IRS-1 activates phosphatidylinositol 3'-kinase by associating with src homology 2 domains of p85.

Myers, Martin G.; Backer, Jonathan M.; Sun, Xiao Jian; Shoelson, Steven E.; Hu, Patrick J.; Schlessinger, Joseph; Yoakim, Monique; Schaffhausen, Brian; White, Morris F.

doi:10.1073/pnas.89.21.10350

Cited by 421 publications

(288 citation statements)

References 21 publications

(24 reference statements)

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“…Activation of tyrosine kinase receptors induces the phosphorylation of IRS proteins, enabling them to recruit and activate PI3K through a direct interaction with the p85 catalytic subunit (Myers et al 1992; White 2006). Interestingly, IRS2 signals have been reported to mediate the action of BDNF (Yamada et al 1997) and hippocampal IRS2 is critical for LTP induction upon tetanic stimulation (Martín et al 2012).…”

Section: Resultsmentioning

confidence: 99%

“…In animal models, the insulinotropic effects of caffeine administration have been linked to the signaling pathway mediated by insulin receptor substrate 2 (IRS2) (Park et al 2007). IRS proteins are phosphorylated by active tyrosine kinase receptors, like insulin receptor (IR) and the insulin‐like growth factor‐1 receptor (IGF‐1R), and thereby regulate the cellular response by recruiting downstream signaling components such as phosphoinositide 3‐kinase (PI3K) and Akt (Myers et al 1992; White 2006). Importantly, mice deficient for IRS2 display defects in hippocampal synaptic plasticity (Costello et al 2012; Martín et al 2012).…”

Section: Introductionmentioning

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: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…phorylation sites on IRS-1 and IRS-2 are binding sites for several SH2 domain-containing proteins including p85 (the regulatory subunit of PtdIns 3h-kinase) [19], Syp (tyrosine-specific phosphatase) [20] and Grb-2 (a small adaptor protein) [21]. Although both IRS-1 and Shc interact with the JCT domain via the NPEY motif surrounding residue Tyr-950, IRS-1 might also bind the major autophosphorylation site (Tyr-1131, Tyr-1135 and Tyr-1136) in the tyrosine kinase domain [22].…”

Section: Introductionmentioning

confidence: 99%

Interaction in vitro of the product of the c-Crk-II proto-oncogene with the insulin-like growth factor I receptor

Koval

Blakesley

Roberts

et al. 1998

Biochemical Journal

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The Crk proto-oncogene product is an SH2 and SH3 domaincontaining adaptor protein. We have previously demonstrated that Crk-II becomes rapidly tyrosine-phosphorylated in response to stimulation with insulin-like growth factor I (IGF-I) and might be involved in the IGF-I receptor signalling pathway. To determine whether this involvement includes the direct interaction of Crk-II with the cytoplasmic region of the receptor, studies were performed in itro with glutathione S-transferase (GST) fusion proteins containing various domains of Crk-II. The kinase assay in itro showed that activated IGF-I receptors efficiently phosphorylated the GST-Crk-II fusion protein. This phosphorylation was dependent on the presence of the SH2 domain and Tyr-221 located in the spacer region between the two SH3 domains. Mutation of Tyr-221 not only prevented phosphorylation of GST-Crk in itro, but also significantly increased the ability of GST-Crk proteins to co-precipitate activated IGF-I receptors from total cell lysates. Additional binding experiments in itro showed that Crk-II might interact with the phosphorylated IGF-I receptor through its SH2 domain. To elucidate which

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“…The activation of PI3K by insulin is mediated by the p85 regulatory subunit binding to tyrosine-phosphorylated insulin receptor substrate (IRS) proteins Myers et al 1992). Akt, a downstream target of PI3-kinase, has been reported to mediate insulin-induced glycogen synthase activation and glucose uptake, and is activated mainly at two regulatory sites, Thr 308 and Ser 473 (Palanivel et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Resistin disrupts glycogen synthesis under high insulin and high glucose levels by down-regulating the hepatic levels of GSK3β

Song¹,

Wang²,

Mao³

et al. 2013

Gene

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The effect of mouse resistin on hepatic insulin resistance in vivo and in vitro, and its possible molecular mechanism were examined. Focusing on liver glycogen metabolism and gluconeogenesis, which are important parts of glucose metabolism, in primary cultures of rat hepatocytes we found that glycogen content was significantly lower (P<0.05) after treatment with recombinant murine resistin only in the presence of insulin plus glucose stimulation. Protein levels of factors in the insulin signaling pathway involved in glycogen synthesis were examined by Western blot analysis, with the only significant change observed being the level of phosphorylated (at Ser 9) glycogen synthase kinase-3β (GSK-3β) (P<0.001). No differences in the protein levels for the insulin receptor β (IRβ), insulin receptor substrates (IRS1 and IRS2), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) or their phosphorylated forms were observed between control and resistin treated primary rat hepatocytes. In a mouse model with high liver-specific expression of resistin, fasting blood glucose levels and liver glycogen content changed. Fasting blood glucose levels were significantly higher (P<0.001) in the model mice, compared to the control mice, while the glycogen content of the liver tissue was about 60% of that of the control mice (P<0.05). The gluconeogenic response was not altered between the experimental and control mice. The level of phosphorylated GSK-3β in the liver tissue was also decreased (P<0.05) in the model mice, consistent with the results from the primary rat hepatocytes. Our results suggests that resistin reduces the levels of GSK-3β phosphorylated at Ser 9 leading to impaired hepatic insulin

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IRS-1 activates phosphatidylinositol 3'-kinase by associating with src homology 2 domains of p85.

Cited by 421 publications

References 21 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

Interaction in vitro of the product of the c-Crk-II proto-oncogene with the insulin-like growth factor I receptor

Resistin disrupts glycogen synthesis under high insulin and high glucose levels by down-regulating the hepatic levels of GSK3β

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