Targeting the IGF-1R: The Tale of the Tortoise and the Hare

Crudden, Caitrin; Girnita, Leonard

doi:10.3389/fendo.2015.00064

Cited by 69 publications

(58 citation statements)

References 54 publications

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“…Normal and immortalized cell lines have been shown to express hybrid receptors that are frequently the predominant receptor present (Belfiore et al, ; Frasca, Pandini, Vigneri, & Goldfine, ; Pandini et al, ; Vigneri et al, ). Moreover, hybrid receptor signaling may occur through non‐kinase pathways, being different from IGF1 and/or insulin receptor signaling (Belfiore et al, ; Crudden, Girnita, & Girnita, ). It is not known if PPPT inhibits activation of IGF‐1R/INSR hybrids (Gao, Chang, Jallal, & Viner, ).…”

Section: Discussionmentioning

confidence: 99%

Activation of the IGF1 receptor stimulates glycogen synthesis by mink uterine epithelial cells

Dean

Rose

2018

Molecular Reproduction Devel

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Glycogen synthesis by mink uterine epithelial cells is stimulated by estradiol (E ) during estrus, although the mechanism/s through which the steroid promotes glycogen accumulation are unknown. Our aim was to determine if insulin is required for E induced glycogen synthesis by an immortalized mink uterine epithelial cell line (GMMe). We show that the cells expressed the genes for glycogen metabolizing enzymes (hexokinase 1, glucose-6-phosphatase 3, glycogen synthase 1, and glycogen phosphorylase-muscle), receptors for insulin, insulin-like growth factor 1 and E (Esr1). Interestingly, treatment of cells with E alone failed to stimulate glycogen production, whereas supraphysiological concentrations of insulin (50 μg/ml) only, significantly increased glycogen content. Moreover, insulin + E increased glycogen content when compared to insulin alone (p < 0.05), an affect that was blocked when cells were treated with the pure E receptor antagonist ICI 182,780. Glycogen synthesis in response to insulin was significantly inhibited when cells were pre-treated with picropodophyllotoxin, an IGF1R antagonist. Treatment of cells with LY294002, a phosphatidylinositol 3-kinase (PI3K) antagonist, blocked insulin's effects on glycogen production whereas treatment with U0126, an inhibitor of mitogen activated kinase-kinase (MEK1/2) was without effect. These findings suggest to us that the affects of E on glycogen synthesis by GMMe cells is mediated through Esr1 and increased responsiveness of the cells to insulin. Because picropodophylotoxin blocked the effects of insulin on glycogen production, and both insulin and IGF1 act through PI3K, it is possible that IGF1 plays a role in glycogen production by these cells.

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Section: Discussionmentioning

confidence: 99%

Activation of the IGF1 receptor stimulates glycogen synthesis by mink uterine epithelial cells

Dean

Rose

2018

Molecular Reproduction Devel

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“…However, the most promising therapeutic strategy seems to be the IGF signalling pathway. Incidentally, IGF1R has been tested as a therapeutic target in several cancers (Crudden et al, 2015). Our study not only provides a mechanistic insight into the causes of WT but also suggests potential diagnostic and therapeutic strategies involving the microRNA let-7 and the IGF signalling pathway.…”

Section: Discussionmentioning

confidence: 78%

Tumour suppressor WT1 regulates the let-7-Igf1r axis in kidney mesenchyme

Bharathavikru

Slight

Aitken

et al. 2019

Preprint

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Wilms' tumour 1 (WT1) is a transcription factor and a tumour suppressor, essential for the development and homeostasis of multiple tissues derived from the intermediate and lateral plate mesoderm. Germline WT1 mutations result in the eponymous paediatric kidney cancer, genitourinary anomalies and in some cases congenital diaphragmatic hernia One common feature in Wilms' Tumours (WT), is upregulation of IGF2 through genetic and/or epigenetic mechanisms. Recent studies have identified both somatic and germline mutations in microRNA processing genes (MIRPG) in WT. Whether these different epigenetic and genetic causes converge on common targets and the mechanisms by which they act are still unclear. WT1 is involved in RNA binding and regulates the RNA stability of important developmental genes. We now show that WT1 interacts with let-7 family of microRNAs, and the absence of WT1 results in reduced levels of mature microRNA in cell lines and kidney mesenchyme. As a consequence, let-7 targets, including Igf1 receptor (Igf1r), are upregulated in the absence of Wt1, thus confirming the presence of a WT1-let7-Igf1r axis. These findings suggest a possible mechanism by which WT1 mutations

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“…In contrast, MSCs showed 24 genes whose expression changed, the second most significant of which was Igfbp5 ( Figure 2E). Interestingly, Pappa itself was slightly but significantly upregulated, and Igf2 showed a trend toward upregulation, perhaps suggesting a partial compensatory 7 response. We did not observe a striking downregulation of collagen/ECM genes, but when we submitted the top 105 genes affected by PAPP-A inhibition (p < 0.005) to GO term analysis, we saw significant enrichment for the same collagen and extracellular-matrix GO terms that we identified previously ( Figure 2F), whereas no such enrichment was found for HPSC or myeloid cell types, irrespective of statistical cutoff.…”

Section: Mesenchymal Stromal Cells Are the Primary Source Of Papp-a Imentioning

confidence: 99%

Pharmacological inhibition of longevity regulator PAPP-A restrains mesenchymal stromal cell activity

Mohrin

Liu

Zavala-Solorio

et al. 2020

Preprint

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Reducing insulin-like growth factor (IGF) signaling is one of the best conserved and characterized mechanisms to extend longevity. Pregnancy associated plasma protein A (PAPP-A) is a secreted metalloprotease that increases IGF availability by cleaving IGF binding proteins. PAPP-A inhibition reduces local IGF signaling, limits the progression of multiple age-related diseases, and extends lifespan, but the mechanisms behind these pleiotropic effects remains unknown. Here, we developed and utilized a PAPP-A neutralizing antibody to discover that adulthood inhibition of this protease reduced collagen and extracellular matrix (ECM) gene expression in multiple tissues in mice. Using bone marrow to explore this effect, we identified mesenchymal stromal cells (MSCs) as the source of PAPP-A and primary responders to PAPP-A inhibition. Short-term treatment with anti-PAPP-A reduced IGF signaling in MSCs, altered MSC expression of collagen/ECM, and decreased MSC number. This affected MSC-dependent functions, decreasing myelopoiesis and osteogenesis. Our data demonstrate that PAPP-A inhibition reduces the activity and number of IGF-dependent mesenchymal progenitor cells and their differentiated progeny, and that this reduction leads to functional changes at the tissue level. MSC-like cells are present in virtually all tissues, and aberrant collagen and ECM production from mesenchymal cells drives aspects of aging and age-related diseases, thus this may be a mechanism by which PAPP-A deficiency enhances lifespan and healthspan.SummaryInhibition of PAPP-A, a regulator of IGF signaling, decreases multi-tissue collagen and extracellular matrix gene expression and modulates mesenchymal stromal cell activity in murine bone marrow.

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Targeting the IGF-1R: The Tale of the Tortoise and the Hare

Cited by 69 publications

References 54 publications

Activation of the IGF1 receptor stimulates glycogen synthesis by mink uterine epithelial cells

Activation of the IGF1 receptor stimulates glycogen synthesis by mink uterine epithelial cells

Tumour suppressor WT1 regulates the let-7-Igf1r axis in kidney mesenchyme

Pharmacological inhibition of longevity regulator PAPP-A restrains mesenchymal stromal cell activity

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