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Grp94 (HSP90B1)

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Encyclopedia of Signaling Molecules

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Synonyms

94 kDa glucose-regulated protein; Endoplasmin; Erp99; gp96; Grp94; Heat shock protein 90 kDa beta member 1; TRA1; Tumor-rejection antigen gp96

Historical Background

Grp94 is the endoplasmic reticulum (ER) paralog of heat shock protein (Hsp) 90. This chaperone/stress protein belongs to the protein family of glucose-regulated proteins (Grp), whose levels increase in mammalian cell cultures in the absence of glucose. Other ER stressors, such as calcium depletion, inhibition of glycosylation, and reducing agents, similarly affected Grp94 protein levels, making it one of the hallmarks of ER stress response (Lee 1987). Grp94 protein relative amount is increased also after exposure to low doses of endotoxin or curcumin (Vitadello et al. 2014a), to hypoxia or mild ischemia. The upregulation of Grp94 in several tumors explains the other widely used synonyms gp96 and TRA1 (Ansa-Addo et al. 2016).

The apparent Mr of Grp94 is around 94–100 kDa in most vertebrate species and is the product...

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References

  • Ansa-Addo EA, Thaxton J, Hong F, Wu BX, Zhang Y, Fugle CW, Metelli A, Riesenberg B, Williams K, Gewirth DT, Chiosis G, Liu B, Li Z. Clients and oncogenic roles of molecular chaperone gp96/grp94. Curr Top Med Chem. 2016;16:2765–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Barton ER, Park SH, James JK, Makarewich CA, Philippou A, Eletto D, Lei H, Brisson B, Ostrovsky O, Li Z, Argon Y. Deletion of muscle GRP94 impairs both muscle and body growth by inhibiting local IGF production. FASEB J. 2012;26:3691–792.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen WT, Ha D, Kanel G, Lee AS. Targeted deletion of ER chaperone GRP94 in the liver results in injury, repopulation of GRP94-positive hepatocytes, and spontaneous hepatocellular carcinoma development in aged mice. Neoplasia. 2014;16:617–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dejeans N, Glorieux C, Guenin S, Beck R, Sid B, Rousseau R, Bisig B, Delvenne P, Buc Calderon P, Verrax J. Overexpression of GRP94 in breast cancer cells resistant to oxidative stress promotes high levels of cancer cell proliferation and migration: implications for tumor recurrence. Free Radic Biol Med. 2012;52:993–1002.

    Article  PubMed  CAS  Google Scholar 

  • Frasson M, Vitadello M, Brunati AM, La Rocca N, Tibaldi E, Pinna LA, Gorza L, Donella-Deana A. Grp94 is Tyr-phosphorylated by Fyn in the lumen of the endoplasmic reticulum and translocates to Golgi in differentiating myoblasts. Biochim Biophys Acta Mol Cell Res. 2009;1793:239–52.

    Article  CAS  Google Scholar 

  • Ghosh S, Shinogle HE, Galeva NA, Dobrowsky RT, Blagg BS. Endoplasmic reticulum-resident heat shock protein 90 (HSP90) isoform glucose-regulated protein 94 (GRP94) regulates cell polarity and cancer cell migration by affecting intracellular transport. J Biol Chem. 2016;291:8309–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Glembotski CC. The role of the unfolded protein response in the heart. J Mol Cell Cardiol. 2008;44:453–9.

    Article  PubMed  CAS  Google Scholar 

  • Gorza L, Vitadello M. Reduced amount of the glucose-regulated protein GRP94 in skeletal myoblasts results in loss of fusion competence. FASEB J. 2000;14:461–75.

    Article  PubMed  CAS  Google Scholar 

  • Han JM, Kwon NH, Lee JY, Jeong SJ, Jung HJ, Kim HR, Li Z, Kim S. Identification of gp96 as a novel target for treatment of autoimmune disease in mice. PLoS One. 2010;5(3):e9792. https://doi.org/10.1371/journal.pone.0009792.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Huang QQ, Sobkoviak R, Jockheck-Clark AR, Shi B, Mandelin AM, Tak PP, Haines GK, Nicchitta CV, Pope RM. Heat shock protein 96 is elevated in rheumatoid arthritis and activates macrophages primarily via TLR2 signaling. J Immunol. 2009;182:4965–73.

