Skip to main content

HSPA5

  • Reference work entry
  • First Online:

Synonyms

78 kDa glucose-regulated protein; Binding immunoglobulin protein; BiP; GRP78; Heat shock protein family A member 5

Historical Background

HSPA5 gene encodes heat shock protein family A member 5 protein commonly known as GRP78 (glucose-regulated protein 78) or BiP (binding immunoglobulin protein) (“GRP78” will be used to refer to the protein throughout the remainder of this text for simplicity). It is an ER-resident molecular chaperone that belongs to the Hsp70 family of proteins.

GRP78 is ubiquitously expressed in mammalian cells, and, structurally, it is highly conserved across species. The cDNA clones encoding GRP78 were isolated in 1981 from the hamster mutant cell line k12 (Lee 1981). The gene locus was mapped to chromosome 9 in human-hamster somatic cell hybrids using a cross-reactive hamster cDNA probe (Law et al. 1984). In 1988, two different types of human GRP78 genes (functional and processed gene) were isolated after screening of a human genomic library with a...

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   4,499.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   4,499.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Arndt V, Rogon C, Hohfeld J. To be, or not to be – molecular chaperones in protein degradation. Cell Mol Life Sci. 2007;64:2525–41. doi:10.1007/s00018-007-7188-6.

    Article  PubMed  CAS  Google Scholar 

  • Behnke J, Feige MJ, Hendershot LM. BiP and its nucleotide exchange factors Grp170 and Sil1: mechanisms of action and biological functions. J Mol Biol. 2015;427:1589–608. doi:10.1016/j.jmb.2015.02.011.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bellucci A, Navarria L, Zaltieri M, Falarti E, Bodei S, Sigala S, et al. Induction of the unfolded protein response by alpha-synuclein in experimental models of Parkinson’s disease. J Neurochem. 2011;116:588–605. doi:10.1111/j.1471-4159.2010.07143.x.

    Article  PubMed  CAS  Google Scholar 

  • Bertelsen EB, Chang L, Gestwicki JE, Zuiderweg ER. Solution conformation of wild-type E. coli Hsp70 (DnaK) chaperone complexed with ADP and substrate. Proc Natl Acad Sci U S A. 2009;106:8471–6.

    Article  PubMed  PubMed Central  Google Scholar 

  • Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol. 2000;2:326–32. doi:10.1038/35014014.

    Article  PubMed  CAS  Google Scholar 

  • Blau M, Mullapudi S, Becker T, Dudek J, Zimmermann R, Penczek PA, et al. ERj1p uses a universal ribosomal adaptor site to coordinate the 80S ribosome at the membrane. Nat Struct Mol Biol. 2005;12:1015–6. doi:10.1038/nsmb998.

    Article  PubMed  CAS  Google Scholar 

  • Bole DG, Hendershot LM, Kearney JF. Posttranslational association of immunoglobulin heavy chain binding protein with nascent heavy chains in nonsecreting and secreting hybridomas. J Cell Biol. 1986;102:1558–66. doi:10.1083/jcb.102.5.1558.

    Article  PubMed  CAS  Google Scholar 

  • Brodsky JL, Goeckeler J, Schekman R. BiP and Sec63p are required for both co- and posttranslational protein translocation into the yeast endoplasmic reticulum. Proc Natl Acad Sci U S A. 1995;92:9643–6. doi:10.1073/pnas.92.21.9643.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Burikhanov R, Zhao YM, Goswami A, Qiu S, Schwarze SR, Rangnekar VM. The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis. Cell. 2009;138:377–88. doi:10.1016/j.cell.2009.05.022.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cao XJ, Zhou YH, Lee AS. Requirement of tyrosine- and serine/threonine kinases in the transcriptional activation of the mammalian grp78/BiP promoter by thapsigargin. J Biol Chem. 1995;270:494–502.

    Article  PubMed  CAS  Google Scholar 

  • Carla Famá M, Raden D, Zacchi N, Lemos DR, Robinson AS, Silberstein S. The Saccharomyces cerevisiae YFR041C/ERJ5 gene encoding a type I membrane protein with a J domain is required to preserve the folding capacity of the endoplasmic reticulum. Biochim Biophys Acta. 2007;1773:232–42. doi:10.1016/j.bbamcr.2006.10.011.

