40 YEARS OF IGF1: IGF1 receptor signaling pathways

Hakuno, Fumihiko; Takahashi, Shin

doi:10.1530/jme-17-0311

Cited by 304 publications

(287 citation statements)

References 149 publications

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“…The IGF-IR gene is mapped to chromosome 15q25-26. Activation of receptor tyrosine kinase activity results from ligand binding to the α subunit of the receptor leading to a conformational change in the β subunit (160). This leads to the activation of downstream signaling pathways of IGFs including PI 3-kinase pathway and Ras-mitogen-activated protein kinase (MAP kinase) pathway, for cell proliferation, cell differentiation and cell survival (160).…”

Section: Igf-i Receptor and Intracellular Signalingmentioning

confidence: 99%

Growth Hormone(s), Testosterone, Insulin-Like Growth Factors, and Cortisol: Roles and Integration for Cellular Development and Growth With Exercise

et al. 2020

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Hormones are largely responsible for the integrated communication of several physiological systems responsible for modulating cellular growth and development. Although the specific hormonal influence must be considered within the context of the entire endocrine system and its relationship with other physiological systems, three key hormones are considered the "anabolic giants" in cellular growth and repair: testosterone, the growth hormone superfamily, and the insulin-like growth factor (IGF) superfamily. In addition to these anabolic hormones, glucocorticoids, mainly cortisol must also be considered because of their profound opposing influence on human skeletal muscle anabolism in many instances. This review presents emerging research on: (1) Testosterone signaling pathways, responses, and adaptations to resistance training; (2) Growth hormone: presents new complexity with exercise stress; (3) Current perspectives on IGF-I and physiological adaptations and complexity these hormones as related to training; and (4) Glucocorticoid roles in integrated communication for anabolic/catabolic signaling. Specifically, the review describes (1) Testosterone as the primary anabolic hormone, with an anabolic influence largely dictated primarily by genomic and possible non-genomic signaling, satellite cell activation, interaction with other anabolic signaling pathways, upregulation or downregulation of the androgen receptor, and potential roles in co-activators and transcriptional activity; (2) Differential influences of growth hormones depending on the "type" of the hormone being assayed and the magnitude of the physiological stress; (3) The exquisite regulation of IGF-1 by a family of binding proteins (IGFBPs 1-6), which can either stimulate or inhibit biological action depending on binding; and (4) Circadian patterning and newly discovered variants of glucocorticoid isoforms largely dictating glucocorticoid sensitivity and catabolic, muscle sparing, or pathological influence. The downstream integrated anabolic and catabolic mechanisms of these hormones not only affect the ability of skeletal muscle to generate force; they also have Kraemer et al. Anabolic and Catabolic Hormones and Exercise implications for pharmaceutical treatments, aging, and prevalent chronic conditions such as metabolic syndrome, insulin resistance, and hypertension. Thus, advances in our understanding of hormones that impact anabolic: catabolic processes have relevance for athletes and the general population, alike.

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Section: Igf-i Receptor and Intracellular Signalingmentioning

confidence: 99%

Growth Hormone(s), Testosterone, Insulin-Like Growth Factors, and Cortisol: Roles and Integration for Cellular Development and Growth With Exercise

et al. 2020

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“…The explanation for the increase in efficacy may be the massive production of IGF1 by ASC.B6 cells, which contributes to the 4T1 cell proliferation in an in vitro assay (13). We show here that ASC.B6derived factors induce Akt phosphorylation, hence switch on the PI3K/Akt signaling pathway, and thereby promote cell survival, proliferation, growth and cellular metabolic pathways (17,21) In addition, we have identified IGFBP2 in the secretome of vASCs, which sequesters IGF1 and thereby regulates its accessibility and function (15). IGFBP2 was missing from ASC.B6 cells, and supplementation with a recombinant protein abolished tumor cell proliferation, and also mitigated the ASC.B6-induced Akt phosphorylation.…”

Section: Discussionmentioning

confidence: 70%

“…IGF1 is a general mitogen, it induces pro-survival signaling pathways, such as the Ras/MAPK and the PI3K/Akt kinase pathway (17). When we added ASC.B6 conditioned medium to 4T1 cells, it rapidly induced Akt phosphorylation, with a maximum at 5 min (Figure 3A).…”

Section: Igf1/igfbp2 Balance the Survival Signaling Pathway Of Breastmentioning

confidence: 98%

Polyploid Adipose Stem Cells Shift the Balance of IGF1/IGFBP2 to Promote the Growth of Breast Cancer