    Article  PubMed  CAS  Google Scholar 

  • Jockheck-Clark AR, Bowers EV, Totonchy MB, Neubauer J, Pizzo SV, Nicchitta CV. Re-examination of CD91 function in GRP94 (glycoprotein 96) surface binding, uptake, and peptide cross-presentation. J Immunol. 2010;185:6819–30.

    Article  PubMed  CAS  Google Scholar 

  • Kim G, Han JM, Kim S. Toll-like receptor 4-mediated c-Jun N-terminal kinase activation induces gp96 cell surface expression via AIMP1 phosphorylation. Biochem Biophys Res Commun. 2010;397:100–5.

    Article  PubMed  CAS  Google Scholar 

  • Labrador-Garrido A, Cejudo-Guill’en M, Daturpalli S, Leal MM, Klippstein R, De Genst EJ, Villadiego J, Toledo-Aral JJ, Dobson CM, Jackson SE, Pozo D, Roodveldt C. Chaperome screening leads to identification of Grp94/Gp96 and FKBP4/52 as modulators of the a-synuclein–elicited immune response. FASEB J. 2016;30:564–77.

    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.

    Article  CAS  Google Scholar 

  • Liu B, Yang Y, Qiu Z, Staron M, Hong F, Li Y, Wu S, Li Y, Hao B, Bona R, Han D, Li Z. Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone. Nat Commun. 2010;1:79. https://doi.org/10.1038/ncomms1070.

    Article  PubMed  CAS  Google Scholar 

  • Liu B, Staron M, Hong F, Wu BX, Sun S, Morales C, Crosson CE, Tomlinson S, Kim I, Wu D, Li Z. Essential roles of grp94 in gut homeostasis via chaperoning canonical Wnt pathway. Proc Natl Acad Sci USA. 2013;110:6877–82.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ma Y, Hendershot LM. ER chaperone functions during normal and stress conditions. J Chem Neuroanat. 2004;28:51–65.

    Article  PubMed  CAS  Google Scholar 

  • Mao C, Wang M, Luo B, Wey S, Dong D, Wesselschmidt R, Rawlings S, Lee AS. Targeted mutation of the mouse grp94 gene disrupts development and perturbs endoplasmic reticulum stress signaling. PLoS One. 2010;5:e10852. https://doi.org/10.1371/journal.pone.0010852.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Marzec M, Eletto D, Argon Y. GRP94: an HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulum. Biochim Biophys Acta. 2012;1823:774–87.

    Article  PubMed  CAS  Google Scholar 

  • Marzec M, Hawkes CP, Eletto D, Boyle S, Rosenfeld R, Hwa V, Wit JM, van Duyvenvoorde HA, Oostdijk W, Loosekoot M, Pedersen O, Yeap BB, Flicker L, Barzilai N, Atzmon G, Grimberg A, Argon Y. A human variant of glucose-regulated protein 94 that inefficiently supports IGF production. Endocrinology. 2016;157:1914–28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mkaddem SB, Werts C, Goujon JM, Bens M, Pedruzzi E, Ogier-Denis E, Vandewalle A. Heat shock protein gp96 interacts with protein phosphatase 5 and controls toll-like receptor 2 (TLR2)-mediated activation of extracellular signal-regulated kinase (ERK) 1/2 in post-hypoxic kidney cells. J Biol Chem. 2009;284:12541–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Morito D, Nagata K. ER stress proteins in autoimmune and inflammatory diseases. Front Immunol. 2012;3:48. https://doi.org/10.3389/fimmu.2012.00048.

    Article  PubMed  PubMed Central  Google Scholar 

  • Pagetta A, Tramentozzi E, Tibaldi E, Cendron L, Zanotti G, Brunati AM, Vitadello M, Gorza L, Finotti P. Structural insights into complexes of glucose-regulated protein94 (Grp94) with human immunoglobulin G. Relevance for Grp94-IgG complexes that form in vivo in pathological conditions. PLoS One. 2014;9:e86198.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Patel PD, Yan P, Seidler PM, Patel HJ, Sun W, Yang C, Que NS, Taldone T, Finotti P, Stephani AR, Gewirth DT, Chiosis G. Paralog-selective Hsp90 inhibitors define tumor-specific regulation of Her2. Nat Chem Biol. 2013;9:677–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pizzo P, Scapin C, Vitadello M, Florean C, Gorza L. Grp94 acts as a mediator of curcumin-induced antioxidant defence in myogenic cells. J Cell Mol Med. 2010;14:970–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Poirier S, Mamarbachi M, Chen WT, Lee AS, Mayer G. GRP94 regulates circulating cholesterol levels through blockade of PCSK9-induced LDLR regradation. Cell Rep. 2015;13:2064–71.

