Expression of a type I insulin-like growth factor receptor with low affinity for insulin-like growth factor II.
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ABSTRACT:
SUBMITTER: Germain-Lee EL
PROVIDER: S-EPMC1130700 | biostudies-other | 1992 Jan
REPOSITORIES: biostudies-other
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Project description:Human type 1 insulin-like growth factor receptor (IGF-1R) signals chiefly in response to the binding of insulin-like growth factor I. Relatively little is known about the role of insulin-like growth factor II signaling via IGF-1R, despite the affinity of insulin-like growth factor II for IGF-1R being within an order of magnitude of that of insulin-like growth factor I. Here, we describe the cryoelectron microscopy structure of insulin-like growth factor II bound to a leucine-zipper-stabilized IGF-1R ectodomain, determined in two conformations to a maximum average resolution of 3.2 Å. The two conformations differ in the relative separation of their respective points of membrane entry, and comparison with the structure of insulin-like growth factor I bound to IGF-1R reveals long-suspected differences in the way in which the critical C domain of the respective growth factors interact with IGF-1R.
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Project description:We previously demonstrated that inhibition of epidermal growth factor receptor (EGFR) slowed corneal epithelial migration. Here we examine the effect of EGF on transforming growth factor-beta receptor II (TGF-βRII) in a corneal wound-healing model and primary human corneal epithelial cells (pHCE). Corneal debridement wounds were made and allowed to heal ± Tyrphostin AG1478 (EGFR inhibitor), and assayed for EGFR activation and EGFR and TGF-βRII localization. Primary HCE were treated with EGF ± U0126 (MEK inhibitor) and assayed for TGF-βRII expression. EGFR activation was maximal 15 minutes after wounding and localized in the migrating epithelial cells. TGF-βRII localization was also observed in the migrating epithelium and was reduced when EGFR was blocked. When pHCE were treated with EGF for 6 hours, the cells produced enhanced levels of TGF-βRII, which was blocked by U0126. Downstream signaling pathways of MEK (p38MAPK and ERK1/2MAPK) were then examined, and TGF-β1 and EGF were found to have differential effects on the phosphorylation of p38 and ERK1/2, with TGF-β1 upregulating p-p38 but not pERK1/2 and EGF upregulating pERK1/2 but not p-p38. Taken together, these data indicate that EGF stimulates TGF-βRII through ERK1/2 and EGFR signaling, suggesting interplay between EGF- and TGF-β-signaling pathways during corneal wound repair.
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Project description:Pathological cardiac hypertrophy is commonly associated with an upregulation of fetal genes, fibrosis, cardiac dysfunction, and heart failure. Previous studies have demonstrated that gastrodin (GAS) exerts cardioprotective action in the treatment of cardiac hypertrophy. However, the mechanism by which GAS protects against cardiac hypertrophy is yet to be elucidated. A mouse model of myocardial hypertrophy was established using an angiotensin II (Ang II) induction. GAS (5 or 50 mg/kg/d) was orally administered every day starting 7 days prior to the Ang II infusion combined with sham-operated controls. Heart samples from each group were collected for RNA sequencing. Using bioinformatics analysis, the key differentially expressed genes (DEGs) that are involved in reversing cardiac function were identified. Through bioinformatics analysis, the key DEGs that are involved in GAS's inhibition of Ang II-induced abnormal gene expression within the heart were identified. This was further validated using quantitative real-time PCR and Western blotting in neonatal rat cardiomyocytes (NRCMs). Oral administration of GAS significantly suppressed the Ang II-induced increase in heart size and heart weight to body weight. Furthermore, pretreatment of the NRCMs with GAS led to a dose-dependent inhibition of Ang II-induced increases in Nppb mRNA expression. We identified 620 upregulated and 87 downregulated Ang II-induced DEGs II, among which the expression patterns of 58 and 146 genes were inverted by low-dose and high-dose GAS, respectively. These inverted DEGs were found to be mainly enriched in the biological processes of regulation of Ras protein signal transduction, heart contraction, covalent chromatin modification, glucose metabolism, and positive regulation of cell cycle. Among them, the insulin-like growth factor type 2 (Igf2) gene, which was found to be highly reversed and downregulated by GAS, served as a core gene linking energy metabolism, immune regulation, and systemic development. Subsequent functional verification demonstrated that IGF2, and its receptor IGF2R, is one of the targets of GAS that helps protect against cardiac hypertrophy. Taken together, we have identified, for the first time, IGF2/IGF2R as a potential target influenced by GAS in the prevention of cardiac hypertrophy.
