Role of IRS-2 in insulin and cytokine signalling

Sun, Xiao Jian; Wang, Ling Mei; Zhang, Yitao; Yenush, Lynne; Myers, Martin G.; Glasheen, Erin; Lane, William S.; Pierce, Jacalyn H.; White, Morris F.

doi:10.1038/377173a0

Cited by 790 publications

(591 citation statements)

References 35 publications

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“…In the present work, we show that caffeine rapidly induces the tyrosine phosphorylation of IRS2, but not IRS1, and that treatment of hippocampal slices with ryanodine blocks caffeine‐induced IRS2 phosphorylation, indicating that release of Ca 2+ from intracellular ryanodine‐sensitive stores is necessary for the activation of PI3K/Akt signaling in postsynaptic neurons. Although IR and IGF‐1R can also induce IRS phosphorylation (Sun et al 1995), we did not detect their activation in caffeine‐treated hippocampal slices. On the other hand, TrkB‐IgG blocked caffeine‐induced tyrosine phosphorylation of IRS2, further demonstrating the specific involvement of TrkB activation on the downstream signaling that supports CAF LTP.…”

Section: Discussioncontrasting

confidence: 74%

“…4C), suggesting that IRS2 might participate in caffeine‐induced TrkB‐mediated signaling leading to LTP. Importantly, other receptor tyrosine kinases that can phosphorylate IRS proteins such as the IR and IGF‐1R (Sun et al 1995) were not activated as assessed by their tyrosine phosphorylation levels in immunocomplexes obtained from hippocampal slices 5 and 30 min after caffeine application (Fig. S3).…”

Section: Resultsmentioning

confidence: 99%

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Caffeine‐mediated BDNF release regulates long‐term synaptic plasticity through activation of IRS2 signaling

et al. 2016

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Caffeine has cognitive‐enhancing properties with effects on learning and memory, concentration, arousal and mood. These effects imply changes at circuital and synaptic level, but the mechanism by which caffeine modifies synaptic plasticity remains elusive. Here we report that caffeine, at concentrations representing moderate to high levels of consumption in humans, induces an NMDA receptor‐independent form of LTP (CAFLTP) in the CA1 region of the hippocampus by promoting calcium‐dependent secretion of BDNF, which subsequently activates TrkB‐mediated signaling required for the expression of CAFLTP. Our data include the novel observation that insulin receptor substrate 2 (IRS2) is phosphorylated during induction of CAFLTP, a process that requires cytosolic free Ca2+. Consistent with the involvement of IRS2 signals in caffeine‐mediated synaptic plasticity, phosphorylation of Akt (Ser473) in response to LTP induction is defective in Irs2−/− mice, demonstrating that these plasticity changes are associated with downstream targets of the phosphoinositide 3‐kinase (PI3K) pathway. These findings indicate that TrkB‐IRS2 signals are essential for activation of PI3K during the induction of LTP by caffeine.

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Section: Discussioncontrasting

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Caffeine‐mediated BDNF release regulates long‐term synaptic plasticity through activation of IRS2 signaling

et al. 2016

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“…The insulin receptor is a protein tyrosine kinase which, when activated by insulin binding, undergoes rapid autophosphorylation and phosphorylates intracellular protein substrates, including insulin receptor substrates (IRSs-IRS-1 and IRS-2 are the most important) [9,10,11] and Shc [12]. Following tyrosine phosphorylation, the IRSs act as docking proteins for several Src homology 2 domaincontaining proteins, including phosphatidylinositol 3-kinase (PI3-kinase), Grb2, SHP2, Nck and Fyn [13,14,15,16,17].…”

