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Insulin/IGF Signaling in Early Brain Development
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Selma Yagoub, Rachel N. Lippert
The growth cone is the actively extending portion of the developing neuron, providing a leading point for emerging neurites searching for the proper synaptic targets. While this is an extremely complex system, utilizing gradients of molecular cues and both presynaptic and postsynaptic signaling, the expression and activity of receptor tyrosine kinases in the developing extension are critical for this process. The IGF-1R is found localized in the developing growth cone, underscoring the necessary balance of insulin and IGF-1 hormones in development (36, 37). Enrichment specifically of the beta subunit of the IGF-1R is found at the developing growth cone in cultured hippocampal pyramidal neurons (38, 39). Additionally, this region within the developing growth cone is critical for glial cell interactions, necessary for proper brain structure organization (40). Studies using cell culture of PC12 cells overexpressing the insulin receptor also indicate that insulin itself plays a role in neurite outgrowth of cultured neuronal cells (41, 42). This action is via MAP kinase activation, where translocation of MAP kinase to the nucleus is correlated with increased expression of insulin receptors on the cell surface. Insulin acts on the cone growth also by activating the Shc/Grb-2/MAPK signaling pathways (43).
Companion Animals Models of Human Disease
Published in Rebecca A. Krimins, Learning from Disease in Pets, 2020
of canine OSA cell lines and tissue samples, respectively, suggesting an involvement in the pathogenesis of this tumor. Furthermore, as in humans, 79% of canine OSA samples overexpress the MET oncogenes; cell motility and invasiveness appear to be MET-dependent since they can be inhibited by small interfering RNAs (siRNAs) that are specific for MET. Finally, recent evidence demonstrated that PDGF receptors are overexpressed in canine OSA, adding a new potential therapeutic target. Insulin-like growth factor-1 receptor (IGF-1R) is a transmembrane TKR consisting of two extracellular α-subunits responsible for ligand binding, two β-subunits with a transmembrane domain, and an intracellular tyrosine kinase COOH-terminal domain. The specific interaction between IGF-1 and IGF-1R induces the phosphorylation of intracellular tyrosine residue (β-subunit) and results in activation of the receptor. The activated form of IGF-1R is able to activate the PI3K/AKT and mitogen-activated protein kinase (MAPK) signaling pathways.
Energy Metabolism, Metabolic Sensors, and Nutritional Interventions in Polycystic Kidney Disease
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Sonu Kashyap, Eduardo Nunes Chini
Developing alternative therapeutic approaches that will mimic dietary restriction will be of great clinical interest. Beneficial effects of FR appear to be mediated by suppression of IGF-1.103,104 Our study also demonstrates the possibility of IGF-1/IGF-1R pathway mediated effects of FR.5 Although IGF-1 has been reported in ADPKD patients and cystic cells,105,106 the role of IGF-1 in cystogenesis in PKD is still limited. Therefore, the studies that can explore the precise mechanistic role of IGF-1 in ADPKD and its implications in FR will be imperative.5
State-of-the-art, approved therapeutics for the pharmacological management of osteosarcoma
Published in Expert Opinion on Pharmacotherapy, 2021
Cristina Meazza, Sebastian Dorin Asaftei
Several therapeutically targetable kinases or their ligands, crucial for tumor growth, progression, and spread – such as vascular endothelial growth factors (VEGF), platelet-derived growth factor (PDGF), insulin growth factor 1 (IGF1), and MET – are overexpressed in OS [98]. VEGF is one of the most important stimulators of angiogenesis and high VEGF levels correlate with development of lung metastases, progression, and poor survival [99]. PDGF/PDGFR pathway plays an important role in the cell proliferation, cell survival, and cell migration. IGF1/IGF1R is important for growth, differentiation, and metabolism. High circulating levels of IGF-1 were associated with metastases and poorer survival in patients with OS. MET is essential for cell motility, proliferation, and scattering. Aberrant MET expression is widely observed in various malignancies, also in OS (Table 3).
Effects of Heshouwuyin on gene expression of the insulin/IGF signalling pathway in rat testis and spermatogenic cells
Published in Pharmaceutical Biology, 2020
Hongjie Wang, Boying Shan, Yulei Duan, Juan Zhu, Liping Jiang, Yang Liu, Yan Zhang, Feng Qi, Siyun Niu
The IRS protein is a key mediator of insulin and IGF signalling and is involved in the control of metabolic hormones (Copps and White 2012). Phosphorylated INSR and IGF1R activate common substrates for downstream effector networks, including IRS, phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinase pathways (Frezza et al. 2018). Insulin and IGF1 bind and phosphorylate INSR and IGF1R, respectively. Phosphorylated INSR and IGF1R are also involved in the regulation of cell proliferation, differentiation, and survival. The IRS family includes four isoforms, IRS1-4 (Al-Salam and Irwin 2017; Machado-Neto et al. 2018). IRS1 is a mediator of insulin and IGF1, both of which can bind to INSR (Simpson et al. 2017; Frezza et al. 2018). The PI3K/protein kinase B (also known as Akt) signalling pathway is mediated by IRS2 and plays an important role in cell growth, proliferation, and apoptosis (Lei et al. 2018). IGF1 is involved in testicular development during embryogenesis, SC proliferation, and germ cells (GS) proliferation and differentiation (Cannarella et al. 2018).
Co-delivery of insulin-like growth factor 1 receptor specific siRNA and doxorubicin using chitosan-based nanoparticles enhanced anticancer efficacy in A549 lung cancer cell line
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Hajar Shali, Mahdi Shabani, Fatemeh Pourgholi, Mahsa Hajivalili, Leili Aghebati-Maleki, Farhad Jadidi-Niaragh, Behzad Baradaran, Ali Akbar Movassaghpour Akbari, Vahid Younesi, Mehdi Yousefi
The IGF-1R is a tetrameric transmembrane protein, which belongs to receptor tyrosine kinase family (RTKs). IGF-1R is activated by insulin-like growth factor 1 (IGF-1) and IGF-2 hormones. The activation of IGF-1R triggers tumour cell growth, resistance to apoptosis, angiogenesis, migration and invasion. Aberrant IGF-1R signalling has been reported in several tumour types, including colorectal and lung cancers [22,23]. IGF-1R is expressed in 39–84% of NSCLC patients [24]. Moreover, several studies demonstrated that IGF-1R expression confers resistance to EGFR therapy in lung cancer [25]. These findings show role of IGF-1R in numerous features of malignancy and suggesting this receptor could be a potential target for anticancer therapy. There are several therapeutic approaches to inhibit IGF-1R signalling such as using antibodies against IGF-IR or kinase inhibitors. Gene silencing potentially could be considered as another alternative in IGF-1R targeting in lung cancer [26]. Thus, for the first time to our knowledge, we persuaded to investigate the efficiency of co-delivery of doxorubicin (DOX) and IGF-1R siRNA by ChiNP in A549 lung cancer cell line.