    Article  PubMed  CAS  Google Scholar 

  • Cerezo M, Lehraiki A, Millet A, Rouaud F, Plaisant M, Jaune E, et al. Compounds triggering ER stress exert anti-melanoma effects and overcome BRAF inhibitor resistance. Cancer Cell. 2016;29:805–19. doi:10.1016/j.ccell.2016.04.013.

    Article  PubMed  CAS  Google Scholar 

  • Chang L, Bertelsen EB, Wisen S, Larsen EM, Zuiderweg ER, Gestwicki JE. High-throughput screen for small molecules that modulate the ATPase activity of the molecular chaperone DnaK. Anal Biochem. 2008;372:167–76. doi:10.1016/j.ab.2007.08.020. S0003-2697(07)00541-6 [pii].

    Article  PubMed  CAS  Google Scholar 

  • Craven RA, Egerton M, Stirling CJ. A novel Hsp70 of the yeast ER lumen is required for the efficient translocation of a number of protein precursors. EMBO J. 1996;15:2640–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Davidson DJ, Haskell C, Majest S, Kherzai A, Egan DA, Walter KA, et al. Kringle 5 of human plasminogen induces apoptosis of endothelial and tumor cells through surface-expressed glucose-regulated protein 78. Cancer Res. 2005;65:4663–72. doi:10.1158/0008-5472.can-04-3426.

    Article  PubMed  CAS  Google Scholar 

  • Deng WG, Ruan KH, Du M, Saunders MA, Wu KK. Aspirin and salicylate bind to immunoglobulin heavy chain binding protein (BiP) and inhibit its ATPase activity in human fibroblasts. FASEB J. 2001;15:2463–70. doi:10.1096/fj.01-0259com.

    Article  PubMed  CAS  Google Scholar 

  • Dong D, Ni M, Li J, Xiong S, Ye W, Virrey JJ, et al. Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. Cancer Res. 2008;68:498–505. doi:10.1158/0008-5472.can-07-2950.

    Article  PubMed  CAS  Google Scholar 

  • Dong DZ, Stapleton C, Luo BQ, Xiong SG, Ye W, Zhang Y, et al. A critical role for GRP78/BiP in the tumor microenvironment for neovascularization during tumor growth and metastasis. Cancer Res. 2011;71:2848–57. doi:10.1158/0008-5472.can-10-3151.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dorner AJ, Bole DG, Kaufman RJ. The relationship of N-linked glycosylation and heavy chain-binding protein association with the secretion of glycoproteins. J Cell Biol. 1987;105:2665–74. doi:10.1083/jcb.105.6.2665.

    Article  PubMed  CAS  Google Scholar 

  • Dudek J, Volkmer J, Bies C, Guth S, Muller A, Lerner M, et al. A novel type of co-chaperone mediates transmembrane recruitment of DnaK-like chaperones to ribosomes. EMBO J. 2002;21:2958–67. doi:10.1093/emboj/cdf315.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dudek J, Greiner M, Müller A, Hendershot LM, Kopsch K, Nastainczyk W, et al. ERj1p has a basic role in protein biogenesis at the endoplasmic reticulum. Nat Struct Mol Biol. 2005;12:1008–14. doi:10.1038/nsmb1007.

    Article  PubMed  CAS  Google Scholar 

  • Dudek J, Pfeffer S, Lee P-H, Jung M, Cavalie A, Helms V, et al. Protein transport into the human endoplasmic reticulum. J Mol Biol. 2015;427:1159–75. doi:10.1016/j.jmb.2014.06.011.

    Article  PubMed  CAS  Google Scholar 

  • Ermakova SP, Kang BS, Choi BY, Choi HS, Schuster TF, Ma WY, et al. (-)-epigallocatechin gallate overcomes resistance to etoposide-induced cell death by targeting the molecular chaperone glucose-regulated protein 78. Cancer Res. 2006;66:9260–9. doi:10.1158/0008-5472.can-06-1586.

    Article  PubMed  CAS  Google Scholar 

  • Fu Y, Lee AS. Glucose regulated proteins in cancer progression, drug resistance and immunotherapy. Cancer Biol Ther. 2006;5:741–4.

    Article  PubMed  CAS  Google Scholar 

  • Fu R, Yang P, HL W, Li ZW, Li ZY. GRP78 secreted by colon cancer cells facilitates cell proliferation via PI3K/Akt signaling. Asian Pac J Cancer Prev. 2014;15:7245–9.

