Tyrphostin ErbB2 Inhibitors AG825 and AG879 Have Non-specific Suppressive Effects on gp130/ STAT3 Signaling

Lee, Hyun Kyoung; Seo, Incheol; Lee, Sang Hwa; Seo, Suyoung; Kim, Kyung‐Sup; Park, Hwan Tae

doi:10.4196/kjpp.2008.12.5.281

Cited by 4 publications

(4 citation statements)

References 25 publications

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“…MIN-6 cells were stimulated with BTC (0.5 nM) for 24 h in the presence of 4 nM of AG1478 or AG825. AG1478 is known as a potent and selective inhibitor of ErbB-1 (IC 50 = 3 nM), but does not inhibit ErbB-2 (IC 50 >100 µM) [23] , and AG825 is a specific inhibitor of ErbB-2 [24] . Treatment of the cells with either inhibitor significantly suppressed BTC-induced DNA synthesis ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Betacellulin-Induced Beta Cell Proliferation and Regeneration Is Mediated by Activation of ErbB-1 and ErbB-2 Receptors

Shin

Lee

et al. 2011

PLoS ONE

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BackgroundBetacellulin (BTC), a member of the epidermal growth factor family, is known to play an important role in regulating growth and differentiation of pancreatic beta cells. Growth-promoting actions of BTC are mediated by epidermal growth factor receptors (ErbBs), namely ErbB-1, ErbB-2, ErbB-3 and ErbB-4; however, the exact mechanism for beta cell proliferation has not been elucidated. Therefore, we investigated which ErbBs are involved and some molecular mechanisms by which BTC regulates beta cell proliferation.Methodology/Principal FindingsThe expression of ErbB-1, ErbB-2, ErbB-3, and ErbB-4 mRNA was detected by RT-PCR in both a beta cell line (MIN-6 cells) and C57BL/6 mouse islets. Immunoprecipitation and western blotting analysis showed that BTC treatment of MIN-6 cells induced phosphorylation of only ErbB-1 and ErbB-2 among the four EGF receptors. BTC treatment resulted in DNA synthetic activity, cell cycle progression, and bromodeoxyuridine (BrdU)-positive staining. The proliferative effect was blocked by treatment with AG1478 or AG825, specific tyrosine kinase inhibitors of ErbB-1 and ErbB-2, respectively. BTC treatment increased mRNA and protein levels of insulin receptor substrate-2 (IRS-2), and this was blocked by the ErbB-1 and ErbB-2 inhibitors. Inhibition of IRS-2 by siRNA blocked cell cycle progression induced by BTC treatment. Streptozotocin-induced diabetic mice injected with a recombinant adenovirus expressing BTC and treated with AG1478 or AG825 showed reduced islet size, reduced numbers of BrdU-positive cells in the islets, and did not attain BTC-mediated remission of diabetes.Conclusions/SignificanceThese results suggest that BTC exerts proliferative activity on beta cells through the activation of ErbB-1 and ErbB-2 receptors, which may increase IRS-2 expression, contributing to the regeneration of beta cells.

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Section: Resultsmentioning

confidence: 99%

Betacellulin-Induced Beta Cell Proliferation and Regeneration Is Mediated by Activation of ErbB-1 and ErbB-2 Receptors

Shin

Lee

et al. 2011

PLoS ONE

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“…To predict the agent that might reverse the DEGs profiles, the DEGs were submitted to CMAP tool [24] for analysis. Consequently, a list of agents was screened out, of which Tyrphostin AG-825, a specific tyrphostin inhibitor of ErbB2, [25,26] had the highest negative enrichment score. Evidence showed that AG-825 have tumor suppressive function for multiple ErbB2-overexpressing cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…Evidence showed that AG-825 have tumor suppressive function for multiple ErbB2-overexpressing cancer cells. [25,26] Meanwhile, Bo-Jeng Wang et al [27] found that ErbB2 may play a critical role in the pathogenesis of AD. The expression of ErbB2 is considered dormant during adulthood but reactivated during the pathogenesis of AD.…”

Section: Discussionmentioning

confidence: 99%

Identifying key genes, pathways and screening therapeutic agents for manganese-induced Alzheimer disease using bioinformatics analysis

et al. 2018

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Alzheimer disease (AD) is a progressive neurodegenerative disease, the etiology of which remains largely unknown. Accumulating evidence indicates that elevated manganese (Mn) in brain exerts toxic effects on neurons and contributes to AD development. Thus, we aimed to explore the gene and pathway variations through analysis of high through-put data in this process.To screen the differentially expressed genes (DEGs) that may play critical roles in Mn-induced AD, public microarray data regarding Mn-treated neurocytes versus controls (GSE70845), and AD versus controls (GSE48350), were downloaded and the DEGs were screened out, respectively. The intersection of the DEGs of each datasets was obtained by using Venn analysis. Then, gene ontology (GO) function analysis and KEGG pathway analysis were carried out. For screening hub genes, protein-protein interaction network was constructed. At last, DEGs were analyzed in Connectivity Map (CMAP) for identification of small molecules that overcome Mn-induced neurotoxicity or AD development.The intersection of the DEGs obtained 140 upregulated and 267 downregulated genes. The top 5 items of biological processes of GO analysis were taxis, chemotaxis, cell-cell signaling, regulation of cellular physiological process, and response to wounding. The top 5 items of KEGG pathway analysis were cytokine-cytokine receptor interaction, apoptosis, oxidative phosphorylation, Toll-like receptor signaling pathway, and insulin signaling pathway. Afterwards, several hub genes such as INSR, VEGFA, PRKACB, DLG4, and BCL2 that might play key roles in Mn-induced AD were further screened out. Interestingly, tyrphostin AG-825, an inhibitor of tyrosine phosphorylation, was predicted to be a potential agent for overcoming Mn-induced neurotoxicity or AD development.The present study provided a novel insight into the molecular mechanisms of Mn-induced neurotoxicity or AD development and screened out several small molecular candidates that might be critical for Mn neurotoxicity prevention and Mn-induced AD treatment.