et al. 2020

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Background: The close proximity of adipose tissue and mammary epithelium predispose involvement of adipose cells in breast cancer development. Adipose-tissue stem cells (ASCs) contribute to tumor stroma and promote growth of cancer cells. In our previous study, we have shown that murine ASCs, which undergo polyploidization during their prolonged in vitro culturing, enhanced the proliferation of 4T1 murine breast cancer cells in IGF1 dependent manner.Aims: In the present study, our aim was to clarify the regulation of ASC-derived IGF1.Methods: 4T1 murine breast carcinoma cells were co-transplanted with visceral fat-derived ASCs (vASC) or with the polyploid ASC.B6 cell line into female BALB/c mice and tumor growth and lung metastasis were monitored. The conditioned media of vASCs and ASC.B6 cells were subjected to LC-MS/MS analysis and the production of IGFBP2 was verified by Western blotting. The regulatory effect was examined by adding recombinant IGFBP2 to the co-culture of ASC.B6 and 4T1. Akt/protein kinase B (PKB) activation was detected by Western blotting.Results: Polyploid ASCs promoted the tumor growth and metastasis more potently than vASCs with normal karyotype. vASCs produced the IGF1 regulator IGFBP2, which inhibited proliferation of 4T1 cells. Downregulation of IGFBP2 by polyploidization of ASCs and enhanced secretion of IGF1 allowed survival signaling in 4T1 cells, leading to Akt phosphorylation. Conclusions:Our results implicate that ASCs in the tumor microenvironment actively regulate the growth of breast cancer cells through the IGF/IGFBP system. Keywords: adipose stem cells, breast cancer, tumor stroma, insulin-like growth factor 1, insulin-like growth factor binding protein 2

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“…IGF-1 bound activated IGF-1R phosphorylates insulin receptor substrates (such as IRS1, IRS2 and Shc). The Src homology 2 (SH2) domains of these substrates are recognized by signaling molecules to activate the intracellular effectors such as RAS, RAF and SOS and the RAS/MAPK pathway [36,37]. Interestingly, in our previous study, we observed significant downregulation of NRAS with miR-29a overexpression in PDAC cell lines [38].…”

Section: Igf-1 Belonging To the Igf Family Members Is One Of The Kementioning

confidence: 81%

“…Network analysis with the targets identified three overlapping pathways related to IGF, RAS/MAPK signaling and laminin interactions. IGF-1 secreted by activated PSCs and CAFs via sonic hedgehog pathway activates IGF-1R in cancer cells triggering phosphorylation of insulin-receptor or Src substrates to promote PDAC metastasis via intracellular pathways such as RAS/MAPK [36,52]. In addition, high IGF-1 with low IGFBP3 expressions associated with enhanced risks for PDAC [53].…”

Section: Discussionmentioning

confidence: 99%

Global targetome analysis reveals critical role of miR-29a in pancreatic stellate cell mediated regulation of PDAC tumor microenvironment

Dey

Liu

Factora

et al. 2020

Preprint

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BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of malignancies with a nearly equal incidence and mortality rates in patients. Pancreatic stellate cells (PSCs) are critical players in PDAC microenvironment to promote the aggressiveness and pathogenesis of the disease.Dysregulation of microRNAs (miRNAs) have been shown to play a significant role in progression of PDAC. Earlier, we observed a PSC-specific downregulation of miR-29a in PDAC pancreas, however, the mechanism of action of the molecule in PSCs is still to be elucidated. The current study aims to clarify the regulation of miR-29a in PSCs and identifies functionally important downstream targets that contribute to tumorigenic activities during PDAC progression. MethodsIn this study, using RNAseq approach, we performed transcriptome analysis of paired miR-29a overexpressing hPSC cells and controls. Enrichment analysis was performed with the identified differentially expressed genes (DEGs). miR-29a targets in the dataset were identified, which were utilized to create network interactions. Western blots were performed with the top candidate miR-29a targets in hPSC cells transfected with miR-29a mimic or scramble control. ResultsRNAseq analysis identified 202 differentially expressed genes, which included 19 downregulated direct miR-29a targets. Translational repression of eight key pro-tumorigenic and -fibrotic targets namely IGF-1, COL5A3, CLDN1, E2F7, MYBL2, ITGA6 and ADAMTS2 by miR-29a was observed in PSCs.Using pathway analysis, we find that miR-29a modulates effectors of IGF-1-p53 signaling in PSCs that may hinder carcinogenesis. We further observe a regulatory role of the molecule in pathways associated with PDAC ECM remodeling and tumor-stromal crosstalk, such as INS/IGF-1, RAS/MAPK, laminin interactions and collagen biosynthesis. ConclusionsTogether, our study presents a comprehensive understanding of miR-29a regulation of PSCs, and identifies essential pathways associated with PSC-mediated PDAC pathogenesis. The findings suggest an anti-tumorigenic role of miR-29a in the context of PSC-tumor cell crosstalk and advocates for the potential of the molecule in PDAC targeted therapies. 4

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40 YEARS OF IGF1: IGF1 receptor signaling pathways

Cited by 304 publications

References 149 publications

Growth Hormone(s), Testosterone, Insulin-Like Growth Factors, and Cortisol: Roles and Integration for Cellular Development and Growth With Exercise

Growth Hormone(s), Testosterone, Insulin-Like Growth Factors, and Cortisol: Roles and Integration for Cellular Development and Growth With Exercise

Polyploid Adipose Stem Cells Shift the Balance of IGF1/IGFBP2 to Promote the Growth of Breast Cancer

Global targetome analysis reveals critical role of miR-29a in pancreatic stellate cell mediated regulation of PDAC tumor microenvironment

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