Modulation of Rab7a-mediated growth factor receptor trafficking inhibits islet beta cell apoptosis and autophagy under conditions of metabolic stress

Hewawasam, Nirun Videesha; Lhaf, Fadel; Taylor, Henry Adegbite; Viloria, Katrina; Austin, Amazon; King, Aileen; Jones, Peter M.; Jones, Lucy; Turner, Martha; Hill, Natasha J.

doi:10.1038/s41598-020-72939-y

Cited by 3 publications

(3 citation statements)

References 41 publications

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“…Rab7a GTPase is involved in regulating endocytosis-mediated protein trafficking [ 15 , 16 ]. In particular, Rab7A facilitates trafficking of membrane receptors, such as growth factor receptor, from early endosome to late endosome and lysosome for their ultimate degradation [ 17 ]. Therefore, we focused on the relation between RAB7a phosphorylation and EGFR trafficking.…”

Section: Resultsmentioning

confidence: 99%

EGFR tyrosine kinase activity and Rab GTPases coordinate EGFR trafficking to regulate macrophage activation in sepsis

et al. 2022

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EGFR phosphorylation is required for TLR4-mediated macrophage activation during sepsis. However, whether and how intracellular EGFR is transported during endotoxemia have largely been unknown. Here, we show that LPS promotes high levels cell surface expression of EGFR in macrophages through two different transport mechanisms. On one hand, Rab10 is required for EEA1-mediated the membrane translocation of EGFR from the Golgi. On the other hand, EGFR phosphorylation prevents its endocytosis in a kinase activity-dependent manner. Erlotinib, an EGFR tyrosine kinase inhibitor, significantly reduced membrane EGFR expression in LPS-activated macrophage. Mechanistically, upon LPS induced TLR4/EGFR phosphorylation, MAPK14 phosphorylated Rab7a at S72 impaired membrane receptor late endocytosis, which maintains EGFR membrane localization though blocking its lysosomal degradation. Meanwhile, Rab5a is also involved in the early endocytosis of EGFR. Subsequently, inhibition of EGFR phosphorylation switches M1 phenotype to M2 phenotype and alleviates sepsis-induced acute lung injury. Mechanistic study demonstrated that Erlotinib suppressed glycolysis-dependent M1 polarization via PKM2/HIF-1ɑ pathway and promoted M2 polarization through up-regulating PPARγ induced glutamine metabolism. Collectively, our data elucidated a more in-depth mechanism of macrophages activation, and provided stronger evidence supporting EGFR as a potential therapeutic target for the treatment of sepsis.

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Section: Resultsmentioning

confidence: 99%

EGFR tyrosine kinase activity and Rab GTPases coordinate EGFR trafficking to regulate macrophage activation in sepsis

et al. 2022

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“…We demonstrated that the LAMP2 was suppressed in T2DM by experiment validation, which might indicate that downregulated LAMP2 affected the density and integrity of lysosome during T2DM development. Under metabolic stress, RAB7A inhibits pancreatic β-cell apoptosis and autophagy through mediated growth factor receptor trafficking ( 38 ). RB1-inducible coiled-coil 1 (RB1CC1) is a member of the ULK1-ATG13-RB1CC1/FIP200 complex protein and is suppressed by mTOR and is a key autophagy inducer ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

Identification and analysis of type 2 diabetes-mellitus-associated autophagy-related genes

Chen

2023

Front. Endocrinol.

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IntroductionAutophagy, an innate safeguard mechanism for protecting the organism against harmful agents, is implicated in the survival of pancreatic â cells and the development of type 2 diabetes mellitus (T2DM). Potential autophagy-related genes (ARGs) may serve as potential biomarkers for T2DM treatment.MethodsThe GSE25724 dataset was downloaded from the Gene Expression Omnibus (GEO) database, and ARGs were obtained from the Human Autophagy Database. The differentially expressed autophagy-related genes (DEARGs) were screened at the intersection of ARGs and differentially expressed genes (DEGs) between T2DM and non-diabetic islet samples, which were subjected to functional enrichment analyses. A protein–protein interaction (PPI) network was constructed to identify hub DEARGs. Expressions of top 10 DEARGs were validated in human pancreatic â-cell line NES2Y and rat pancreatic INS-1 cells using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell viability and insulin secretion were measured after cell transfection with lentiviral vector EIF2AK3 or RB1CC1 into islet cells.ResultsIn total, we discovered 1,270 DEGs (266 upregulated and 1,004 downregulated genes) and 30 DEARGs enriched in autophagy- and mitophagy-related pathways. In addition, we identified GAPDH, ITPR1, EIF2AK3, FOXO3, HSPA5, RB1CC1, LAMP2, GABARAPL2, RAB7A, and WIPI1 genes as the hub ARGs. Next, qRT-PCR analysis revealed that expressions of hub DEARGs were consistent with findings from bioinformatics analysis. EIF2AK3, GABARAPL2, HSPA5, LAMP2, and RB1CC1 were both differentially expressed in the two cell types. Overexpression of EIF2AK3 or RB1CC1 promoted cell viability of islet cells and increased the insulin secretion.DiscussionThis study provides potential biomarkers as therapeutic targets for T2DM.

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“…The key role played by Rab7a in receptor degradation and cell signalling regulation has been demonstrated in β-pancreatic cells under metabolic stress. Inhibition of Rab7 increased IGF-I receptor density and signalling and promoted β-cell survival, suggesting this could be a therapeutical approach for type-II diabetes [58].…”

Section: From the Late Endosome To The Lysosomementioning

confidence: 99%

Revising Endosomal Trafficking under Insulin Receptor Activation

Iraburu

Garner

Montiel-Duarte

2021

IJMS

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The endocytosis of ligand-bound receptors and their eventual recycling to the plasma membrane (PM) are processes that have an influence on signalling activity and therefore on many cell functions, including migration and proliferation. Like other tyrosine kinase receptors (TKR), the insulin receptor (INSR) has been shown to be endocytosed by clathrin-dependent and -independent mechanisms. Once at the early endosome (EE), the sorting of the receptor, either to the late endosome (LE) for degradation or back to the PM through slow or fast recycling pathways, will determine the intensity and duration of insulin effects. Both the endocytic and the endosomic pathways are regulated by many proteins, the Arf and Rab families of small GTPases being some of the most relevant. Here, we argue for a specific role for the slow recycling route, whilst we review the main molecular mechanisms involved in INSR endocytosis, sorting and recycling, as well as their possible role in cell functions.

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Modulation of Rab7a-mediated growth factor receptor trafficking inhibits islet beta cell apoptosis and autophagy under conditions of metabolic stress

Cited by 3 publications

References 41 publications

EGFR tyrosine kinase activity and Rab GTPases coordinate EGFR trafficking to regulate macrophage activation in sepsis

EGFR tyrosine kinase activity and Rab GTPases coordinate EGFR trafficking to regulate macrophage activation in sepsis

Identification and analysis of type 2 diabetes-mellitus-associated autophagy-related genes

Revising Endosomal Trafficking under Insulin Receptor Activation

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