    Article  PubMed  Google Scholar 

  • Gardner BM, Pincus D, Gotthardt K, Gallagher CM, Walter P. Endoplasmic reticulum stress sensing in the unfolded protein response. Cold Spring Harb Perspect Biol. 2013;5:a013169. doi:10.1101/cshperspect.a013169.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gething MJ. Role and regulation of the ER chaperone BiP. Semin Cell Dev Biol. 1999;10:465–72. doi:10.1006/scdb.1999.0318.

    Article  PubMed  CAS  Google Scholar 

  • Gething MJ, Sambrook J. Protein folding in cell. Nature. 1992;355:33–45. doi:10.1038/355033a0.

    Article  PubMed  CAS  Google Scholar 

  • Gething MJ, McCammon K, Sambrook J. Expression of wild-type and mutant forms of influenza hemagglutinin: the role of folding in intracellular transport. Cell. 1986;46:939–50. doi:10.1016/0092-8674(86)90076-0.

    Article  PubMed  CAS  Google Scholar 

  • Giaever G, Chu AM, Ni L, Connelly C, Riles L, Véronneau S, et al. Functional profiling of the Saccharomyces cerevisiae genome. Nature. 2002;418:387–91. doi:10.1038/nature00935.

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez-Gronow M, Selim MA, Papalas J, Pizzo SV. GRP78: a multifunctional receptor on the cell surface. Antioxid Redox Signal. 2009;11:2299–306. doi:10.1089/ars.2009.2568.

    Article  PubMed  CAS  Google Scholar 

  • Gorbatyuk MS, Shabashvili A, Chen WJ, Meyers C, Sullivan LF, Salganik M, et al. Glucose regulated protein 78 diminishes alpha-synuclein neurotoxicity in a rat model of Parkinson disease. Mol Ther. 2012;20:1327–37. doi:10.1038/mt.2012.28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99. doi:10.1016/j.cell.2010.01.025.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Haas IG, Wabl M. Immunoglobulin heavy-chain binding-protein. Nature. 1983;306:387–9. doi:10.1038/306387a0.

    Article  PubMed  CAS  Google Scholar 

  • Hamilton TG, Flynn GC. Cer1p, a novel Hsp70-related protein required for posttranslational endoplasmic reticulum translocation in yeast. J Biol Chem. 1996;271:30610–3.

    Article  PubMed  CAS  Google Scholar 

  • Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74. doi:10.1016/j.cell.2011.02.013.

    Article  PubMed  CAS  Google Scholar 

  • Haze K, Yoshida H, Yanagi H, Yura T, Mori K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell. 1999;10:3787–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Heath-Engel HM, Chang NC, Shore GC. The endoplasmic reticulum in apoptosis and autophagy: role of the BCL-2 protein family. Oncogene. 2008;27:6419–33.

    Article  PubMed  CAS  Google Scholar 

  • Hendershot LM, Ting J, Lee AS. Identity of the immunoglobulin heavy-chain-binding protein with the 78,000-dalton glucose-regulated protein and the role of posttranslational modifications in its binding function. Mol Cell Biol. 1988;8:4250–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hendershot LM, Valentine VA, Lee AS, Morris SW, Shapiro DN. Localization of the gene encoding human BiP/GRP78, the endoplasmic reticulum cognate of the HSP70 family, to chromosome 9q34. Genomics. 1994;20:281–4. doi:10.1006/geno.1994.1166.

    Article  PubMed  CAS  Google Scholar 

  • Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012;13:89–102. doi:10.1038/nrm3270.

    Article  PubMed  CAS  Google Scholar 

  • Hetz C, Glimcher LH. Fine-tuning of the unfolded protein response: assembling the IRE1α interactome. Mol Cell. 2009;35:551–61. doi:10.1016/j.molcel.2009.08.021.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hoozemans JJM, Veerhuis R, Van Haastert ES, Rozemuller JM, Baas F, Eikelenboom P, et al. The unfolded protein response is activated in Alzheimer’s disease. Acta Neuropathol. 2005;110:165–72. doi:10.1007/s00401-005-1038-0.

