From signal transduction to signal interpretation: An alternative model for the molecular function of insulin receptor substrates

Boller, Simone; Joblin, Bradley A.; Xu, Linan; Item, Flurin; Trüb, Thomas; Boschetti, Nicola; Spinas, Giatgen A.; Nießen, Markus

doi:10.3109/13813455.2012.671333

Cited by 25 publications

(27 citation statements)

References 68 publications

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“…The activation of the Akt-1 signalling pathway by the IGF-1 receptor is mediated by IRS-1, a docking protein capable of recruiting many intracellular signalling molecules (Baserga, 2009;Boller et al, 2012). IRS-1 is found to be recruited to the basal body (Zhu et al, 2009).…”

Section: Heat Shock Induces Hsp90a Dissipation and Primary Cilia Resomentioning

confidence: 99%

“…As IRS-1 is the docking site for many signalling molecules (Baserga, 2009;Boller et al, 2012), its localisation at the basal body could recruit signalling molecules into proximity with the receptor in the axonemal membrane. The association of IRS-1 with the basal body was mediated by its C-terminal region (amino acids 816-1231) (Fig.…”

Section: Heat Shock Induces Hsp90a Dissipation and Primary Cilia Resomentioning

confidence: 99%

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Hsp90α forms a stable complex at cilia neck for signal molecules interaction in cilia-mediated IGF-1 receptor signaling

Wang

Zou

Zhuang

et al. 2014

Journal of Cell Science

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The primary cilium is composed of an axoneme that protrudes from the cell surface, a basal body beneath the membrane and a transition neck in between. It is a sensory organelle on the plasma membrane, involved in mediating extracellular signals. In the transition neck region of the cilium, the microtubules change from triplet to doublet microtubules. This region also contains the transition fibres that crosslink the axoneme with the membrane and the necklace proteins that regulate molecules being transported into and out of the cilium. In this protein-enriched, complex area it is important to maintain the correct assembly of all of these proteins. Here, through immunofluorescent staining and protein isolation, we identify the molecular chaperone Hsp90a clustered at the periciliary base. At the transition neck region, phosphorylated Hsp90a forms a stable ring around the axoneme. Heat shock treatment causes Hsp90a to dissipate and induces resorption of cilia. We further identify that Hsp90a at the transition neck region represents a signalling platform on which IRS-1 interacts with intracellular downstream signalling molecules involved in IGF-1 receptor signalling.

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Section: Heat Shock Induces Hsp90a Dissipation and Primary Cilia Resomentioning

confidence: 99%

Section: Heat Shock Induces Hsp90a Dissipation and Primary Cilia Resomentioning

confidence: 99%

Hsp90α forms a stable complex at cilia neck for signal molecules interaction in cilia-mediated IGF-1 receptor signaling

Wang

Zou

Zhuang

et al. 2014

Journal of Cell Science

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“…For instance, SIK2-dependent phosphorylation might be priming IRS1 for a final inhibitory readout from stress, nutrient sensing and inflammatory cytokine cascades. 47 It has been reported previously that SIK2 activation also is required for Akt phosphorylation in ovarian cancer cell lines during cell cycle progression. 48 However, in hepatocytes and adipocytes where insulin mainly regulates gluconeogenesis and lipogenesis, respectively, SIK2 was proposed to be an Akt substrate.…”

Section: Sik2 Negatively Regulatesmentioning

confidence: 99%

SIK2 Is Involved in the Negative Modulation of Insulin-Dependent Müller Cell Survival and Implicated in Hyperglycemia-Induced Cell Death

Küser-Abali

Özcan

Uğurlu

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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“…The insulin receptor substrate (IRS) protein family plays a crucial role in the insulin signaling cascade and the insulinlike growth factor (IGF) signal transduction pathway (1,2). The importance of the IRS-1 isoform, one of four IRS family proteins, has been established by experiments on metabolic signaling pathways (3).…”

Section: Introductionmentioning

confidence: 99%

The role of quantitative changes in the epxression of insulin receptor substrate-1 and nuclear ubiquitin in abnormal glycometabolism in the livers of KKay mice and the relative therapeutic mechanisms of Astragalus polysaccharide

Yan

Deng

Wan

et al. 2013

International Journal of Molecular Medicine

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Abstract. Ubiquitin and the ubiquitination pathway are important regulators of insulin signaling. The insulin receptor substrate-1 (IRS-1), an ubiquitin-interacting adaptor protein, serves as the key docking protein in insulin signaling. The effects of this dynamic interaction and the changes in ubiquitin expression on hepatic insulin signaling, as well as the relative therapeutic effects of Astragalus polysaccharide (APS) have not yet been elucidated. In this study, we aimed to investigate the abnormal changes which occur in the levels of IRS-1 and ubiquitin in the livers of mice (mice with insulin resistance and diabetes), and to elucidate the possible mechanisms responsible for these changes. A control group (CG), an insulin resistance group (IG) and a diabetes group (DG) were respectively composed of 12-week-old C57BL/6J mice fed a normal diet, C57BL/6J mice fed a high-fat diet and KKay mice fed a high-fat diet, and treatment groups were composed of corresponding groups treated with APS (CG + A, IG + A, DG + A). All the mice were age-matched and grouped at random. After eight weeks, the mouse models were successfully established and the related physiological or biochemical indexes were detected using corresponding methods. Ubiquitin expression in the liver was detected by immunohistochemisty, and western blot analysis was used to detect the expression of IRS-1 and ubiquitin. The results revealed that the expression of IRS-1 in the DG was significantly lower compared to that in the CG and IG; however, the nuclear expression of ubiquitin and the ubiquitination levels of IRS-1, including body weight and blood glucose and triglyceride levels in the DG were significantly higher compared to those in the CG or IG (P<0.05). There was a significant improvement in the ubiquitination levels in DG + A, including the blood glucose and triglyceride levels compared with the DG (P<0.05). From the stage of insulin resistance to the stage of diabetes, the reduced expression of IRS-1 and its enhanced ubiquitination levels combined with the overexpression of nuclear ubiquitin contributed to the abnormal glycometabolism and the disruption of insulin signaling. APS showed beneficial effects, such as lowering body weight, as well as blood glucose and triglyceride levels, and these effects correlated with the downregulation of the ubiquitination levels of IRS-1 and the nuclear expression of ubiquitin.

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From signal transduction to signal interpretation: An alternative model for the molecular function of insulin receptor substrates

Cited by 25 publications

References 68 publications

Hsp90α forms a stable complex at cilia neck for signal molecules interaction in cilia-mediated IGF-1 receptor signaling

Hsp90α forms a stable complex at cilia neck for signal molecules interaction in cilia-mediated IGF-1 receptor signaling

SIK2 Is Involved in the Negative Modulation of Insulin-Dependent Müller Cell Survival and Implicated in Hyperglycemia-Induced Cell Death

The role of quantitative changes in the epxression of insulin receptor substrate-1 and nuclear ubiquitin in abnormal glycometabolism in the livers of KKay mice and the relative therapeutic mechanisms of Astragalus polysaccharide

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