domain of Grp94 binds to protein kinase CK2 alpha but not to CK2 holoenzyme. Roher, N., Sarno, S., Miró, F., Ruzzene, M., Llorens, F., Meggio, F., Itarte, E., Pinna, L.A., Plana, M. FEBS Lett. (2001) [Pubmed]
  15. Nascent lipidated apolipoprotein B is transported to the Golgi as an incompletely folded intermediate as probed by its association with network of endoplasmic reticulum molecular chaperones, GRP94, ERp72, BiP, calreticulin, and cyclophilin B. Zhang, J., Herscovitz, H. J. Biol. Chem. (2003) [Pubmed]
  16. Comparative proteomic studies on the pathogenesis of human ulcerative colitis. Hsieh, S.Y., Shih, T.C., Yeh, C.Y., Lin, C.J., Chou, Y.Y., Lee, Y.S. Proteomics (2006) [Pubmed]
  17. Involvement of oxidative reactions and extracellular protein chaperones in the rescue of misassembled thyroglobulin in the follicular lumen. Delom, F., Lejeune, P.J., Vinet, L., Carayon, P., Mallet, B. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  18. Selective cytotoxic activity of valinomycin against HT-29 Human colon carcinoma cells via down-regulation of GRP78. Ryoo, I.J., Park, H.R., Choo, S.J., Hwang, J.H., Park, Y.M., Bae, K.H., Shin-Ya, K., Yoo, I.D. Biol. Pharm. Bull. (2006) [Pubmed]
  19. Relationship between toxicity of selected insecticides and expression of stress proteins (HSP, GRP) in cultured human cells: Effects of commercial formulations versus pure active molecules. Skandrani, D., Gaubin, Y., Vincent, C., Beau, B., Claude Murat, J., Soleilhavoup, J.P., Croute, F. Biochim. Biophys. Acta (2006) [Pubmed]
  20. p185erbB2 binds to GRP94 in vivo. Dissociation of the p185erbB2/GRP94 heterocomplex by benzoquinone ansamycins precedes depletion of p185erbB2. Chavany, C., Mimnaugh, E., Miller, P., Bitton, R., Nguyen, P., Trepel, J., Whitesell, L., Schnur, R., Moyer, J., Neckers, L. J. Biol. Chem. (1996) [Pubmed]
  21. Molecular chaperone GRP94 binds to the Fanconi anemia group C protein and regulates its intracellular expression. Hoshino, T., Wang, J., Devetten, M.P., Iwata, N., Kajigaya, S., Wise, R.J., Liu, J.M., Youssoufian, H. Blood (1998) [Pubmed]
  22. Dimerization characteristics of the 94-kDa glucose-regulated protein. Nemoto, T., Matsusaka, T., Ota, M., Takagi, T., Collinge, D.B., Walther-Larsen, H. J. Biochem. (1996) [Pubmed]
  23. BAP, a mammalian BiP-associated protein, is a nucleotide exchange factor that regulates the ATPase activity of BiP. Chung, K.T., Shen, Y., Hendershot, L.M. J. Biol. Chem. (2002) [Pubmed]
  24. Decreased protein and mRNA expression of ER stress proteins GRP78 and GRP94 in HepG2 cells over-expressing CYP2E1. Dey, A., Kessova, I.G., Cederbaum, A.I. Arch. Biochem. Biophys. (2006) [Pubmed]
  25. Expression and significance of heat shock protein 70 and glucose-regulated protein 94 in human esophageal carcinoma. Wang, X.P., Liu, G.Z., Song, A.L., Chen, R.F., Li, H.Y., Liu, Y. World J. Gastroenterol. (2005) [Pubmed]
  26. Thyroglobulin transport along the secretory pathway. Investigation of the role of molecular chaperone, GRP94, in protein export from the endoplasmic reticulum. Muresan, Z., Arvan, P. J. Biol. Chem. (1997) [Pubmed]
  27. The 5'-flanking region of the human calreticulin gene shares homology with the human GRP78, GRP94, and protein disulfide isomerase promoters. McCauliffe, D.P., Yang, Y.S., Wilson, J., Sontheimer, R.D., Capra, J.D. J. Biol. Chem. (1992) [Pubmed]
  28. Co-expression of heat shock protein 70 and glucose-regulated protein 94 in human gastric carcinoma cell line BGC-823. Wang, X.P., Liao, J., Liu, G.Z., Wang, X.C., Shang, H.W. World J. Gastroenterol. (2005) [Pubmed]
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