    Article  PubMed  CAS  Google Scholar 

  • Hughes SJ, Antoshchenko T, Chen Y, Lu H, Pizarro JC, Park HW. Probing the ATP site of GRP78 with nucleotide triphosphate analogs. PLoS One. 2016;11:e0154862. doi:10.1371/journal.pone.0154862.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jamora C, Dennert G, Lee AS. Inhibition of tumor progression by suppression of stress protein GRP78/BiP induction in fibrosarcoma B/C10ME. Proc Natl Acad Sci U S A. 1996;93:7690–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kabani M, Beckerich JM, Gaillardin C. Sls1p stimulates Sec63p-mediated activation of Kar2p in a conformation-dependent manner in the yeast endoplasmic reticulum. Mol Cell Biol. 2000;20:6923–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kang J, Zhao G, Lin T, Tang S, Xu G, Hu S, et al. A peptide derived from phage display library exhibits anti-tumor activity by targeting GRP78 in gastric cancer multidrug resistance cells. Cancer Lett. 2013;339:247–59. doi:10.1016/j.canlet.2013.06.016.

    Article  PubMed  CAS  Google Scholar 

  • Kassenbrock CK, Kelly RB. Interaction of heavy chain binding protein (BiP/GRP78) with adenine nucleotides. EMBO J. 1989;8:1461–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Katanasaka Y, Ishii T, Asai T, Naitou H, Maeda N, Koizumi F, et al. Cancer antineovascular therapy with liposome drug delivery systems targeted to BiP/GRP78. Int J Cancer. 2010;127:2685–98. doi:10.1002/ijc.25276.

    Article  PubMed  CAS  Google Scholar 

  • Kelber JA, Panopoulos AD, Shani G, Booker EC, Belmonte JC, Vale WW, et al. Blockade of Cripto binding to cell surface GRP78 inhibits oncogenic Cripto signaling via MAPK/PI3K and Smad2/3 pathways. Oncogene. 2009;28:2324–36. doi:10.1038/onc.2009.97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kern J, Untergasser G, Zenzmaier C, Sarg B, Gastl G, Gunsilius E, et al. GRP-78 secreted by tumor cells blocks the antiangiogenic activity of bortezomib. Blood. 2009;114:3960–7. doi:10.1182/blood-2009-03-209668.

    Article  PubMed  CAS  Google Scholar 

  • Kim Y, Lillo AM, Steiniger SCJ, Liu Y, Ballatore C, Anichini A, et al. Targeting heat shock proteins on cancer cells: selection, characterization, and cell-penetrating properties of a peptidic GRP78 ligand. Biochemistry. 2006;45:9434–44. doi:10.1021/bi060264j.

    Article  PubMed  CAS  Google Scholar 

  • Kumar S, Stokes J, Singh UP, Gunn KS, Acharya A, Manne U, et al. Targeting Hsp70: a possible therapy for cancer. Cancer Lett. 2016;374:156–66. doi:10.1016/j.canlet.2016.01.056.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lang S, Benedix J, Fedeles SV, Schorr S, Schirra C, Schäuble N, et al. Different effects of Sec61α, Sec62 and Sec63 depletion on transport of polypeptides into the endoplasmic reticulum of mammalian cells. J Cell Sci. 2012;125:1958–69. doi:10.1242/jcs.096727.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Laufen T, Mayer MP, Beisel C, Klostermeier D, Mogk A, Reinstein J, et al. Mechanism of regulation of hsp70 chaperones by DnaJ cochaperones. Proc Natl Acad Sci U S A. 1999;96:5452–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Law ML, Seeliger MB, Lee AS, Kao FT. Genetic mapping of the structural gene coding for a glucose-regulated protein (GRP78) of 78k-dalton to the long arm of human chromosome 9. Cytogenet Cell Genet. 1984;37:518–9.

    Google Scholar 

  • Lee AS. The accumulation of three specific proteins related to glucose-regulated proteins in a temperature-sensitive hamster mutant cell line K12. J Cell Physiol. 1981;106:119–25. doi:10.1002/jcp.1041060113.

    Article  PubMed  CAS  Google Scholar 

  • Lee AS. Coordinated regulation of a set of genes by glucose and calcium ionophores in mammalian cells. Trends Biochem Sci. 1987;12:20–3. doi:10.1016/0968-0004(87)90011-9.

    Article  CAS  Google Scholar 

  • Lee AS. Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential. Nat Rev Cancer. 2014;14:263–76. doi:10.1038/nrc3701.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Li ZW, Li ZY. Glucose regulated protein 78: a critical link between tumor microenvironment and cancer hallmarks. Biochim Et Biophys Acta-Rev Cancer. 2012;1826:13–22. doi:10.1016/j.bbcan.2012.02.001.