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“…Tyrphostin AG879 has long been widely used as a protein tyrosine kinase inhibitor and is known to have beneficial anti‐tumour properties, which include inhibition of NGF‐induced PLC‐γ 1 phosphorylation and PI3K activation (Ohmichi et al ., ; Rende et al ., 2000; 2006), inhibition of ErbB2 receptors and the VEGF receptor 2 (FLK‐1) (He et al ., 2001; 2004; Zhou and Brattain, ; Lee et al ., ) and indirect inhibition of the MAPK cascade (Gil et al ., ; Larsson, ). Although AG879 potently inhibits, with an IC 50 of 1 μM, the expression of human epidermal growth factor receptor 2/ErbB2 receptors, the compound starts to cause apoptosis or reduce the proliferation of cells at concentrations more than 5∼20 μM in TrkA‐highly expressed tumour cell lines (Rende et al ., ).…”

Section: Discussionmentioning

confidence: 99%

Effect of tyrphostin AG879 on K_v4.2 and K_v4.3 potassium channels

Zou

Wang

et al. 2015

British J Pharmacology

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Background and Purpose A‐type potassium channels (IA) are important proteins for modulating neuronal membrane excitability. The expression and activity of Kv4.2 channels are critical for neurological functions and pharmacological inhibitors of Kv4.2 channels may have therapeutic potential for Fragile X syndrome. While screening various compounds, we identified tyrphostin AG879, a tyrosine kinase inhibitor, as a Kv4.2 inhibitor from. In the present study we characterized the effect of AG879 on cloned Kv4.2/Kv channel‐interacting protein 2 (KChIP2) channels. Experimental Approach To screen the library of pharmacologically active compounds, the thallium flux assay was performed on HEK‐293 cells transiently‐transfected with Kv4.2 cDNA using the Maxcyte transfection system. The effects of AG879 were further examined on CHO‐K1 cells expressing Kv4.2/KChIP2 channels using a whole‐cell patch‐clamp technique. Key Results Tyrphostin AG879 selectively and dose‐dependently inhibited Kv4.2 and Kv4.3 channels. In Kv4.2/KChIP2 channels, AG879 induced prominent acceleration of the inactivation rate, use‐dependent block and slowed the recovery from inactivation. AG879 induced a hyperpolarizing shift in the voltage‐dependence of the steady‐state inactivation of Kv4.2 channels without apparent effect on the V1/2 of the voltage‐dependent activation. The blocking effect of AG879 was enhanced as channel inactivation increased. Furthermore, AG879 significantly inhibited the A‐type potassium currents in the cultured hippocampus neurons. Conclusion and Implications AG879 was identified as a selective and potent inhibitor the Kv4.2 channel. AG879 inhibited Kv4.2 channels by preferentially interacting with the open state and further accelerating their inactivation.

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Tyrphostin ErbB2 Inhibitors AG825 and AG879 Have Non-specific Suppressive Effects on gp130/ STAT3 Signaling

Cited by 4 publications

References 25 publications

Betacellulin-Induced Beta Cell Proliferation and Regeneration Is Mediated by Activation of ErbB-1 and ErbB-2 Receptors

Betacellulin-Induced Beta Cell Proliferation and Regeneration Is Mediated by Activation of ErbB-1 and ErbB-2 Receptors

Identifying key genes, pathways and screening therapeutic agents for manganese-induced Alzheimer disease using bioinformatics analysis

Effect of tyrphostin AG879 on K_v4.2 and K_v4.3 potassium channels

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Tyrphostin ErbB2 Inhibitors AG825 and AG879 Have Non-specific Suppressive Effects on gp130/ STAT3 Signaling

Cited by 4 publications

References 25 publications

Betacellulin-Induced Beta Cell Proliferation and Regeneration Is Mediated by Activation of ErbB-1 and ErbB-2 Receptors

Betacellulin-Induced Beta Cell Proliferation and Regeneration Is Mediated by Activation of ErbB-1 and ErbB-2 Receptors

Identifying key genes, pathways and screening therapeutic agents for manganese-induced Alzheimer disease using bioinformatics analysis

Effect of tyrphostin AG879 on Kv4.2 and Kv4.3 potassium channels

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Effect of tyrphostin AG879 on K_v4.2 and K_v4.3 potassium channels