Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression

Cai, Weikang; Sakaguchi, Masaji; Kleinridders, André; Pino, Gonzalo Gonzalez-Del; Dreyfuss, Jonathan M.; O’Neill, Brian T.; Ramirez, Alfred K.; Hui, Pei; Winnay, Jonathon N.; Boucher, Jérémie; Eck, Michael J.; Kahn, C. Ronald

doi:10.1038/ncomms14892

Cited by 135 publications

(147 citation statements)

References 56 publications

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“…13,14 The 2 receptors consist of an extracellular a-subunit and a transmembrane b-subunit monomer. 15 Upon IGF-1 binding, the 2 receptors are auto-phosphorylated and insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) are recruited, resulting in the activation of the 2 most prominent downstream signaling pathways, the phosphoinositide 3-kinase (PI3K)-Akt pathway and the MEK-extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. 16,17 PI3K-AKT has been reported to enhance protein synthesis and cellular metabolism via mammalian target of rapamycin (mTOR) and to increase survival via p53, NF-kB, BAD/Bcl2, and FOXOs, whereas MEK-ERK1/2 activation mainly leads to increased cellular expansion.…”

Section: Introductionmentioning

confidence: 99%

IGF-1 facilitates thrombopoiesis primarily through Akt activation

Chen

Shen

et al. 2018

Blood

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It is known that insulin-like growth factor-1 (IGF-1) also functions as a hematopoietic factor, although its direct effect on thrombopoiesis remains unclear. In this study, we show that IGF-1 is able to promote CD34 cell differentiation toward megakaryocytes (MKs), as well as the facilitation of proplatelet formation (PPF) and platelet production from cultured MKs. The in vivo study demonstrates that IGF-1 administration accelerates platelet recovery in mice after 6.0 Gy of irradiation and in mice that received bone marrow transplantation following 10.0 Gy of lethal irradiation. Subsequent investigations reveal that extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt activation mediate the effect of IGF-1 on thrombopoiesis. Notably, Akt activation induced by IGF-1 is more apparent than that of ERK1/2, compared with that of thrombopoietin (TPO) treatment. Moreover, the effect of IGF-1 on thrombopoiesis is independent of TPO signaling because IGF-1 treatment can also lead to a significant increase of platelet counts in homozygous TPO receptor mutant mice. Further analysis indicates that the activation of Akt triggered by IGF-1 requires the assistance of steroid receptor coactivator-3 (SRC-3). Therefore, our data reveal a distinct role of IGF-1 in regulating thrombopoiesis, providing new insights into TPO-independent regulation of platelet generation.

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Section: Introductionmentioning

confidence: 99%

IGF-1 facilitates thrombopoiesis primarily through Akt activation

Chen

Shen

et al. 2018

Blood

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“…The metabolic effects of insulin, such as glucose uptake and lipid synthesis, are mainly regulated by the PI3K/AKT pathway 3 . By contrast, the MAPK pathway is the primary mediator of mitogenic effects of insulin, although the PI3K/AKT pathway is also involved 4,5 .…”

Section: Introduction and Resultsmentioning

confidence: 99%

Stepwise autophosphorylation regulates biased agonism of the insulin receptor

Yunn

Park

Noh

et al. 2019

Preprint

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SummaryInsulin is a key regulator of energy metabolism in peripheral tissues but also functions as a growth factor. Insulin binding to the insulin receptor (IR) leads to autophosphorylation of intracellular tyrosine residues, which simultaneously initiates a multitude of signals and functions. In contrast, some artificial (non-insulin) ligands for the IR result in biased agonism, selectively activating the PI3K/AKT pathway and metabolic effects without activating mitogen-activated protein kinase (MAPK) pathway and mitogenic effects. However, the precise mechanism of biased agonism at the receptor level remains unclear. The biased agonist IR-A48 aptamer selectively induces mono-phosphorylation of Tyr1150 residue (m-pY1150) in the kinase domain of IR. Hence, we hypothesized that IR autophosphorylation is a stepwise process in which formation of m-pY1150 represents an intermediate step. To explore this idea, we used hybrid receptors in which insulin can bind only one of the two binding sites of the dimeric receptor. Asymmetric insulin binding selectively induced symmetric m-pY1150 in both kinase domains. Moreover, the juxtamembrane domain, which interacts with the kinase domain, restricted the full activation of IR, and symmetric m-pY1150 played a crucial role in the rearrangement of intracellular domains to release this restriction. Our findings demonstrate that the symmetry of insulin binding to a dimeric receptor determines the stepwise autophosphorylation of IR. Furthermore, considering that the degree of ligand symmetry on a receptor depends mainly on ligand concentration, our results suggest that IR may play metabolic-biased roles in peripheral tissues dependent on local insulin concentrations.

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“…Nowadays, growing studies suggested that IGF-1 participates in the modulation of a variety of physiological activities, including in cellular development, differentiation and proliferation [20] . For its positive role in improving muscle growth, association between IGF-1 polymorphisms and growth traits in livestock was extensively studied.…”

Section: Discussionmentioning

confidence: 99%

IGF-1 Gen Polimorfizmi Çin Qinchuan Sığırında Büyüme Özelliklerini Etkiler

Gui¹,

Wang²,

Jia³

et al. 2018

Kafkas Univ Vet Fak Derg

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Insulin-like growth factor I (IGF-1) influences gonadotrophin-releasing hormone (GnRH) neurons during puberty, and plays an important role in muscle growth in farm animals. The objective of this study was to estimate the genotype frequencies of the polymorphisms of IGF-1 and to determine associations between these polymorphisms and growth traits in Chinese Qinchuan cattle breeds. Five single nucleotide polymorphisms (SNPs), including one in intron 2 (g.5172T>G) and four in intron 3 (g.56495C>A, g.56501C>T, g.56801C>T and g.71090T>G) were identified according to the sequencing results of 487 individual of a Qinchuan cattle population. The chi-square test showed g.5172T>G, g.56495C>A and g.56801C>T were in Hardy-Weinberg equilibrium in all the samples. Six different haplotypes were identified, of which two major haplotypes had a frequency of 48.2% (-TCTTT-) and 16.3% (-TCCTT-). The single marker association analysis showed that the three polymorphisms (g.5172T>G, g.56501C>T and g.71090T>G) were significantly associated with growth traits (at P<0.01 or P<0.05). In conclusion, our results suggest that some polymorphisms in IGF-1 may play a role in determining one of the important genetic factors that influence growth traits in Chinese Qinchuan cattle.

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Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression

Cited by 135 publications

References 56 publications

IGF-1 facilitates thrombopoiesis primarily through Akt activation

IGF-1 facilitates thrombopoiesis primarily through Akt activation

Stepwise autophosphorylation regulates biased agonism of the insulin receptor

IGF-1 Gen Polimorfizmi Çin Qinchuan Sığırında Büyüme Özelliklerini Etkiler

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