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Project description:BackgroundInsulin and insulin-like growth factors (IGFs) act on tetrameric tyrosine kinase receptors controlling essential functions including growth, metabolism, reproduction and longevity. The insulin receptor (IR) binds insulin and IGFs with different affinities triggering different cell responses.ResultsWe showed that IGF-II induces cell proliferation and gene transcription when IR-B is over-expressed. We combined biotinylated ligands with streptavidin conjugated quantum dots and visible fluorescent proteins to visualize the binding of IGF-II and insulin to IR-B and their ensuing internalization. By confocal microscopy and flow cytometry in living cells, we studied the internalization kinetic through the IR-B of both IGF-II, known to elicit proliferative responses, and insulin, a regulator of metabolism.ConclusionsIGF-II promotes a faster internalization of IR-B than insulin. We propose that IGF-II differentially activates mitogenic responses through endosomes, while insulin-activated IR-B remains at the plasma membrane. This fact could facilitate the interaction with key effector molecules involved in metabolism regulation.
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Project description:Human multipotent mesenchymal stromal cells (MSC) are isolated from a plethora of tissue sources for cell therapy purposes. In 2006, the International Society for Cellular Therapy (ISCT) published minimal guidelines to define MSC identity. Nevertheless, many independent studies demonstrated that cells meeting the ISCT criteria possessed heterogeneous phenotypes and functionalities, heavily influenced by culture conditions. In this study, human MSC derived from many adult (bone marrow and adipose tissue) or fetal (cord blood, Wharton's jelly, umbilical cord perivascular compartment and amniotic fluid) tissues were investigated. Their immunophenotype was analyzed to define consistent source-specific markers by extensive flow cytometry analysis and real-time qRT-PCR. CD271+ subpopulations were detected in adult MSC, whereas NG2 was significantly more expressed in fetal MSC but failed validation on independent samples coming from an external laboratory. The highest number of CD271+ adult MSC were detected soon after isolation in serum-based culture conditions. Furthermore, heterogeneous percentages of CD271 expression were found in platelet lysate-based or serum-free culture conditions. Finally, CD271+ adult MSC showed high clonogenic and osteogenic properties as compared to CD271- cells. To conclude, in this phenotype-function correlation study CD271+ subpopulation confers heterogeneity on adult MSC, confirming the need of more specific markers to address MSC properties.
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Project description:Background: Pathological cardiac hypertrophy is commonly associated with upregulation of fetal genes, fibrosis, cardiac dysfunction and leads to heart failure. Previous studies demonstrated that gastrodin (GAS) inhibited cardiac hypertrophy and thus improved cardiac function. However, the theraputic targets by which GAS regulates in the regression of cardiac hypertrophy has not been well elucidated yet. Methods: A mouse model of myocardial hypertrophy was estavlished by angiotensin II (Ang II) induction, then treated with GAS (0, 5 or 50 mg/kg/d) combined with the sham-operated controls. Heart samples from each dose group were collected for the next RNA sequencing.Through bioinformatics analysis, the key differentially expressed genes (DEG) involved in the recovery of cardiac function were identidied. They were further confirmed by quantitative real-time PCR (qRT-PCR) and western blotting in neonatal rat cardiomyocytes (NRCMs). Results: We identified 620 up-regulated and 87 down-regulated DEGs induced by Ang II, of which the expression patterns of 58 and 146 genes were reversed by low-dose and high-dose GAS, respectively. These reversed DEGs are mainly enriched in biological processs of regulation of Ras protein signal transduction, heart contraction, covalent chromatin modification, glucose metabolism and positive regulation of cell cycle. Among them, insulin-like growth factor type 2 (Igf2) gene, which was highly reversed and down-regulated by GAS, served as the core gene linking energy metabolism, immune regulation and system development. Subsequent functional verification demonstrated that the system of Igf2 and its receptor Igf2r is one of the targets of GAS in the treatment of cardiac hypertrophy, and knocking out Igf2r can protect NRCM from cardiac hypertrophy. Conclusions: Taken together, we, for the first time, identified Igf2/Igf2r as a therapeutic target influenced by GAS in the pharmacological intervention of cardiac hypertrophy
