The 78 kDa Glucose-Regulated Protein (GRP78/BIP) Is Expressed on the Cell Membrane, Is Released into Cell Culture Medium and Is Also Present in Human Peripheral Circulation

Delpino, Andrea; Castelli, Mauro

doi:10.1023/a:1020966008615

Cited by 130 publications

(83 citation statements)

References 28 publications

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“…We demonstrate that during in vitro differentiation there is an increase in the expression levels of GRP-78 in primary calvarial cells. This observation corroborates well with the published report showing expression of GRP-78 on the plasma membrane as well as in the culture medium of rabdomiosarcoma cells (1). Recently, GRP-78 has also been reported to be present in the secretome of mesenchymal stem cells, and the expression levels increased upon induction of in vitro differentiation for 48 h (12).…”

Section: Discussionsupporting

confidence: 93%

“…It plays a critical role in viral entry of Coxsackie B and Dengue viruses (6 -9). Recent studies have demonstrated GRP-78 as a secretory protein (1,12), indicating a possible extracellular function for GRP-78. One study points to an extracellular role of GRP-78 in the zona pellucida regulating the penetration of sperm by modulating calcium ions (29).…”

Section: Discussionmentioning

confidence: 99%

“…Its primary function is to act as a molecular chaperone in the endoplasmic reticulum (ER) and facilitates the proper folding and assembly of membrane and secretory proteins. However, GRP-78 has been shown to be up-regulated under stress conditions such as the presence of toxic agents (1)(2)(3)(4). GRP-78 has been reported to be translocated to the detergent-resistant fractions of the plasma membrane of these cells (5,6).…”

Section: Grp-78mentioning

confidence: 99%

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Stress Chaperone GRP-78 Functions in Mineralized Matrix Formation

Ravindran¹,

Gao²,

Ramachandran³

et al. 2011

Journal of Biological Chemistry

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Mineralized matrix formation is a well orchestrated event requiring several players. Glucose-regulated protein-78 (GRP-78) is an endoplasmic reticulum chaperone protein that has been implicated in functional roles ranging from involvement in cancer biology to serving as a receptor for viruses. In the present study we explored the role of GRP-78 in mineralized matrix formation. Differential expression of GRP-78 mRNA and protein was observed upon in vitro differentiation of primary mouse calvarial cells. An interesting observation was that GRP-78 was identified in the secretome of these cells and in the bone matrix, suggesting an extracellular function during matrix formation. In vitro nucleation experiments under physiological concentrations of calcium and phosphate ions indicated that GRP-78 can induce the formation of calcium phosphate polymorphs by itself, when bound to immobilized type I collagen and on demineralized collagen wafers. We provide evidence that GRP-78 can bind to DMP1 and type I collagen independent of each other in a simulated extracellular environment. Furthermore, we demonstrate the cell surface localization of GRP-78 and provide evidence that it functions as a receptor for DMP1 endocytosis in pre-osteoblasts and primary calvarial cells. Overall, this study represents a paradigm shift in the biological function of GRP-78. GRP-78,2 also known as hspa5, is a member of the heat shock protein 70 family. Its primary function is to act as a molecular chaperone in the endoplasmic reticulum (ER) and facilitates the proper folding and assembly of membrane and secretory proteins. However, GRP-78 has been shown to be up-regulated under stress conditions such as the presence of toxic agents (1-4). GRP-78 has been reported to be translocated to the detergent-resistant fractions of the plasma membrane of these cells (5, 6). It has also been implicated to function as a receptor for ␣2-macroglobulin and different viruses through lipid rafts (7-9). Interestingly, GRP-78 has been shown to possess calcium binding properties with reports of calcium binding affinity ranging from 1-2 mol of calcium/mol of GRP-78 to much larger quantities (10). The biological significance of the calcium binding ability of GRP-78 is, however, a subject of debate, with its role primarily being attributed to binding of ER Ca 2ϩ similar to other sequestering proteins.Recent studies have shown that several stress proteins play a significant role in osteoblast differentiation. Specifically, Old Astrocyte Specifically Induced Substance, an ER stress transducer, has been implicated to be involved in bone formation (11). Additionally, a study on the analysis of the secretome of differentiating human mesenchymal stem cells showed an increase in the amount of secreted stress proteins (12). This study quantitatively analyzed the presence of GRP-78 in the secreted pool of proteins and showed that the amount of secreted protein increased when the cells were subjected to in vitro differentiation. Increase in expression of GRP-78 was attributed to...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Grp-78mentioning

confidence: 99%

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Stress Chaperone GRP-78 Functions in Mineralized Matrix Formation

Ravindran¹,

Gao²,

Ramachandran³

et al. 2011

Journal of Biological Chemistry

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“…Whereas BiP is generally thought to play a role in the structural maturation of nascent proteins in the ER, recent observations have shown that it may also have functions at the cell surface (23,27,28). BiP has been shown to associate with major histocompatibility complex class I protein (MHC class I) at the cell surface (29,30).…”

Section: Discussionmentioning

confidence: 99%

Cell-surface Processing of the Metalloprotease Pro-ADAMTS9 Is Influenced by the Chaperone GRP94/gp96

