EGF receptor in pancreatic β-cell mass regulation

Miettinen, Päivi J.; Ormio, Päivi; Hakonen, Elina; Banerjee, Meenal; Otonkoski, Timo

doi:10.1042/bst0360280

Cited by 58 publications

(44 citation statements)

References 57 publications

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“…As dCbl and EGFR have been implicated in the regulation of cell survival and proliferation (28,33,63), we first utilized the UAS-srcGFP line to produce dilp2G4ϾGFP, dCblRNAi and dilp2G4ϾGFP, dEGFR-DN flies and tested whether dCbl suppression or blocking of dEGFR signaling affects the survival of IPCs. GFP-facilitated visualization showed no alterations in the morphology and number of IPCs in dilp2G4ϾGFP, dCbl-RNAi or dilp2G4ϾGFP, dEGFR-DN flies compared to dilp2G4ϾGFP controls (Fig.…”

Section: Resultsmentioning

confidence: 99%

Neuronal Cbl Controls Biosynthesis of Insulin-Like Peptides in Drosophila melanogaster

Sun

et al. 2012

Molecular and Cellular Biology

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bThe Cbl family proteins function as both E3 ubiquitin ligases and adaptor proteins to regulate various cellular signaling events, including the insulin/insulin-like growth factor 1 (IGF1) and epidermal growth factor (EGF) pathways. These pathways play essential roles in growth, development, metabolism, and survival. Here we show that in Drosophila melanogaster, Drosophila Cbl (dCbl) regulates longevity and carbohydrate metabolism through downregulating the production of Drosophila insulin-like peptides (dILPs) in the brain. We found that dCbl was highly expressed in the brain and knockdown of the expression of dCbl specifically in neurons by RNA interference increased sensitivity to oxidative stress or starvation, decreased carbohydrate levels, and shortened life span. Insulin-producing neuron-specific knockdown of dCbl resulted in similar phenotypes. dCbl deficiency in either the brain or insulin-producing cells upregulated the expression of dilp genes, resulting in elevated activation of the dILP pathway, including phosphorylation of Drosophila Akt and Drosophila extracellular signal-regulated kinase (dERK). Genetic interaction analyses revealed that blocking Drosophila epidermal growth factor receptor (dEGFR)-dERK signaling in pan-neurons or insulin-producing cells by overexpressing a dominant-negative form of dEGFR abolished the effect of dCbl deficiency on the upregulation of dilp genes. Furthermore, knockdown of c-Cbl in INS-1 cells, a rat ␤-cell line, also increased insulin biosynthesis and glucose-stimulated secretion in an ERK-dependent manner. Collectively, these results suggest that neuronal dCbl regulates life span, stress responses, and metabolism by suppressing dILP production and the EGFR-ERK pathway mediates the dCbl action. Cbl suppression of insulin biosynthesis is evolutionarily conserved, raising the possibility that Cbl may similarly exert its physiological actions through regulating insulin production in ␤ cells.

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Section: Resultsmentioning

confidence: 99%

Neuronal Cbl Controls Biosynthesis of Insulin-Like Peptides in Drosophila melanogaster

Sun

et al. 2012

Molecular and Cellular Biology

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“…BTC is involved in both pathways; it is known to induce proliferation of insulinoma cells in vitro [33], improve glucose tolerance, enhance insulin secretion [34], reverse streptozotocin-induced hyperglycemia in mice [35], and induce endocrine differentiation of the exocrine cell line AR42J [23]. This differentiation potency can be explained because EGFR activation affects cell function on multiple levels, depending on the signaling pathways that are activated [18]. Our in vitro results indicate that the overexpression of BTC in rat MSCs may induce the expression of PDX1 as well as …”

Section: Discussionmentioning

confidence: 99%

“…Betacellulin (BTC) is a multifunctional polypeptide growth factor belonging to the family of epidermal growth factor receptor (EGFR) ligands [17]. BTC was first described as a mitogen from a mouse pancreatic insulinoma cell line [18]. BTC is initially produced as a transmembrane protein that can be cleaved by metalloproteinase to release the mature circulating form [19].…”

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confidence: 99%

Betacellulin Overexpression in Mesenchymal Stem Cells Induces Insulin Secretion In Vitro and Ameliorates Streptozotocin-Induced Hyperglycemia in Rats

