Cell Surface Relocalization of the Endoplasmic Reticulum Chaperone and Unfolded Protein Response Regulator GRP78/BiP

Zhang, Yi; Liu, Ren; Ni, Min; Gill, Parkash S.; Lee, Amy

doi:10.1074/jbc.m109.087445

Cited by 286 publications

(304 citation statements)

References 39 publications

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“…20,22 Overexpression of GRP78 triggers the re-localization of GRP78 to cell surface and is associated with advanced stages of tumor progression and invasiveness. 8,23 Thus, we investigated the relationship between levels of cell-surface GRP78 and susceptibility of cells to ISM-induced apoptosis.…”

Section: Resultsmentioning

confidence: 99%

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

Zhang

et al. 2014

Cell Death Differ

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Isthmin (ISM) is a secreted 60-kDa protein that potently induces endothelial cell (EC) apoptosis. It suppresses tumor growth and angiogenesis in mice when stably overexpressed in cancer cells. Although avb5 integrin serves as a low-affinity receptor for ISM, the mechanism by which ISM mediates antiangiogenesis and apoptosis in ECs remain to be fully resolved. In this work, we report the identification of cell-surface glucose-regulated protein 78 kDa (GRP78) as a high-affinity receptor for ISM (K d ¼ 8.6 nM). We demonstrated that ISM-GRP78 interaction triggers apoptosis not only in activated ECs but also in cancer cells expressing high level of cell-surface GRP78. Normal cells and benign tumor cells tend to express low level of cell-surface GRP78 and are resistant to ISM-induced apoptosis. Upon binding to GRP78, ISM is internalized into ECs through clathrin-dependent endocytosis that is essential for its proapoptotic activity. Once inside the cell, ISM co-targets with GRP78 to mitochondria where it interacts with ADP/ATP carriers on the inner membrane and blocks ATP transport from mitochondria to cytosol, thereby causing apoptosis. Hence, ISM is a novel proapoptotic ligand that targets cell-surface GRP78 to trigger apoptosis by inducing mitochondrial dysfunction. The restricted and high-level expression of cell-surface GRP78 on cancer cells and cancer ECs make them uniquely susceptible to ISM-targeted apoptosis. Indeed, systemic delivery of recombinant ISM potently suppressed subcutaneous 4T1 breast carcinoma and B16 melanoma growth in mice by eliciting apoptosis selectively in the cancer cells and cancer ECs. Together, this work reveals a novel ISM-GRP78 apoptosis pathway and demonstrates the potential of ISM as a cancer-specific and dual-targeting anticancer agent.

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Section: Resultsmentioning

confidence: 99%

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

Zhang

et al. 2014

Cell Death Differ

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“…Previous studies using transmembrane prediction programs have suggested that GRP78 has four potential transmembrane domains at the cell surface: I (amino acids (aa) [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17], II (aa 29 -45), III (aa 222-242), and IV (aa 414 -431) (34). However, the studies performed here demonstrate that at least residues 416 -417 are exposed on the cell surface, as this is the sole SubA cleavage site, and we observe cell-surface cleavage.…”

Section: Discussionmentioning

confidence: 99%

The Escherichia coli Subtilase Cytotoxin A Subunit Specifically Cleaves Cell-surface GRP78 Protein and Abolishes COOH-terminal-dependent Signaling

Ray

Ridder

et al. 2012

Journal of Biological Chemistry

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Background: GRP78 is aberrantly expressed on the surface of many different tumor cells where it functions as a growth factor-like receptor. Results: SubA cleavage of cell-surface GRP78 abrogates signaling initiated by ligation of the GRP78 COOH-terminal. Conclusion: SubA specifically cleaves cell-surface GPR78. Significance: SubA is a powerful tool that can be used to specifically probe the functions of cell-surface GPR78.

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“…Recently, it was discovered that ER stress can actively promote cell-surface localization of GRP78 (15), where it assumes coreceptor functions with cell-surface protein partners in regulating signal transduction pathways, including PI3K/AKT/S6 activation (16)(17)(18)(19). Although homozygous knockout of Grp78 results in embryonic lethality, heterozygous Grp78 mice expressing an ∼50% level of GRP78 are viable and phenotypically normal (20).…”

mentioning

confidence: 99%

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

Shen

Zhu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease in critical need of new therapeutic strategies. Here, we report that the stress-inducible 78-kDa glucose-regulated protein (GRP78/HSPA5), a key regulator of endoplasmic reticulum homeostasis and PI3K/AKT signaling, is overexpressed in the acini and PDAC of Pdx1-Cre;Kras G12D/+ ;p53 f/+ (PKC) mice as early as 2 mo, suggesting that GRP78 could exert a protective effect on acinar cells under stress, as during PDAC development. The PKC pancreata bearing wild-type Grp78 showed detectable PDAC by 3 mo and rapid subsequent tumor growth. In contrast, the PKC pancreata bearing a Grp78 f/+ allele (PKC78 f/+ mice) expressing about 50% of GRP78 maintained normal sizes during the early months, with reduced proliferation and suppression of AKT, S6, ERK, and STAT3 activation. Acinar-to-ductal metaplasia (ADM) has been identified as a key tumor initiation mechanism of PDAC. Compared with PKC, the PKC78 f/+ pancreata showed substantial reduction of ADM as well as pancreatic intraepithelial neoplasia-1 (PanIN-1), PanIN-2, and PanIN-3 and delayed onset of PDAC. ADM in response to transforming growth factor α was also suppressed in ex vivo cultures of acinar cell clusters isolated from mouse pancreas bearing targeted heterozygous knockout of Grp78 (c78 f/+ ) and subjected to 3D culture in collagen. We further discovered that GRP78 haploinsufficiency in both the PKC78 f/+ and c78 f/+ pancreata leads to reduction of epidermal growth factor receptor, which is critical for ADM initiation. Collectively, our studies establish a role for GRP78 in ADM and PDAC development.glucose-regulated protein 78 | GRP78 | pancreatic ductal adenocarcinoma | acinar-to-ductal metaplasia | Kras P ancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest diseases with limited therapeutic options and an overall 5-y survival rate of <10%; therefore, identification of targetable key players in tumor initiation as well as tumor maintenance is urgently needed (1). PDAC is believed to arise from a range of preneoplastic mucinous lesions with ductal morphology, pancreatic intraepithelial neoplasia (PanIN) being the most common in humans (2). About 90% of PDAC contains activating mutations of KRAS whereas 50-75% contain mutations in Tp53 (1). Mutationally activated oncogenic KRAS signals through the PI3K-PDK1-AKT pathway and the canonical mitogen-activated protein kinase pathway via RAF-MEK1/2-ERK1/2, as well as via positive feedback activation of receptor tyrosine kinases engaged by autocrine and paracrine stimuli (3). Although the histological appearance of PDAC suggests a ductal cell of origin, accumulating evidence reveals that PDAC originates primarily through transdifferentiation of acinar cells into ductal cells in a process referred to as acinar-to-ductal metaplasia (ADM), although centroacinar cells and pancreas precursor cells could also give rise to PDAC (2, 4, 5). To study PDAC, a pancreatic cancer mouse model mimicking human PDAC has been established using the pancreatic...

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Cell Surface Relocalization of the Endoplasmic Reticulum Chaperone and Unfolded Protein Response Regulator GRP78/BiP

Cited by 286 publications

References 39 publications

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

The Escherichia coli Subtilase Cytotoxin A Subunit Specifically Cleaves Cell-surface GRP78 Protein and Abolishes COOH-terminal-dependent Signaling

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

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