Koo

2010

Journal of Biological Chemistry

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A disintegrin-like and metalloprotease domain with thrombospondin type 1 motifs 9 (ADAMTS9) is a highly conserved metalloprotease that has been identified as a tumor suppressor gene and is required for normal mouse development. The secreted ADAMTS9 zymogen undergoes proteolytic excision of its N-terminal propeptide by the proprotein convertase furin. However, in contrast to other metalloproteases, propeptide excision occurs at the cell surface and leads to decreased activity of the zymogen. Here, we investigated the potential cellular mechanisms regulating ADAMTS9 biosynthesis and cell-surface processing by analysis of molecular complexes formed by a construct containing the propeptide and catalytic domain of pro-ADAMTS9 (Pro-Cat) in HEK293F cells. Cross-linking of cellular proteins bound to Pro-Cat followed by mass spectrometric analysis identified UDP-glucose:glycoprotein glucosyltransferase I, heat shock protein gp96 (GRP94), BiP (GRP78), and ERdj3 (Hsp40 homolog) as associated proteins. gp96 and BiP were present at the cell surface in an immunoprecipitable complex with pro-ADAMTS9 and furin. Treatment with geldanamycin, an inhibitor of the HSP90␣ family (including gp96), led to decreased furin processing of pro-ADAMTS9 and accumulation of the unprocessed pro-ADAMTS9 at the cell surface. gp96 siRNA down-regulated the levels of cell-surface pro-ADAMTS9 and furin, whereas the levels of cell-surface pro-ADAMTS9, but not of cell-surface furin, were decreased upon treatment with BiP siRNA. These data identify for the first time the cellular chaperones associated with secretion of an ADAMTS protease and suggest a role for gp96 in modulating pro-ADAMTS9 processing.A disintegrin-like and metalloprotease domain with thrombospondin type 1 motifs (ADAMTS) 2 proteases are a large family of secreted metalloproteases implicated in diverse biological functions including angiogenesis, hemostasis, connective tissue disorders, inflammation, arthritis, and cancer (1, 2). ADAMTS9 is the most highly conserved member of the family (3). It was recently implicated in regulation of melanoblast development (4) and limb development in mice (5) and was previously identified as a tumor suppressor gene in esophageal and nasopharyngeal cancer (6, 7). Early lethality of the Adamts9-null allele in mice (5, 8) strongly suggests additional critical biological roles. The extracellular matrix proteoglycans aggrecan and versican were previously identified as its substrates (3), and they are relevant to its potential roles in arthritis and embryonic development, respectively (4, 9). Characterization of ADAMTS9 protein showed it to be located at the cell surface in transfected cells, suggesting that despite the absence of a membrane anchor, it could be an operational cell-surface protease (3). Its potential contribution to cell-surface proteolysis is supported by the requirement of its Caenorhabditis elegans ortholog Gon-1 for cell migration during gonadal morphogenesis (10).Although these observations strongly suggest that ADAMTS9 has considerable...

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“…However, a number of studies demonstrate that GRP78 is also located on the cell surface. Cell surface expression of GRP78 was first detected in thapsigargin-treated human rhabdomyosarcoma cells [18,19]. Second, GRP78 was found to associate with MHC class I molecules on the cell surface.…”

Section: Grp78 Protein and Expressionmentioning

confidence: 98%

Stress Induction of GRP78/BiP and Its Role in Cancer

Lee²

2006

CMM

532

464

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GRP78, also referred to as BiP, is a central regulator of endoplasmic reticulum (ER) function due to its roles in protein folding and assembly, targeting misfolded protein for degradation, ER Ca(2+)-binding and controlling the activation of trans-membrane ER stress sensors. Further, due to its anti-apoptotic property, stress induction of GRP78 represents an important pro-survival component of the unfolded protein response. GRP78 is induced in a wide variety of cancer cells and cancer biopsy tissues. Recent progress, utilizing overexpression and siRNA approaches, establishes that GRP78 contributes to tumor growth and confers drug resistance to cancer cells. The discovery of GRP78 expression on the cell surface of cancer cells further leads to the development of new therapeutic approaches targeted against cancer, in particular, hypoxic tumors where GRP78 is highly induced. Progress has also been made in understanding how Grp78 is induced by ER stress. The identification of the transcription factors interacting with the ER stress response element leads to the discovery of multiple pathways whereby mammalian cells can sense ER stress and trigger the transcription of Grp78. In addition, advances have been made in understanding how Grp78 expression is regulated in the context of chromatin modification. This review summarizes the transcriptional regulation of Grp78, the molecular basis for the cytoprotective function of GRP78 and its role in cancer progression, drug resistance and potential future cancer therapy.

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The 78 kDa Glucose-Regulated Protein (GRP78/BIP) Is Expressed on the Cell Membrane, Is Released into Cell Culture Medium and Is Also Present in Human Peripheral Circulation

Cited by 130 publications

References 28 publications

Stress Chaperone GRP-78 Functions in Mineralized Matrix Formation

Stress Chaperone GRP-78 Functions in Mineralized Matrix Formation

Cell-surface Processing of the Metalloprotease Pro-ADAMTS9 Is Influenced by the Chaperone GRP94/gp96

Stress Induction of GRP78/BiP and Its Role in Cancer

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