Essential roles of grp94 in gut homeostasis via chaperoning canonical Wnt pathway

Liu, Bei; Staron, Matthew; Hong, Feng; Wu, Bill X.; Sun, Shaoli; Morales, Crystal; Crosson, Craig E.; Tomlinson, Stephen; Kim, Ingyu; Wu, Dianqing; Li, Zihai

doi:10.1073/pnas.1302933110

Cited by 103 publications

(115 citation statements)

References 41 publications

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“…Clinically, gp96 expression correlates with advanced stage and poor survival in a variety of cancers and is closely linked to cancer growth and metastasis in melanoma, breast, prostate, multiple myeloma, lung cancer, and colon cancer (22- 29). gp96 has also been found to confer decreased sensitivity to x-ray irradiation (30), and it is required for the canonical Wnt pathway (31). Recently, our group showed that the maturation of a majority of integrins is dependent on gp96, which folds integrins in the ER and controls their surface expression (32)(33)(34).…”

mentioning

confidence: 99%

α7 Helix Region of αI Domain Is Crucial for Integrin Binding to Endoplasmic Reticulum Chaperone gp96

Hong¹,

Liu²,

Chiosis³

et al. 2013

Journal of Biological Chemistry

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Background:Integrins are chaperoned by gp96, but the binding region to gp96 remains unknown. Results: Deletion of ␣7 helix from ␣I domain of integrin abolished the interaction between integrin and gp96. Targeting this region by corresponding peptide blocked cell invasion. Conclusion: We successfully mapped the binding region of integrin to gp96. Significance: This study will facilitate the development of new cancer therapeutics.

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confidence: 99%

α7 Helix Region of αI Domain Is Crucial for Integrin Binding to Endoplasmic Reticulum Chaperone gp96

Hong¹,

Liu²,

Chiosis³

et al. 2013

Journal of Biological Chemistry

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“…LRP6/GRP complex 1C) and slightly reduced the level of LRP6 (Fig. 1B), which is dependent on GRP94 for its cell-surface expression (29). In contrast, 3 mmol/L of TAS-116 did not markedly affect the LRP6-GRP94 interaction.…”

Section: Tas-116 Selectively Inhibits Hsp90a and Bmentioning

confidence: 87%

“…Recently, it was discovered that GRP94, a critical chaperone for the Wnt coreceptor LRP6, has a functional role in gut homeostasis via regulation of the canonical Wnt signaling pathway (29). Conditional deletion of grp94 results in rapid weight loss, diarrhea, and hematochezia in mice that are characterized by a gut-intrinsic defect in the proliferation of intestinal crypts, as well as compromised nuclear b-catenin translocation, loss of crypt-villus structure, and impaired barrier function (29). It however remains unclear whether pharmacologic inhibition of GRP94 would mimic such effect.…”

Section: Discussionmentioning

confidence: 99%

“…1B), thereby demonstrating the compounds' cytosolic HSP90 inhibitory effects. GRP94 interacts with low-density lipoprotein receptor-related protein 6 (LRP6) and has a role in chaperoning LRP6 (29). Therefore, LRP6/GRP94 complex formation was evaluated in HCT116 cells in situ by means of a proximity ligation assay in which PLA-probe-labeled LRP6 or GRP94 molecules in close proximity were detected as red dots (30).…”

Section: Tas-116 Selectively Inhibits Hsp90a and Bmentioning

confidence: 99%

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TAS-116, a Highly Selective Inhibitor of Heat Shock Protein 90α and β, Demonstrates Potent Antitumor Activity and Minimal Ocular Toxicity in Preclinical Models

Ohkubo

Kodama

Muraoka

et al. 2015

Molecular Cancer Therapeutics

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The molecular chaperone HSP90 plays a crucial role in cancer cell growth and survival by stabilizing cancer-related proteins. A number of HSP90 inhibitors have been developed clinically for cancer therapy; however, potential off-target and/or HSP90-related toxicities have proved problematic. The 4-(1H-pyrazolo [3,4-b]pyridine-1-yl)benzamide TAS-116 is a selective inhibitor of cytosolic HSP90a and b that does not inhibit HSP90 paralogs such as endoplasmic reticulum GRP94 or mitochondrial TRAP1. Oral administration of TAS-116 led to tumor shrinkage in human tumor xenograft mouse models accompanied by depletion of multiple HSP90 clients, demonstrating that the inhibition of HSP90a and b alone was sufficient to exert antitumor activity in certain tumor models. One of the most notable HSP90-related adverse events universally observed to differing degrees in the clinical setting is visual disturbance. A two-week administration of the isoxazole resorcinol NVP-AUY922, an HSP90 inhibitor, caused marked degeneration and disarrangement of the outer nuclear layer of the retina and induced photoreceptor cell death in rats. In contrast, TAS-116 did not produce detectable photoreceptor injury in rats, probably due to its lower distribution in retinal tissue. Importantly, in a rat model, the antitumor activity of TAS-116 was accompanied by a higher distribution of the compound in subcutaneously xenografted NCI-H1975 non-small cell lung carcinoma tumors than in retina. Moreover, TAS-116 showed activity against orthotopically transplanted NCI-H1975 lung tumors. Together, these data suggest that TAS-116 has a potential to maximize antitumor activity while minimizing adverse effects such as visual disturbances that are observed with other compounds of this class.

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“…63 LRP6, in turn, is required for canonical Wnt signaling and functions as a coreceptor for the cell surface Wnt receptor, Frizzled. 69 Genetic deletion of GRP94 attenuates multiple myeloma in a mouse model of the disease. 70 Additionally, silencing GRP94 compromised human multiple myeloma cell growth.…”

mentioning

confidence: 99%

Hsp90 as a therapeutic target in endocrinology: current evidence

Ratajczak¹,

Ward²,

Walsh³

et al. 2015

RRED

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Abstract:The ability of heat shock protein 90 (Hsp90) to modulate many growth and signaling pathways simultaneously makes it an attractive target in the field of cancer therapeutics and provided the initial impetus for significant efforts over the past decade to identify Hsp90 inhibitors, several of which are now showing promise in the clinic for cancer treatment. The four known human Hsp90 members are compartmentalized: Hsp90α and β in the cytoplasm, GRP94 in the endoplasmic reticulum, and TRAP1 in the mitochondrial matrix. While these isoforms share a similar N-terminal domain adenosine triphosphate-binding pocket, structural variations allow unique interactions for inhibitors targeting this binding site, providing an avenue for the development of paralog-selective drugs with different biological effects applicable therapeutically to a wide range of diseases. At the same time, the conformational flexibility of the Hsp90 molecular chaperone has unveiled multiple small-molecule target sites within all subdomains of the protein, greatly expanding opportunities for viable drug development. This review summarizes the function, expression, and clinical significance of the Hsp90 isoforms and elaborates on the inhibitors and modulators that impact Hsp90 chaperone activity. Finally, the review focuses on the therapeutic utility of a range of Hsp90-modulating agents in the treatment of specific diseases associated with the endocrine system.

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Essential roles of grp94 in gut homeostasis via chaperoning canonical Wnt pathway

Cited by 103 publications

References 41 publications

α7 Helix Region of αI Domain Is Crucial for Integrin Binding to Endoplasmic Reticulum Chaperone gp96

α7 Helix Region of αI Domain Is Crucial for Integrin Binding to Endoplasmic Reticulum Chaperone gp96

TAS-116, a Highly Selective Inhibitor of Heat Shock Protein 90α and β, Demonstrates Potent Antitumor Activity and Minimal Ocular Toxicity in Preclinical Models

Hsp90 as a therapeutic target in endocrinology: current evidence

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