    Article  CAS  Google Scholar 

  • Li Z, Zhang L, Zhao Y, Li H, Xiao H, Fu R, et al. Cell-surface GRP78 facilitates colorectal cancer cell migration and invasion. Int J Biochem Cell Biol. 2013;45:987–94. doi:10.1016/j.biocel.2013.02.002.

    Article  PubMed  CAS  Google Scholar 

  • Li Z, Zhuang M, Zhang L, Zheng X, Yang P. Acetylation modification regulates GRP78 secretion in colon cancer cells. Sci Rep. 2016;6:30406. doi:10.1038/srep30406.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lindquist S, Craig EA. The heat-shock proteins. Annu Rev Genet. 1988;22:631–77. doi:10.1146/annurev.ge.22.120188.003215.

    Article  PubMed  CAS  Google Scholar 

  • Luo B, Lee AS. The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies. Oncogene. 2013;32:805–18. doi:10.1038/onc.2012.130.

    Article  PubMed  CAS  Google Scholar 

  • Luo SZ, Mao CH, Lee B, Lee AS. GRP78/BiP is required for cell proliferation and protecting the inner cell mass from apoptosis during early mouse embryonic development. Mol Cell Biol. 2006;26:5688–97. doi:10.1128/mcb.00779-06.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Macias AT, Williamson DS, Allen N, Borgognoni J, Clay A, Daniels Z, et al. Adenosine-derived inhibitors of 78 kDa glucose regulated protein (Grp78) ATPase: insights into isoform selectivity. J Med Chem. 2011;54:4034–41. doi:10.1021/jm101625x.

    Article  PubMed  CAS  Google Scholar 

  • Massey AJ, Williamson DS, Browne H, Murray JB, Dokurno P, Shaw T, et al. A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells. Cancer Chemother Pharmacol. 2010;66:535–45. doi:10.1007/s00280-009-1194-3.

    Article  PubMed  CAS  Google Scholar 

  • Matlack KE, Misselwitz B, Plath K, Rapoport TA. BiP acts as a molecular ratchet during posttranslational transport of prepro-alpha factor across the ER membrane. Cell. 1999;97:553–64.

    Article  PubMed  CAS  Google Scholar 

  • Matsumoto A, Hanawalt PC. Histone H3 and heat shock protein GRP78 are selectively cross-linked to DNA by photoactivated gilvocarcin V in human fibroblasts. Cancer Res. 2000;60:3921–6.

    PubMed  CAS  Google Scholar 

  • Mayer MP, Bukau B. Hsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci. 2005;62:670–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Meyer HA, Grau H, Kraft R, Kostka S, Prehn S, Kalies KU, et al. Mammalian Sec61 is associated with Sec62 and Sec63. J Biol Chem. 2000;275:14550–7.

    Article  PubMed  CAS  Google Scholar 

  • Misra UK, Gonzalez-Gronow M, Gawdi G, Hart JP, Johnson CE, Pizzo SV. The role of Grp 78 in alpha 2-macroglobulin-induced signal transduction. Evidence from RNA interference that the low density lipoprotein receptor-related protein is associated with, but not necessary for, GRP 78-mediated signal transduction. J Biol Chem. 2002;277:42082–7. doi:10.1074/jbc.M206174200.

    Article  PubMed  CAS  Google Scholar 

  • Misra UK, Deedwania R, Pizzo SV. Binding of activated alpha(2)-macroglobulin to its cell surface receptor GRP78 in 1-LN prostate cancer cells regulates PAK-2-dependent activation of LIMK. J Biol Chem. 2005;280:26278–86. doi:10.1074/jbc.M414467200.

    Article  PubMed  CAS  Google Scholar 

  • Morris JA, Dorner AJ, Edwards CA, Hendershot LM, Kaufman RJ. Immunoglobulin binding protein (BiP) function is required to protect cells from endoplasmic reticulum stress but is not required for the secretion of selective proteins. J Biol Chem. 1997;272:4327–34.

    Article  PubMed  CAS  Google Scholar 

  • Munro S, Pelham HR. An Hsp70-like protein in the ER: identity with the 78 kd glucose-regulated protein and immunoglobulin heavy chain binding protein. Cell. 1986;46:291–300.

    Article  PubMed  CAS  Google Scholar 

  • Ni M, Zhou H, Wey S, Baumeister P, Lee AS. Regulation of PERK signaling and leukemic cell survival by a novel cytosolic isoform of the UPR regulator GRP78/BiP. PLoS One. 2009;4:e6868. doi:10.1371/journal.pone.0006868.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ni M, Zhang Y, Lee AS. Beyond the endoplasmic reticulum: atypical GRP78 in cell viability, signalling and therapeutic targeting. Biochem J. 2011;434:181–8. doi:10.1042/bj20101569.

