Hydrogen Sulfide Targets EGFR Cys797/Cys798 Residues to Induce Na<sup>+</sup>/K<sup>+</sup>-ATPase Endocytosis and Inhibition in Renal Tubular Epithelial Cells and Increase Sodium Excretion in Chronic Salt-Loaded Rats

Ge, Shun-Na; Zhao, Manman; Wu, Dongdong; Chen, Ying; Wang, Yi; Zhu, Jianhua; Cai, Wenjie; Zhu, Yi‐Zhun; Zhu, Yi‐Chun

doi:10.1089/ars.2013.5304

Cited by 57 publications

(38 citation statements)

References 38 publications

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“…Analyzing the EGCG binding with the wild type EGFR, one preferential and favorite binding pose was found, involving directly the ATP binding pocket ( Figure 7A) in agreement with experimental results. Due to the high number of OH groups of this catechin, five different Hbond interactions were found, involving Ile744, Gly796, Asn842 and Asp855 residues, and in particular with Cys797, which is very important for the EGFR inhibition as already demonstrated in other studies [40]. In addition, further hydrophobic interactions with different aminoacid residues were observed ( Figure 7B).…”

Section: Erl and Egcg Binding Mode With Egfr Wild Typesupporting

confidence: 64%

Conformational Insight on WT- and Mutated-EGFR Receptor Activation and Inhibition by Epigallocatechin-3-Gallate: Over a Rational Basis for the Design of Selective Non-Small-Cell Lung Anticancer Agents

Minnelli

Laudadio

Mobbili

et al. 2020

IJMS

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Non-small cell lung cancer (NSCLC) represents a difficult condition to treat, due to epidermal growth factor receptor (EGFR) kinase domain mutations, which lead to ligand-independent phosphorylation. Deletion of five amino acids (ELREA) in exon 19 and mutational change from leucine to arginine at position 858 (L858R) are responsible for tyrosine kinase domain aberrant activation. These two common types of EGFR-mutated forms are clinically associated with high response with Tyrosine Kinase Inhibitors (TKI); however, the secondary T790M mutation within the Tyrosine Kinase Domain (TKD) determines a resistance to these EGFR-TKIs. Using molecular dynamic simulation (MD), the present study investigated the architectural changes of wild-type and mutants EGFR’s kinase domains in order to detect any conformational differences that could be associated with a constitutively activated state and thus to evaluate the differences between the wild-type and its mutated forms. In addition, in order to evaluate to which extent the EGFR mutations affect its inhibition, Epigallocatechin 3-Gallate (EGCG) and Erlotinib (Erl), known EGFR-TKI, were included in our study. Their binding modes with the EGFR-TK domain were elucidated and the binding differences between EGFR wild-type and the mutated forms were evidenced. The aminoacids mutations directly influence the binding affinity of these two inhibitors, resulting in a different efficacy of Erl and EGCG inhibition. In particular, for the T790M/L858R EGFR, the binding modes of studied inhibitors were compromised by aminoacidic substitution confirming the experimental findings. These results may be useful for novel drug design strategies targeting the dimerization domain of the EGFR mutated forms, thus preventing receptor activation.

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Section: Erl and Egcg Binding Mode With Egfr Wild Typesupporting

confidence: 64%

Conformational Insight on WT- and Mutated-EGFR Receptor Activation and Inhibition by Epigallocatechin-3-Gallate: Over a Rational Basis for the Design of Selective Non-Small-Cell Lung Anticancer Agents

Minnelli

Laudadio

Mobbili

et al. 2020

IJMS

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“…Consistent with this idea, a recent study demonstrated reduced granule exocytosis in H 2 S-exposed platelets, which may be due to interference of H 2 S with SNARE-mediated vesicle exocytosis (34). Aside from the trafficking machinery, the translocation of ENaCcontaining vesicles in lung epithelial cells may involve additional, yet unidentified, pathways involving protein tyrosine kinase (8,51,90), and H 2 S has recently been implicated in the modulation of tyrosine kinase-dependent signaling pathways (32,78).…”

Section: ϫ5mentioning

confidence: 72%

Hydrogen sulfide decreases β-adrenergic agonist-stimulated lung liquid clearance by inhibiting ENaC-mediated transepithelial sodium absorption

Agné

Baldin

Benjamin

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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-In pulmonary epithelia, ␤-adrenergic agonists regulate the membrane abundance of the epithelial sodium channel (ENaC) and, thereby, control the rate of transepithelial electrolyte absorption. This is a crucial regulatory mechanism for lung liquid clearance at birth and thereafter. This study investigated the influence of the gaseous signaling molecule hydrogen sulfide (H 2S) on ␤-adrenergic agonistregulated pulmonary sodium and liquid absorption. Application of the H2S-liberating molecule Na2S (50 M) to the alveolar compartment of rat lungs in situ decreased baseline liquid absorption and abrogated the stimulation of liquid absorption by the ␤-adrenergic agonist terbutaline. There was no additional effect of Na2S over that of the ENaC inhibitor amiloride. In electrophysiological Ussing chamber experiments with native lung epithelia (Xenopus laevis), Na 2S inhibited the stimulation of amiloride-sensitive current by terbutaline. ␤-adrenergic agonists generally increase ENaC abundance by cAMP formation and activation of PKA. Activation of this pathway by forskolin and 3-isobutyl-1-methylxanthine increased amiloride-sensitive currents in H441 pulmonary epithelial cells. This effect was inhibited by Na 2S in a dose-dependent manner (5-50 M). Na2S had no effect on cellular ATP concentration, cAMP formation, and activation of PKA. By contrast, Na 2S prevented the cAMP-induced increase in ENaC activity in the apical membrane of H441 cells. H441 cells expressed the H 2S-generating enzymes cystathionine-␤-synthase, cystathionine-␥-lyase, and 3-mercaptopyruvate sulfurtransferase, and they produced H 2S amounts within the employed concentration range. These data demonstrate that H 2S prevents the stimulation of ENaC by cAMP/PKA and, thereby, inhibits the proabsorptive effect of ␤-adrenergic agonists on lung liquid clearance.