2021-01-05 | GSE164187 | GEO
Project description:The insulin receptor (IR) isoforms and the IGF type 1 receptor (IGF-1R) share a high degree of structural homology but differ in ligand binding kinetics and functions. We developed a highly specific quantitative PCR assay to quantify and compare IR-A, IR-B, and IGF-1R expression within an RNA population. We determined receptor expression in primary murine mammary epithelial cells (MECs) during postnatal development. Both IR isoform mRNAs were 3- to 16-fold higher than IGF-1R expression at all developmental times. IR protein was also 3- to 10-fold higher than IGF-1R protein; however, significantly less IGF-1R was found in hybrid receptors at early (49%) vs. late (79%) pregnancy, indicating that the amount of hybrid receptor is developmentally regulated. Despite high IR expression, IGF ligands were more effective than insulin in stimulating the insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt pathway in acutely isolated MECs from virgin glands. Although approximately 40% of IR transcripts were the IGF-II-sensitive IR-A isoform, IGF-II failed to stimulate IR phosphorylation, and an IGF-1R-specific blocking antibody completely abrogated IGF-II-mediated Akt phosphorylation in the virgin MECs. Taken together, these data suggest that the IGF-1R is more active in signaling than the IR and is the predominant mediator of IGF actions in virgin MECs.
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Project description:Previous research in the Nurses' Health Study (NHS) and the NHSII observed that, among women diagnosed with benign breast disease (BBD), those with predominant type 1/no type 3 lobules (a marker of complete involution) versus other lobule types were at lower risk of subsequent breast cancer. Studies in animal models suggest that insulin-like growth factor-1 (IGF-1) may inhibit involution of lobules in the breast; however, this has not been studied in humans.We conducted a cross-sectional study among 472 women in the NHSII who were diagnosed with biopsy-confirmed proliferative BBD between 1991 and 2002 and provided blood samples between 1996 and 1999. A pathologist, blinded to exposure status, classified lobule type in normal adjacent tissue on available biopsy slides according to the number of acini per lobule. For each participant, the pathologist determined the predominant lobule type (that is, type 1, type 2, or type 3) and whether any type 1 or any type 3 lobules were present. Lobule type was then classified as: predominant type 1/no type 3 lobules, which is suggestive of complete involution; or other lobule types. Multivariate logistic models were used to assess the associations between plasma IGF-1, insulin-like growth factor binding protein-3 (IGFBP-3), and the ratio of IGF-1:IGFBP-3 levels with lobule type.In univariate analyses, greater age, higher body mass index, postmenopausal status, nulliparity, and lower IGF-1 levels were associated with predominant type 1/no type 3 lobules (P < 0.05). In multivariate models adjusting for age and assay batch, higher IGF-1 levels were associated with decreased odds of predominant type 1/no type 3 lobules (odds ratio quartile 4 vs. quartile 1 = 0.37, 95% confidence interval = 0.15 to 0.89). Greater ratios of IGF-1:IGFBP-3 levels were also associated with decreased odds of predominant type 1/no type 3 lobules (odds ratio quartile 4 vs. quartile 1 = 0.26, 95% confidence interval = 0.11 to 0.64). These results were slightly attenuated after adjustment for other potential predictors of lobule type.Higher IGF-1 levels and a greater IGF-1:IGFBP-3 ratio were associated with decreased odds of having predominant type 1 lobules/no type 3 lobules among women with proliferative BBD in the NHSII. This study provides further evidence for the role of insulin-like growth factors in the structure of breast lobules and lobular involution.