    Article  PubMed  CAS  Google Scholar 

  • Nishikawa S, Brodsky JL, Nakatsukasa K. Roles of molecular chaperones in endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD). J Biochem. 2005;137:551–5. doi:10.1093/jb/mvi068.

    Article  PubMed  CAS  Google Scholar 

  • Nyathi Y, Wilkinson BM, Pool MR. Co-translational targeting and translocation of proteins to the endoplasmic reticulum. Biochim Biophys Acta. 2013;1833:2392–402. doi:10.1016/j.bbamcr.2013.02.021.

    Article  PubMed  CAS  Google Scholar 

  • Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol. 2006;26:9220–31. doi:10.1128/mcb.01453-06.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Oida T, Weiner HL. Overexpression of TGF-ß 1 gene induces cell surface localized glucose-regulated protein 78-associated latency-associated peptide/TGF-ß. J Immunol. 2010;185:3529–35. doi:10.4049/jimmunol.0904121.

    Article  PubMed  CAS  Google Scholar 

  • Otero JH, Lizak B, Hendershot LM. Life and death of a BiP substrate. Semin Cell Dev Biol. 2010;21:472–8. doi:10.1016/j.semcdb.2009.12.008.

    Article  PubMed  CAS  Google Scholar 

  • Panzner S, Dreier L, Hartmann E, Kostka S, Rapoport TA. Posttranslational protein transport in yeast reconstituted with a purified complex of Sec proteins and Kar2p. Cell. 1995;81:561–70.

    Article  PubMed  CAS  Google Scholar 

  • Park HR, Furihata K, Hayakawa Y, Shin-ya K. Versipelostatin, a novel GRP78/Bip molecular chaperone down-regulator of microbial origin. Tetrahedron Lett. 2002;43:6941–5. doi:10.1016/s0040-4039(02)01624-6.

    Article  CAS  Google Scholar 

  • Park HR, Tomida A, Sato S, Tsukumo Y, Yun J, Yamori T, et al. Effect on tumor cells of blocking survival response to glucose deprivation. J Natl Cancer Inst. 2004;96:1300–10. doi:10.1093/jnci/djh243.

    Article  PubMed  CAS  Google Scholar 

  • Paton AW, Beddoe T, Thorpe CM, Whisstock JC, Wilce MCJ, Rossjohn J, et al. AB(5) subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP. Nature. 2006;443:548–52. doi:10.1038/nature05124.

    Article  PubMed  CAS  Google Scholar 

  • Peng Y, Li Z. GRP78 secreted by tumor cells stimulates differentiation of bone marrow mesenchymal stem cells to cancer-associated fibroblasts. Biochem Biophys Res Commun. 2013;440:558–63. doi:10.1016/j.bbrc.2013.09.108.

    Article  PubMed  CAS  Google Scholar 

  • Philippova M, Ivanov D, Joshi MB, Kyriakakis E, Rupp K, Afonyushkin T, et al. Identification of proteins associating with glycosylphosphatidylinositol-anchored T-cadherin on the surface of vascular endothelial cells: Role for Grp78/BiP in T-cadherin-dependent cell survival. Mol Cell Biol. 2008;28:4004–17. doi:10.1128/mcb.00157-08.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Price BD, Mannheimrodman LA, Calderwood SK. Brefeldin A, thapsigargin, and AIF4- stimulate the accumulation of GRP78 mRNA in a cycloheximide dependent manner, whilst induction by hypoxia is independent of protein synthesis. J Cell Physiol. 1992;152:545–52. doi:10.1002/jcp.1041520314.

    Article  PubMed  CAS  Google Scholar 

  • Pyrko P, Schönthal AH, Hofman FM, Chen TC, Lee AS. The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas. Cancer Res. 2007;67:9809–16. doi:10.1158/0008-5472.CAN-07-0625.

    Article  PubMed  CAS  Google Scholar 

  • Rapoport TA. Protein translocation across the eukaryotic endoplasmic reticulum and bacterial plasma membranes. Nature. 2007;450:663–9. doi:10.1038/nature06384.

