scholarly journals Podocyte EGFR Inhibits Autophagy Through Upregulation of Rubicon in Type II Diabetic Nephropathy

2020 ◽  
Author(s):  
Yan Li ◽  
Yu Pan ◽  
Shirong Cao ◽  
Kensuke Sasaki ◽  
Yinqiu Wang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
High Glucose ◽  
Growth Factor Receptor ◽  
Type Ii ◽  
Egfr Signaling ◽  
Podocyte Injury ◽  
Egfr Signaling Pathway ◽  
Epidermal Growth ◽  
Sirna Knockdown ◽  
Autophagy Activity

Renal epidermal growth factor receptor (EGFR) signaling is activated in models of diabetic nephropathy (DN), and inhibition of EGFR signaling pathway protects against the development of DN. We have now determined that in cultured podocytes, high glucose led to increases in activation of EGFR signaling but decreases in autophagy activity as indicated by decreased beclin-1 and inhibition of LC3B autophagosome formation as well as increased rubicon (an autophagy inhibitor) and SQSTM1 (autophagy substrate). Either genetic (siEGFR) or pharmacologic (AG1478) inhibition of EGFR signaling attenuated the decreased autophagy activity. In addition, rubicon siRNA knockdown prevented high glucose-induced inhibition of autophagy in podocytes. We further examined whether selective EGFR deletion in podocytes affected the progression of DN in type II diabetes. Selective podocyte EGFR deletion had no effect on body weight or fasting blood sugars in either <i>db/db</i> mice or <i>nos3</i><sup>-/-</sup>; <i>db/db </i>mice, a model of accelerated type II DN. However selective podocyte EGFR deletion led to relative podocyte preservation and marked reduction in albuminuria and glomerulosclerosis, renal proinflammatory cytokine/chemokine expression and decreased pro-fibrotic and fibrotic components in <i>nos3</i><sup>-/-</sup>; <i>db/db</i> mice. Podocyte EGFR deletion led to decreased podocyte expression of rubicon, in association with increased podocyte autophagy activity. Therefore, activation of EGFR signaling in podocytes contributes to progression of DN at least in part by increasing rubicon expression, leading to subsequent autophagy inhibition and podocyte injury.

scholarly journals Podocyte EGFR Inhibits Autophagy Through Upregulation of Rubicon in Type II Diabetic Nephropathy

2020 ◽  
Author(s):  
Yan Li ◽  
Yu Pan ◽  
Shirong Cao ◽  
Kensuke Sasaki ◽  
Yinqiu Wang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
High Glucose ◽  
Growth Factor Receptor ◽  
Type Ii ◽  
Egfr Signaling ◽  
Podocyte Injury ◽  
Egfr Signaling Pathway ◽  
Epidermal Growth ◽  
Sirna Knockdown ◽  
Autophagy Activity

Renal epidermal growth factor receptor (EGFR) signaling is activated in models of diabetic nephropathy (DN), and inhibition of EGFR signaling pathway protects against the development of DN. We have now determined that in cultured podocytes, high glucose led to increases in activation of EGFR signaling but decreases in autophagy activity as indicated by decreased beclin-1 and inhibition of LC3B autophagosome formation as well as increased rubicon (an autophagy inhibitor) and SQSTM1 (autophagy substrate). Either genetic (siEGFR) or pharmacologic (AG1478) inhibition of EGFR signaling attenuated the decreased autophagy activity. In addition, rubicon siRNA knockdown prevented high glucose-induced inhibition of autophagy in podocytes. We further examined whether selective EGFR deletion in podocytes affected the progression of DN in type II diabetes. Selective podocyte EGFR deletion had no effect on body weight or fasting blood sugars in either <i>db/db</i> mice or <i>nos3</i><sup>-/-</sup>; <i>db/db </i>mice, a model of accelerated type II DN. However selective podocyte EGFR deletion led to relative podocyte preservation and marked reduction in albuminuria and glomerulosclerosis, renal proinflammatory cytokine/chemokine expression and decreased pro-fibrotic and fibrotic components in <i>nos3</i><sup>-/-</sup>; <i>db/db</i> mice. Podocyte EGFR deletion led to decreased podocyte expression of rubicon, in association with increased podocyte autophagy activity. Therefore, activation of EGFR signaling in podocytes contributes to progression of DN at least in part by increasing rubicon expression, leading to subsequent autophagy inhibition and podocyte injury.

scholarly journals Quercetin Attenuates Podocyte Apoptosis of Diabetic Nephropathy Through Targeting EGFR Signaling