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confidence: 99%

Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

et al. 2003

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Aim/hypothesis. By acting in the brain, insulin suppresses food intake. However, little is known with regard to insulin signalling in the hypothalamus in insulin-resistant states. Methods. Western blotting, immunohistochemistry and polymerase chain reaction assays were combined to compare in vivo hypothalamic insulin signalling through the PI3-kinase and MAP kinase pathways between lean and obese Zucker rats. Results. Intracerebroventricular insulin infusion reduced food intake in lean rats to a greater extent than that observed in obese rats, and pre-treatment with PI3-kinase inhibitors prevented insulin-induced anorexia. The relative abundance of IRS-2 was considerably higher than that of IRS-1 in hypothalamus of both lean and obese rats. Insulin-stimulated phosphorylation of IR, IRS-1/2, the associations of PI 3-kinase to IRS-1/2 and phosphorylation of Akt in hypothalamus were decreased in obese rats compared to lean rats. These effects seem to be mediated by increased phosphoserine content of IR, IRS-1/2 and decreased protein levels of IRS-1/2 in obese rats. In contrast, insulin stimulated the phosphorylation of MAP kinase equally in lean and obese rats. Conclusion/interpretation. This study provides direct measurements of insulin signalling in hypothalamus, and documents selective resistance to insulin signalling in hypothalamus of Zucker rats. These findings provide support for the hypothesis that insulin could have anti-obesity actions mediated by the PI3-kinase pathway, and that impaired insulin signalling in hypothalamus could play a role in the development of obesity in this animal model of insulin-resistance. [Diabetologia (2003[Diabetologia ( ) 46:1629[Diabetologia ( -1640 Keywords Obesity, insulin resistance, hypothalamus, anorexia, signal transduction, phosphatidylinositol 3-kinase/antagonists & inhibitors/*metabolism, mitogen-activated protein kinase. Abbreviations: ERK, extracellular signal-regulated kinase; Grb2, growth factor receptor binding protein 2; IR, insulin receptor; IRS, insulin receptor substrate; MAPK, mitogen-activated protein kinase; PI 3-kinase, phosphatidylinositol 3-kinase; PKC, Protein kinase C; Shc, Src-homology and collagen homology; SHP2, Src-homology phosphatase 2; TNF-α, Tumor-necrosis factor-α.

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“…Insulin binding to the α-subunit elicits a conformational change of the receptor resulting in activation of the β-subunit tyrosine kinase which, in turn, phosphorylates multiple endogenous proteins including the IR substrates (IRS 1 to 4), Shc and other cellular proteins [1,2,3,4,5,6,7,8]. IRS and Shc serve as docking proteins for several specific signalling molecules [9].…”

mentioning

confidence: 99%

An arginine to cysteine252 mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalisation but preserves signalling events

et al. 2002

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Aims/hypothesis. We examined the properties of a mutant insulin receptor (IR) with an Arg 252 to Cys (IR R252C ) substitution in the α-subunit originally identified in a patient with extreme insulin resistance and acanthosis nigricans. Methods. We studied IR cell biology and signalling pathways in Chinese Hamster Ovary cells overexpressing this IR R252C . Results. Our investigation showed an impairment in insulin binding to IR R252C related mostly to a reduced affinity of the receptor for insulin and to a reduced rate of IR R252C maturation; an inhibition of IR R252C -mediated endocytosis resulting in a decreased insulin degradation and insulin-induced receptor down-regulation; a maintenance of IR R252C on microvilli even in the presence of insulin; a similar autophosphorylation of mutant IR R252C followed by IRS 1/IRS 2 phosphorylation, p85 association with IRS 1 and IRS 2 and Akt phosphorylation similar to those observed in cells expressing wild type IR (IRwt); and finally, a reduced insulin-induced Shc phosphorylation accompanied by decreased ERK1/2 phosphorylation and activity and of thymidine incorporation into DNA in cells expressing IR R252C as compared to cells expressing IRwt. Conclusion/interpretation. These observations suggest that: parameters other than tyrosine kinase activation participate in or control the first steps of IR internalisation or both; IR-mediated IRS 1/2 phosphorylation can be achieved from the cell surface and microvilli in particular; Shc phosphorylation and its subsequent signalling pathway might require IR internalisation; defective IR endocytosis correlates with an enhancement of some biological responses to insulin and attenuation of others. [Diabetologia (2002) 45:657-667]

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Role of IRS-2 in insulin and cytokine signalling

Cited by 790 publications

References 35 publications

Caffeine‐mediated BDNF release regulates long‐term synaptic plasticity through activation of IRS2 signaling

Caffeine‐mediated BDNF release regulates long‐term synaptic plasticity through activation of IRS2 signaling

Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

An arginine to cysteine252 mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalisation but preserves signalling events

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