Stable complexes formed by Grp94 with human IgG promoting angiogenic differentiation of HUVECs by a cytokine-like mechanism

Tramentozzi, Elisa; Montopoli, Monica; Orso, Genny; Pagetta, Andrea; Caparrotta, Laura; Frasson, Martina; Brunati, Anna Maria; Finotti, Paola

doi:10.1016/j.molimm.2008.04.020

Cited by 15 publications

(41 citation statements)

References 47 publications

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“…6) proves that the cell signaling targeted by Grp94 is specific and adds further evidence to previous observations showing that Grp94 is able to regulate the proliferation and differentiation of cells of the innate and adaptive immunity by a fine, cytokine-like mechanism (Reed et al 2003;Tramentozzi et al 2008).…”

Section: Discussionsupporting

confidence: 69%

“…6). Increases in the expression of HSP90 have been demonstrated to occur in the presence of Grp94 in HUVECs, in which HSP90 plays a paracrine role in the Grp94-dependent cell growth stimulation and angiogenic differentiation (Tramentozzi et al 2008). Considering that the stimulation of HSP90 expression by Grp94 appeared at 7 days and lasted up to 15 days, it is possible that also in PBMCs HSP90 is involved in mediating the effects of Grp94, by promoting the growth of T cells that in turn affect maturation and differentiation of B cells.…”

Section: Discussionmentioning

confidence: 99%

“…Effects of Grp94 on PBMCs are mediated by activation of the ERK1/2 pathway Since Grp94 promotes the proliferation and differentiation of cells of the innate immunity by stimulating the ERK1/2 phosphorylation-an effect that leads to the downstream activation of cytokine-mediated immune responses (Reed et al 2003;Tramentozzi et al 2008)-it was reasonable to hypothesize that the Grp94-mediated proliferation of PBMCs could also be sustained by the activation of the MEK-ERK1/ 2 pathway. The expression of P-ERK1/2 was measured in cell lysates after incubation at 1.5, 3, and 7 days in absence of FBS.…”

Section: Grp94 Induces the Proliferation Of Pbmcsmentioning

confidence: 99%

“…We have observed that Grp94 can induce the growth and promote the differentiation of human umbilical vein endothelial cells (HUVECs) with a cytokine-like mechanism (Tramentozzi et al 2008). Since HUVECs are cells of the innate immunity (Carmeliet 2000), we speculated that Grp94 might activate the same mechanism in other, more specialized cells of immunity, thereby eliciting a different panel of effects.…”

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confidence: 99%

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Effects of glucose-regulated protein94 (Grp94) on Ig secretion from human blood mononuclear cells

Tramentozzi

Zamarchi

Pagetta

et al. 2011

Cell Stress and Chaperones

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Grp94 is the main endoplasmic reticulum-resident heat shock protein (HSP) that besides chaperoning native proteins, displays important modulatory effects on both the innate and adaptive immune response. Since the knowledge of a direct influence of Grp94 on the humoral response is lacking, in this work we tested the effect of Grp94 on Ig secretion from peripheral blood mononuclear cells (PBMCs) of five normal volunteers. The concentration of Ig secreted in the medium after incubation of 15 days was found increased in a dose-dependent manner in the presence of Grp94, used at the final concentrations of 10 and 100 ng/ml. However, by measuring the Ig secretion at different incubation times, it was apparent that maximal percent stimulation by Grp94 occurred at 7 days, decreasing thereafter. In addition, the pattern of Ig secretion in time significantly differed in the presence of Grp94 with respect to that of control PBMCs. Grp94 also stimulated in a dose-dependent manner the PBMC proliferation, an effect that preceded the Ig secretion and was accompanied by morphological changes of cells similar to those induced by the pokeweed mitogen. Effects of Grp94 on PBMCs were mediated by an intense activation of the MEK-ERK1/2 pathway and by an increased expression of HSP90. Results indicate that Grp94 can activate the humoral response by a cytokine-like, cell-mediated mechanism that leads to an accelerated process of B cell maturation and differentiation.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Grp94 Induces the Proliferation Of Pbmcsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Effects of glucose-regulated protein94 (Grp94) on Ig secretion from human blood mononuclear cells

Tramentozzi

Zamarchi

Pagetta

et al. 2011

Cell Stress and Chaperones

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“…Consequently, the applications of Hsp90␣ antibody or impermeable inhibitors of Hsp90␣ will be extended and not only limited to the inhibition of metastasis. Moreover, it was shown that other molecular chaperones, such as Hsp70, GRP78, and GRP94/gp96, also exist extracellularly and are involved in the regulation of angiogenesis (36,47,48) or other components of tumor microenvironment (7). The applications of these extracellular chaperones as therapeutic targets in cancer treatment all merit further investigation.…”

Section: Discussionmentioning

confidence: 99%

The Regulatory Mechanism of Extracellular Hsp90α on Matrix Metalloproteinase-2 Processing and Tumor Angiogenesis