2022 ◽  
Vol 12 ◽  
Author(s):  
Yiqi Liu ◽  
Yuan Li ◽  
Liu Xu ◽  
Jiasen Shi ◽  
Xiujuan Yu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Signaling Pathway ◽  
Growth Factor Receptor ◽  
Network Pharmacology ◽  
Egfr Signaling ◽  
Egfr Signaling Pathway ◽  
Novel Approach ◽  
Apoptotic Protein ◽  
Epidermal Growth

Podocytes injury is one of the leading causes of proteinuria in patients with diabetic nephropathy (DN), and is accompanied by podocytes apoptosis and the reduction of podocyte markers such as synaptopodin and nephrin. Therefore, attenuation of podocyte apoptosis is considered as an effective strategy to prevent the proteinuria in DN. In this study, we evaluated the anti-podocyte-apoptosis effect of quercetin which is a flavonol compound possessing an important role in prevention and treatment of DN and verified the effect by using db/db mice and high glucose (HG)-induced mouse podocytes (MPs). The results show that administration of quercetin attenuated the level of podocyte apoptosis by decreasing the expression of pro-apoptotic protein Bax, cleaved caspase 3 and increasing the expression of anti-apoptotic protein Bcl-2 in the db/db mice and HG-induced MPs. Furthermore, epidermal growth factor receptor (EGFR) was predicted to be the potential physiological target of quercetin by network pharmacology. In vitro and vivo experiments confirmed that quercetin inhibited activation of the EGFR signaling pathway by decreasing phosphorylation of EGFR and ERK1/2. Taken together, this study demonstrates that quercetin attenuated podocyte apoptosis through inhibiting EGFR signaling pathway, which provided a novel approach for further research of the mechanism of quercetin in the treatment of DN.

scholarly journals CG6015 controls spermatogonia transit-amplifying divisions by epidermal growth factor receptor signaling in Drosophila testes

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Jun Yu ◽  
Qianwen Zheng ◽  
Zhiran Li ◽  
Yunhao Wu ◽  
Yangbo Fu ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Stem Cell ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Gene Set Enrichment Analysis ◽  
Germline Stem Cell ◽  
Egfr Signaling ◽  
Egfr Signaling Pathway ◽  
Epidermal Growth

AbstractSpermatogonia transit-amplifying (TA) divisions are crucial for the differentiation of germline stem cell daughters. However, the underlying mechanism is largely unknown. In the present study, we demonstrated that CG6015 was essential for spermatogonia TA-divisions and elongated spermatozoon development in Drosophila melanogaster. Spermatogonia deficient in CG6015 inhibited germline differentiation leading to the accumulation of undifferentiated cell populations. Transcriptome profiling using RNA sequencing indicated that CG6015 was involved in spermatogenesis, spermatid differentiation, and metabolic processes. Gene Set Enrichment Analysis (GSEA) revealed the relationship between CG6015 and the epidermal growth factor receptor (EGFR) signaling pathway. Unexpectedly, we discovered that phosphorylated extracellular regulated kinase (dpERK) signals were activated in germline stem cell (GSC)-like cells after reduction of CG6015 in spermatogonia. Moreover, Downstream of raf1 (Dsor1), a key downstream target of EGFR, mimicked the phenotype of CG6015, and germline dpERK signals were activated in spermatogonia of Dsor1 RNAi testes. Together, these findings revealed a potential regulatory mechanism of CG6015 via EGFR signaling during spermatogonia TA-divisions in Drosophila testes.

scholarly journals Progress toward resistance mechanism to epidermal growth factor receptor tyrosine kinase inhibitor

2016 ◽  
Vol 11 (1) ◽  
pp. 427-431
Author(s):  
Lingling Zhang ◽  
Xiaoxue Zhang ◽  
Liang Zhao
Keyword(s):  
Drug Resistance ◽  
Epidermal Growth Factor Receptor ◽  
Signaling Pathway ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Egfr Signaling ◽  
Egfr Signaling Pathway ◽  
Epidermal Growth ◽  
Egfr Tki

AbstractThe EGFR signaling pathway plays an important role in the occurrence and development of many malignant tumors. It has become a hot spot in the treatment of advanced cancer. At present, the small molecule epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has been shown to advanced non-small-cell lung cancer (NSCLC), has a marked drug resistance or has developed one. The EGFR signaling pathway regulates a variety of cellular functions, and its drug resistance may be related to a number of signal transduction pathways, including drug resistance mutations, structural activation, downstream signaling pathway activation and VEGF expression changes, and so on. In this paper, we review the production mechanism of EGFR-TKI drug resistance.

scholarly journals MYLK4 promotes tumor progression through the activation of epidermal growth factor receptor signaling in osteosarcoma