    Article  PubMed  CAS  Google Scholar 

  • Rachidi S, Sun S, Wu BX, Jones E, Drake RR, Ogretmen B, Cowart LA, Clarke CJ, Hannun YA, Chiosis G, Liu B, Li Z. Endoplasmic reticulum heat shock protein gp96 maintains liver homeostasis and promotes hepatocellular carcinogenesis. J Hepatol. 2015;62:879–88.

    Article  PubMed  CAS  Google Scholar 

  • Randazzo M, Terness P, Opelz G, Kleist C. Active-specific immunotherapy of human cancers with the heat shock protein Gp96-revisited. Int J Cancer. 2012;130:2219–31.

    Article  PubMed  CAS  Google Scholar 

  • Randow F, Seed B. Endoplasmic reticulum chaperone gp96 is required for innate immunity but not cell viability. Nat Cell Biol. 2001;3:891–6.

    Article  PubMed  CAS  Google Scholar 

  • Rosenbaum M, Andreani V, Kapoor T, Herp S, Flach H, Duchniewicz M, Grosschedl R. MZB1 is a GRP94 cochaperone that enables proper immunoglobulin heavy chain biosynthesis upon ER stress. Genes Dev. 2014;28:1165–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Srivastava PK. Therapeutic cancer vaccines. Curr Opin Immunol. 2006;18:201–5.

    Article  PubMed  CAS  Google Scholar 

  • Staron M, Yang Y, Liu B, Li J, Shen Y, Zúñiga-Pflücker JC, Aguila HL, Goldschneider I, Li Z. gp96, an endoplasmic reticulum master chaperone for integrins and Toll-like receptors, selectively regulates early T and B lymphopoiesis. Blood. 2010;115:2380–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vitadello M, Germinario E, Ravara B, Dalla Libera L, Danieli-Betto D, Gorza L. Curcumin counteracts loss of force and atrophy of hindlimb unloaded rat soleus by hampering neuronal nitric oxide synthase untethering from sarcolemma. J Physiol. 2014a;592:2637–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vitadello M, Gherardini J, Gorza L. The stress protein/chaperone Grp94 counteracts muscle disuse atrophy by stabilizing subsarcolemmal neuronal nitric oxide synthase. Antioxid Redox Signal. 2014b;16:2479–96.

    Article  CAS  Google Scholar 

  • Wanderling S, Eletto D, Makarewich C, Barton ER, Argon Y. Grp94 is essential for mesoderm induction and muscle development because it regulates insulin-like growth factor secretion. Mol Biol Cell. 2007;18:3764–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhang Y, Wu BX, Metelli A, Thaxton JE, Hong F, Rachidi S, Ansa-Addo E, Sun S, Vasu C, Yang Y, Liu B, Li Z. GP96 is a GARP chaperone and controls regulatory T cell functions. J Clin Invest. 2015;125:859–69.

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhu G, Lee AS. Role of the unfolded protein response, GRP78 and GRP94 in organ homeostasis. J Cell Physiol. 2015;230:1413–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Biomedical Sciences, University of Padova, via U. Bassi 58B, Padova, 35131, Italy

    Luisa Gorza

  2. CNR-Institute of Neuroscience, Padova section, Padova, 35131, Italy

    Maurizio Vitadello

Authors
  1. Luisa Gorza
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  2. Maurizio Vitadello
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Corresponding author

Correspondence to Luisa Gorza .

Editor information

Editors and Affiliations

  1. Department of Molecular Science and Technology, Ajou University, Suwon, Korea

    Sangdun Choi

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Gorza, L., Vitadello, M. (2018). Grp94 (HSP90B1). In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_77

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