    Article  PubMed  CAS  Google Scholar 

  • Reddy RK, Mao C, Baumeister P, Austin RC, Kaufman RJ, Lee AS. Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: role of ATP binding site in suppression of caspase-7 activation. J Biol Chem. 2003;278:20915–24. doi:10.1074/jbc.M212328200.

    Article  PubMed  CAS  Google Scholar 

  • Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8:519–29. doi:10.1038/nrm2199.

    Article  PubMed  CAS  Google Scholar 

  • Roussel BD, Kruppa AJ, Miranda E, Crowther DC, Lomas DA, Marciniak SJ. Endoplasmic reticulum dysfunction in neurological disease. Lancet Neurol. 2013;12:105–18. doi:10.1016/S1474-4422(12)70238-7.

    Article  PubMed  CAS  Google Scholar 

  • Sano R, Reed JC. ER stress-induced cell death mechanisms. Biochim Biophys Acta. 2013. doi:10.1016/j.bbamcr.2013.06.028.

    Article  PubMed  PubMed Central  Google Scholar 

  • Schäuble N, Lang S, Jung M, Cappel S, Schorr S, Ulucan Ö, et al. BiP-mediated closing of the Sec61 channel limits Ca2+ leakage from the ER. EMBO J. 2012;31:3282–96. doi:10.1038/emboj.2012.189.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Schlenstedt G, Harris S, Risse B, Lill R, Silver PA. A yeast DnaJ homologue, Scj1p, can function in the endoplasmic reticulum with BiP/Kar2p via a conserved domain that specifies interactions with Hsp70s. J Cell Biol. 1995;129:979–88.

    Article  PubMed  CAS  Google Scholar 

  • Scidmore MA, Okamura HH, Rose MD. Genetic interactions between KAR2 and SEC63, encoding eukaryotic homologues of DnaK and DnaJ in the endoplasmic reticulum. Mol Biol Cell. 1993;4:1145–59.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shen JS, Chen X, Hendershot L, Prywes R. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of golgi localization signals. Dev Cell. 2002;3:99–111. doi:10.1016/s1534-5807(02)00203-4.

    Article  PubMed  CAS  Google Scholar 

  • Shu CW, Sun FC, Cho JH, Lin CC, Liu PF, Chen PY, et al. GRP78 and Raf-1 cooperatively confer resistance to endoplasmic reticulum stress-induced apoptosis. J Cell Physiol. 2008;215:627–35. doi:10.1002/jcp.21340.

    Article  PubMed  CAS  Google Scholar 

  • Sun FC, Wei S, Li CW, Chang YS, Chao CC, Lai YK. Localization of GRP78 to mitochondria under the unfolded protein response. Biochem J. 2006;396:31–9. doi:10.1042/bj20051916.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sun Q, Hua J, Wang Q, Xu W, Zhang J, Kang J, et al. Expressions of GRP78 and Bax associate with differentiation, metastasis, and apoptosis in non-small cell lung cancer. Mol Biol Rep. 2012;39:6753–61. doi:10.1007/s11033-012-1500-8.

    Article  PubMed  CAS  Google Scholar 

  • Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 2011;13:184–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Takemoto H, Yoshimori T, Yamamoto A, Miyata Y, Yahara I, Inoue K, et al. Heavy chain binding protein (BiP/GRP78) and endoplasmin are exported from the endoplasmic reticulum in rat exocrine pancreatic cells, similar to protein disulfide-isomerase. Arch Biochem Biophys. 1992;296:129–36.

    Article  PubMed  CAS  Google Scholar 

  • Takeuchi M, Kimata Y, Hirata A, Oka M, Kohno K. Saccharomyces cerevisiae Rot1p is an ER-localized membrane protein that may function with BiP/Kar2p in protein folding. J Biochem. 2006;139:597–605. doi:10.1093/jb/mvj063.

    Article  PubMed  CAS  Google Scholar 

  • Ting J, Lee AS. Human gene encoding the 78,000-dalton glucose-regulated protein and its pseudogene: structure, conservation, and regulation. DNA-a J Mol Cell Biol. 1988;7:275–86. doi:10.1089/dna.1988.7.275.

    Article  CAS  Google Scholar 

  • Tyedmers J, Mogk A, Bukau B. Cellular strategies for controlling protein aggregation. Nat Rev Mol Cell Biol. 2010;11:777–88. doi:10.1038/nrm2993.

    Article  PubMed  CAS  Google Scholar 

  • Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science. 2000;287:664–6.