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Mengkai Yang ◽  
Tao Zhang ◽  
Yangfeng Zhang ◽  
Xiaojun Ma ◽  
Jing Han ◽  
...  
Keyword(s):  
Light Chain ◽  
Myosin Light Chain Kinase ◽  
Myosin Light Chain ◽  
Growth Factor Receptor ◽  
Tissue Microarrays ◽  
Egfr Signaling ◽  
Egfr Signaling Pathway ◽  
Kinase Family ◽  
Epidermal Growth

Abstract Background Osteosarcoma (OS) is the most common primary bone cancer in adolescents and lung metastasis is the leading cause of death in patients with OS. However, the molecular mechanisms that promote OS growth and metastasis remain unknown. Methods We investigated the expression of myosin light chain kinase family members between metastasis and non-metastasis patients in the TARGET database and ensured that only myosin light chain kinase family member 4 (MYLK4) had higher expression in metastatic osteosarcoma patients. Then we confirmed the results by immunohistochemistry (IHC) and Western blotting (WB) of OS tissues. The effect of MYLK4 on the metastasis and proliferation of OS cells was investigated by wound healing, Transwell and colony-formation assays. Mass spectrum analysis was used to ensure the new binding protein of MYLK4. Tissue microarrays analysis was used to show the correlation between MYLK4 and pEGFR (Y1068). A series of in vivo experiments were conducted to reveal the mechanisms by which MYLK4 modulated the metastasis and proliferation of OS. Results Myosin Light Chain Kinase Family Member 4 (MYLK4) was significantly upregulated in metastatic human OS tissues. Growth and metastasis of OS could be accelerated by MYLK4 overexpression, whereas silencing MYLK4 expression resulted in decreased cell growth and metastasis. Mechanistically, mass spectrum analysis showed that MYLK4 interacted with the epidermal growth factor receptor (EGFR) in osteosarcoma cells and promoted growth and metastasis via the EGFR signaling pathway. Tissue microarrays analysis also showed that MYLK4 expression had a positive correlation with the expression of pEGFR (Y1068). Moreover, the EGFR inhibitor gefitinib could partially reverse the effect of cell proliferation and metastasis caused by MYLK4 overexpression. Importantly, the combination of MYLK4 and EGFR inhibitors had synergistic effects on growth and metastasis of OS in vitro and in vivo. Conclusion Our results indicate that MYLK4 promotes OS growth and metastasis by activating the EGFR signaling pathway and can be a novel therapeutic target for the treatment of OS patients.

Single Nucleotide Polymorphisms in MicroRNA-Binding Site of Epidermal Growth Factor Receptor Signaling Pathway and Susceptibility to Esophageal Squamous Cell Carcinoma

2019 ◽  
Vol 38 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Yanhong Qu ◽  
Yougai Zhang ◽  
Kaijuan Wang ◽  
Chunhua Song ◽  
Peng Wang ◽  
...  
Keyword(s):  
Binding Site ◽  
Signaling Pathway ◽  
Target Genes ◽  
Growth Factor Receptor ◽  
Nucleotide Polymorphisms ◽  
Egfr Signaling ◽  
Single Nucleotide ◽  
Egfr Signaling Pathway ◽  
Gene Environment ◽  
Epidermal Growth

Background: Epidermal growth factor receptor (EGFR) signaling pathway plays a fundamental role in regulating cell proliferation, differentiation, apoptosis, migration, and so on, which are associated with tumor development, including the esophageal squamous cell carcinoma (ESCC). The single nucleotide polymorphisms (SNPs) of microRNA-binding sites with target genes in the EGFR pathway could lead to alteration in the combination of microRNA with target genes and contribute to the susceptibility of cancer. Methods: A case-control study including 494 ESCC patients and 494 controls was carried out to investigate the genetic susceptibility of 4 microRNA-binding site SNPs (rs712 in the binding site of KRAS to let-7, rs8904 in the binding site of NFBIA to mir-507, rs3738894 in the binding site of protein kinase C epsilon to mir-218, rs701848 in the binding site of phosphatase and tensin to mir-1304) as well as the interactions of gene-environment in the development of ESCC. Results: The results showed that compared with CC genotype, the individuals with TT and TT + CT genotypes of rs701848 were significantly associated with increased ESCC risk (OR adjusted 1.56, 95% CI 1.07–2.27 and 1.41, 1.01–1.97). The gene-Environment interaction between rs3738894 and smoking history was associated with the risk of esophageal cancer. Conclusions: Results of these analyses underline the support of the notion that SNPs in microRNA-binding site of EGFR signaling pathway play certain important roles in the susceptibility to ESCC.

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