Paz

Salton

Ayala-Lugo

et al. 2011

Stem Cells and Development

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Betacellulin (BTC), a ligand of the epidermal growth factor receptor, has been shown to promote growth and differentiation of pancreatic b-cells and to improve glucose metabolism in experimental diabetic rodent models. Mesenchymal stem cells (MSCs) have been already proved to be multipotent. Recent work has attributed to rat and human MSCs the potential to differentiate into insulin-secreting cells. Our goal was to transfect rat MSCs with a plasmid containing BTC cDNA to guide MSC differentiation into insulin-producing cells. Prior to induction of cell MSC transfection, MSCs were characterized by flow cytometry and the ability to in vitro differentiate into mesoderm cell types was evaluated. After rat MSC characterization, these cells were electroporated with a plasmid containing BTC cDNA. Transfected cells were cultivated in Dulbecco's modified Eagle medium high glucose (H-DMEM) with 10 mM nicotinamide. Then, the capability of MSC-BTC to produce insulin in vitro and in vivo was evaluated. It was possible to demonstrate by radioimmunoassay analysis that 10 4 MSC-BTC cells produced up to 0.4 ng=mL of insulin, whereas MSCs transfected with the empty vector (negative control) produced no detectable insulin levels. Moreover, MSC-BTC were positive for insulin in immunohistochemistry assay. In parallel, the expression of pancreatic marker genes was demonstrated by molecular analysis of MSC-BTC. Further, when MSC-BTC were transplanted to streptozotocin diabetic rats, BTC-transfected cells ameliorated hyperglycemia from over 500 to about 200 mg=dL at 35 days post-cell transplantation. In this way, our results clearly demonstrate that BTC overabundance enhances glucose-induced insulin secretion in MSCs in vitro as well as in vivo.

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“…Egf-null mutant mice show no change in the pancreatic phenotype, probably due to redundant expression of ErbB ligands [33]. In adult pancreas, EGF receptor (EGFR) is detected in islet and duct cells, but not in acinar cells [34].…”

Section: Discussionmentioning

confidence: 99%

A combination of cytokines EGF and CNTF protects the functional beta cell mass in mice with short-term hyperglycaemia

et al. 2016

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Aims/hypothesis When the beta cell mass or function declines beyond a critical point, hyperglycaemia arises. Little is known about the potential pathways involved in beta cell rescue. As two cytokines, epidermal growth factor (EGF) and ciliary neurotrophic factor (CNTF), restored a functional beta cell mass in mice with long-term hyperglycaemia by reprogramming acinar cells that transiently expressed neurogenin 3 (NGN3), the current study assesses the effect of these cytokines on the functional beta cell mass after an acute chemical toxic insult. Methods Glycaemia and insulin levels, pro-endocrine gene expression and beta cell origin, as well as the role of signal transducer and activator of transcription 3 (STAT3) signalling, were assessed in EGF+CNTF-treated mice following acute hyperglycaemia. Results The mice were hyperglycaemic 1 day following i.v. injection of the beta cell toxin alloxan, when the two cytokines were applied. One week later, 68.6 ± 4.6% of the mice had responded to the cytokine treatment and increased their insulin + cell number to 30% that of normoglycaemic control mice, resulting in restoration of euglycaemia. Although insulin − NGN3 + cells appeared following acute EGF+CNTF treatment, genetic lineage tracing showed that the majority of the insulin + cells originated from pre-existing beta cells. Beta cell rescue by EGF+CNTF depends on glycaemia rather than on STAT3-induced NGN3 expression in acinar cells. Conclusions/interpretation In adult mice, EGF+CNTF allows the rescue of beta cells in distress when treatment is given shortly after the diabetogenic insult. The rescued beta cells restore a functional beta cell mass able to control normal blood glucose levels. These findings may provide new insights into compensatory pathways activated early after beta cell loss.

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EGF receptor in pancreatic β-cell mass regulation

Cited by 58 publications

References 57 publications

Neuronal Cbl Controls Biosynthesis of Insulin-Like Peptides in Drosophila melanogaster

Neuronal Cbl Controls Biosynthesis of Insulin-Like Peptides in Drosophila melanogaster

Betacellulin Overexpression in Mesenchymal Stem Cells Induces Insulin Secretion In Vitro and Ameliorates Streptozotocin-Induced Hyperglycemia in Rats

A combination of cytokines EGF and CNTF protects the functional beta cell mass in mice with short-term hyperglycaemia

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