Song

Wang

Zhuo

et al. 2010

Journal of Biological Chemistry

104

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Heat shock protein 90␣ (Hsp90␣) is a ubiquitously expressed molecular chaperone that is essential for eukaryotic homeostasis. Hsp90␣ can also be secreted extracellularly, where it has been shown to be involved in tumor metastasis. Extracellular Hsp90␣ interacts with and promotes the proteolytic activity of matrix metalloproteinase-2 (MMP-2). However, the regulatory mechanism of Hsp90␣ on MMP-2 activity is still unknown. Here we show that Hsp90␣ stabilizes MMP-2 and protects it from degradation in tumor cells. Further investigation reveals that this stabilization effect is isoform-specific, ATP-independent, and mediated by the interaction between the Hsp90␣ middle domain and the MMP-2 C-terminal hemopexin domain. Moreover, this mechanism also applies to endothelial cells that secrete more Hsp90␣ in their proliferating status. Furthermore, endothelial cell transmigration, Matrigel plug, and tumor angiogenesis assays demonstrate that extracellular Hsp90␣ promotes angiogenesis in an MMP-2-dependent manner. In sum, this study provides new insights into the molecular mechanism of how Hsp90␣ regulates its extracellular client proteins and also reveals for the first time the function of extracellular Hsp90␣ in promoting tumor angiogenesis.Heat shock protein 90 (Hsp90) 2 is an ATP-dependent molecular chaperone that is ubiquitously expressed and essential for cell viability (1). Unlike other types of chaperones, Hsp90 is not required for the biogenesis of most polypeptides but instead functions in the maintenance of the active state of several conformationally labile signaling proteins (2-4). Many of the Hsp90 client proteins are mutated, chimeric, or overexpressed oncogenic proteins (3). Therefore, the chaperoning function of Hsp90 is subverted to a biochemical buffer for genetic lesions in tumor cells, facilitating the malignant transformations of the cells (3). Hsp90 has emerged as a promising target for cancer therapy (5).There are two isoforms of Hsp90 in the cytosol, referred to as Hsp90␣ and Hsp90␤ (6). Intriguingly, the Hsp90␣ isoform also exists extracellularly (7). Recent studies indicate that extracellular Hsp90␣ is significantly correlated with tumor invasiveness and metastasis (8), and the antibody or impermeable inhibitor of Hsp90␣ can suppress tumor metastasis efficiently in mouse models (9 -11). Furthermore, Hsp90␣ can be detected in the blood of cancer patients, and the level of Hsp90␣ is positively associated with tumor malignancy (9). In addition to tumor cells, extracellular Hsp90␣ has also been identified in neuron cells, dermal fibroblasts, keratinocyte, macrophages, and epithelial cells and participates in neuronal cell migration, wound healing, and viral and bacteria infections (7).Accumulating evidence indicates that extracellular Hsp90␣ plays important roles in both physiological and pathological processes, especially in tumor progression (7). However, the molecular mechanism of how extracellular Hsp90␣ functions is still largely unknown (12). Eustace et al. (8) reported that extracellular Hsp90...

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Effects of purine-scaffold inhibitors on HUVECs: Involvement of the purinergic pathway and interference with ATP. Implications for preventing the adverse effects of extracellular Grp94

Tramentozzi

Finotti

2019

Biochemistry and Biophysics Reports

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Background Extracellular Glucose-regulated protein94 (Grp94) is linked to pathological conditions disrupting the obligatory intracellular location of this Heat Shock Protein (HSP). In plasma, Grp94 is linked to IgG in complexes that drive adverse effects on vascular cells and are biomarker of gastro-intestinal cancer. By blocking ATP site in different HSPs, purine-scaffold inhibitors are used as promising anti-cancer compounds, but their effects on vasculature are not known. Methods We tested the capacity of two purine-scaffold inhibitors, PU-H71 and PU-WS13, to prevent the binding of Grp94 to IgG and to antagonize the effects of Grp94 and native Grp94-IgG complexes on HUVECs in different experimental conditions. Results PU-H71 and PU-WS13 blocked Grp94 and the formation of Grp94-IgG complexes in absence of cells. Instead, in presence of HUVECs rather than Grp94 PU-inhibitors targeted cells causing stimulation of Akt and VEGF pathways and displaying angiogenic-like effects similar to, although less intense than that provoked by Grp94 and Grp94-IgG complexes. Unlike Grp94 and Grp94-IgG complexes, PU-inhibitors also activated the purinergic pathway and increased the expression of the ATP receptor P2X7. Effects of PU-inhibitors on HUVECs were reversed by ATP and in presence of ATP PU-inhibitors were again able to block Grp94. Conclusions PU-inhibitors can display direct effects on endothelial cells by targeting the ATP receptor P2X7. In absence of ATP, PU-inhibitors preferentially bind to cells rather than Grp94. ATP antagonizes the PU-inhibitor binding to cells thus restoring the capacity to block Grp94 and Grp94-IgG complex formation. Results have implications for enhancing the therapeutic efficacy of PU-inhibitors against circulating pathogenic Grp94.

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Stable complexes formed by Grp94 with human IgG promoting angiogenic differentiation of HUVECs by a cytokine-like mechanism

Cited by 15 publications

References 47 publications

Effects of glucose-regulated protein94 (Grp94) on Ig secretion from human blood mononuclear cells

Effects of glucose-regulated protein94 (Grp94) on Ig secretion from human blood mononuclear cells

The Regulatory Mechanism of Extracellular Hsp90α on Matrix Metalloproteinase-2 Processing and Tumor Angiogenesis

Effects of purine-scaffold inhibitors on HUVECs: Involvement of the purinergic pathway and interference with ATP. Implications for preventing the adverse effects of extracellular Grp94

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