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Project description:Abundant experimental data have implicated an important role for insulin-like growth factor (IGF) in protecting neuronal cells from injury, including hypoxia/ischemia (H/I) injury, a major cause of neuron death. While the specific interaction of IGFs with neuronal or glial type 1 IGF receptors (IGF1R) has been shown to be essential to IGF actions during development, the same has not been directly demonstrated following H/I injury. To directly examine the role of neuronal IGF1R following H/I injury, we utilized conditional mutant nes-igf1r(-/Wt) mice and determined the impact of IGF1R haplodeficiency specifically in nestin-expressing neuronal precursors and their progeny on H/I-induced neuronal damage and apoptosis in hippocampus.H/I induced significant damage to the cerebral hemisphere and hippocampus ipsilateral to the ligated right common carotid artery both in control and nes-igf1r(-/Wt) mice at postnatal day 10. Blunting IGF1R expression, however, markedly exacerbated H/I-induced damage and appeared to increase mortality. In the ipsilateral hemisphere and hippocampus, nes-igf1r(-/Wt) mice had infarct areas double the size of those in controls. The size of the ipsilateral hemisphere and hippocampus in nes-igf1r(-/Wt) mice were 15% to 17% larger than those in controls, reflecting more severe edema. Consistent with its effects on infarct area, IGF1R haplodeficiency causes a greater decrease in neurons in the ipsilateral hippocampus of nes-igf1r(-/Wt) mice. The reduction in neurons was largely due to increases in neuronal apoptosis. Judged by pyknotic nuclei, TUNEL and caspase-3 labeling, nes-igf1r(-/Wt) mice had significantly more apoptotic cells than that in controls after injury. To determine possible mechanisms of IGF1R actions, the mRNA expression of the pro-survival proteins IAP-1 and XIAP was determined. Compared to controls, the abundance of cIAP-1 and XIAP mRNA was markedly suppressed in mice with blunted IGF1R or IGF-I expression, while was increased in the brain of IGF-I overexpressing transgenic mice.IGF1R in neuronal cells is critically important for their survival following H/I injury, and IGF-upregulated expression of neuronal cIAP-1 and XIAP likely in part contributes to IGF-IGF1R protection against neuronal apoptosis following H/I injury.
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Project description:Epidermal growth factor receptor (EGFR) is frequently overexpressed in esophageal carcinoma and its precursor lesions. To gain insights into how EGFR overexpression affects cellular functions in primary human esophageal cells, we performed gene expression profiling and identified insulin-like growth factor-binding protein (IGFBP)-3 as the most up-regulated gene. IGFBP-3 regulates cell proliferation through both insulin-like growth factor-dependent and independent mechanisms. We found that IGFBP-3 mRNA and protein expression was increased in EGFR-overexpressing primary and immortalized human esophageal cells. IGFBP-3 was also up-regulated in EGFR-overexpressing cells in organotypic culture and in EGFR transgenic mice. Furthermore, IGFBP-3 mRNA was overexpressed in 80% of primary esophageal squamous cell carcinomas and 60% of primary esophageal adenocarcinomas. Concomitant up-regulation of EGFR and IGFBP-3 was observed in 60% of primary esophageal squamous cell carcinomas. Immunohistochemistry revealed cytoplasmic localization of IGFBP-3 in the preponderance of preneoplastic and neoplastic esophageal lesions. IGFBP-3 was also overexpressed in esophageal cancer cell lines at both mRNA (60%) and protein (40%) levels. IGFBP-3 secreted by cancer cells was capable of binding to insulin-like growth factor I. Functionally, epidermal growth factor appeared to regulate IGFBP-3 expression in esophageal cancer cell lines. Finally, suppression of IGFBP-3 by small interfering RNA augmented cell proliferation, suggesting that IGFBP-3 may inhibit tumor cell proliferation as a negative feedback mechanism. In aggregate, we have identified for the first time that IGFBP-3 is an aberrantly regulated gene through the EGFR signaling pathway and it may modulate EGFR effects during carcinogenesis.
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