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“…The enzyme D-amino acid oxidase constitutes an additional enzymatic pathway for H 2 S production and is highly expressed in mammalian kidneys (Shibuya et al, 2013). In mammals, endogenous H 2 S is proposed to be important for normal kidney function (Lobb et al, 2015) and H 2 S has been shown to increase glomerular filtration rate (Xia et al, 2009) and salt excretion by inhibition of Na + /K + -ATPase (Ge et al, 2014), and to suppress renin release (Cao and Bian, 2016). Given that H 2 S is an ancient vasoregulatory molecule across multiple vertebrate clades (Dombkowski et al, 2004), our data indicate that H 2 S could also have a similar regulatory role in the renal function of turtles.…”

Section: Resultsmentioning

confidence: 99%

Tissue-dependent variations of hydrogen sulfide homeostasis in anoxic freshwater turtles

Jensen

Pardue

Kevil

et al. 2019

Journal of Experimental Biology

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Hydrogen sulfide (H 2 S) controls numerous physiological responses. To understand its proposed role in metabolic suppression, we measured free H 2 S and bound sulfane sulfur (BSS) in tissues of the freshwater turtle Trachemys scripta elegans, a species undergoing strong metabolic suppression when cold and anoxic. In warm normoxic turtles, free H 2 S was higher in red blood cells (RBCs) and kidney (∼9-10 µmol l −1 ) than in brain, liver and lung (∼1-2 µmol l −1 ). These values overall aligned with the tissue H 2 S-generating enzymatic activity. BSS levels were similar in all tissues (∼0.5 µmol l −1 ) but ∼100-fold higher in RBCs, which have a high thiol content, suggesting that RBCs function as a circulating H 2 S reservoir. Cold acclimation caused significant changes in free and bound H 2 S in liver, brain and RBCs, but anoxia had no further effect, except in the brain. These results show tissue-dependent sulfide signaling with a potential role in brain metabolic suppression during anoxia in turtles.

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Hydrogen Sulfide Targets EGFR Cys797/Cys798 Residues to Induce Na⁺/K⁺-ATPase Endocytosis and Inhibition in Renal Tubular Epithelial Cells and Increase Sodium Excretion in Chronic Salt-Loaded Rats

Abstract: Aims: The role of hydrogen sulfide (H 2 S) in renal sodium and water homeostasis is unknown. We investigated whether H 2 S promoted Na + /K +

Cited by 57 publications

References 38 publications

Conformational Insight on WT- and Mutated-EGFR Receptor Activation and Inhibition by Epigallocatechin-3-Gallate: Over a Rational Basis for the Design of Selective Non-Small-Cell Lung Anticancer Agents

Conformational Insight on WT- and Mutated-EGFR Receptor Activation and Inhibition by Epigallocatechin-3-Gallate: Over a Rational Basis for the Design of Selective Non-Small-Cell Lung Anticancer Agents

Hydrogen sulfide decreases β-adrenergic agonist-stimulated lung liquid clearance by inhibiting ENaC-mediated transepithelial sodium absorption

Tissue-dependent variations of hydrogen sulfide homeostasis in anoxic freshwater turtles

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Hydrogen Sulfide Targets EGFR Cys797/Cys798 Residues to Induce Na+/K+-ATPase Endocytosis and Inhibition in Renal Tubular Epithelial Cells and Increase Sodium Excretion in Chronic Salt-Loaded Rats

Abstract: Aims: The role of hydrogen sulfide (H 2 S) in renal sodium and water homeostasis is unknown. We investigated whether H 2 S promoted Na + /K +

Cited by 57 publications

References 38 publications

Conformational Insight on WT- and Mutated-EGFR Receptor Activation and Inhibition by Epigallocatechin-3-Gallate: Over a Rational Basis for the Design of Selective Non-Small-Cell Lung Anticancer Agents

Conformational Insight on WT- and Mutated-EGFR Receptor Activation and Inhibition by Epigallocatechin-3-Gallate: Over a Rational Basis for the Design of Selective Non-Small-Cell Lung Anticancer Agents

Hydrogen sulfide decreases β-adrenergic agonist-stimulated lung liquid clearance by inhibiting ENaC-mediated transepithelial sodium absorption

Tissue-dependent variations of hydrogen sulfide homeostasis in anoxic freshwater turtles

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Hydrogen Sulfide Targets EGFR Cys797/Cys798 Residues to Induce Na⁺/K⁺-ATPase Endocytosis and Inhibition in Renal Tubular Epithelial Cells and Increase Sodium Excretion in Chronic Salt-Loaded Rats