    Article  PubMed  CAS  Google Scholar 

  • Urra H, Dufey E, Avril T, Chevet E, Hetz C. Endoplasmic reticulum stress and the hallmarks of cancer. Trends Cancer. 2016;2:252–62. doi:10.1016/j.trecan.2016.03.007.

    Article  PubMed  Google Scholar 

  • Vembar SS, Jonikas MC, Hendershot LM, Weissman JS, Brodsky JLJ. Domain co-chaperone specificity defines the role of BiP during protein translocation. J Biol Chem. 2010;285:22484–94. doi:10.1074/jbc.M110.102186.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Verras M, Papandreou I, Lim AL, Denko NC. Tumor hypoxia blocks Wnt processing and secretion through the induction of endoplasmic reticulum stress. Mol Cell Biol. 2008;28:7212–24. doi:10.1128/mcb.00947-08.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wabl M, Steinberg C. A theory of allelic and isotypic exclusion for immunoglobulin genes. Proc Natl Acad Sci USA Biol Sci. 1982;79:6976–8. doi:10.1073/pnas.79.22.6976.

    Article  CAS  Google Scholar 

  • Wang X, Li Y, Xu G, Liu M, Xue L, Liu L, et al. Mechanism study of peptide GMBP1 and its receptor GRP78 in modulating gastric cancer MDR by iTRAQ-based proteomic analysis. BMC Cancer. 2015;15:358. doi:10.1186/s12885-015-1361-3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wey S, Luo B, Lee AS. Acute inducible ablation of GRP78 reveals its role in hematopoietic stem cell survival, lymphogenesis and regulation of stress signaling. PLoS One. 2012a;7:e39047. doi:10.1371/journal.pone.0039047.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wey S, Luo B, Tseng CC, Ni M, Zhou H, Fu Y, et al. Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling. Blood. 2012b;119:817–25. doi:10.1182/blood-2011-06-357384.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Williamson DS, Borgognoni J, Clay A, Daniels Z, Dokurno P, Drysdale MJ, et al. Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design. J Med Chem. 2009;52:1510–3.

    Article  PubMed  CAS  Google Scholar 

  • Yang J, Nune M, Zong Y, Zhou L, Liu Q. Close and allosteric opening of the polypeptide-binding site in a human Hsp70 chaperone BiP. Structure. 2015;23:2191–203. doi:10.1016/j.str.2015.10.012.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yoneda Y, Steiniger SCJ, Capkova K, Mee JM, Liu Y, Kaufmann GF, et al. A cell-penetrating peptidic GRP78 ligand for tumor cell-specific prodrug therapy. Bioorg Med Chem Lett. 2008;18:1632–6. doi:10.1016/j.bmcl.2008.01.060.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Young BP, Craven RA, Reid PJ, Willer M, Stirling CJ. Sec63p and Kar2p are required for the translocation of SRP-dependent precursors into the yeast endoplasmic reticulum in vivo. EMBO J. 2001;20:262–71. doi:10.1093/emboj/20.1.262.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhang J, Jiang Y, Jia Z, Li Q, Gong W, Wang L, et al. Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer. Clin Exp Metastasis. 2006;23:401–10. doi:10.1007/s10585-006-9051-9.

    Article  PubMed  CAS  Google Scholar 

  • Zhou YH, Lee AS. Mechanism for the suppression of the mammalian stress response by genistein, an anticancer phytoestrogen from soy. J Natl Cancer Inst. 1998;90:381–8. doi:10.1093/jnci/90.5.381.

    Article  PubMed  CAS  Google Scholar 

  • Zhou H, Zhang Y, Fu Y, Chan L, Lee AS. Novel mechanism of anti-apoptotic function of 78-kDa glucose-regulated protein (GRP78): endocrine resistance factor in breast cancer, through release of B-cell lymphoma 2 (BCL-2) from BCL-2-interacting killer (BIK). J Biol Chem. 2011;286:25687–96. doi:10.1074/jbc.M110.212944.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zimmermann R, Eyrisch S, Ahmad M, Helms V. Protein translocation across the ER membrane. Biochim Biophys Acta. 2011;1808:912–24. doi:10.1016/j.bbamem.2010.06.015.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We acknowledge financial support from the DoD (OCRP: W81XWH-14-1-0172).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nouri Neamati .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Miyata, Y., Badolato, M., Neamati, N. (2018). HSPA5. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_101802

Download citation

Publish with us

Policies and ethics