Molecular dynamics of insulin/IGF‐I receptor transmembrane signaling

Pessin, Jeffrey E.; Frattali, Anne L.

doi:10.1002/mrd.1080350404

Cited by 17 publications

(9 citation statements)

References 42 publications

(19 reference statements)

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“…Insulin not only specifically activates its receptor, but it can also transactivate the insulin-like growth factor I receptor (IGF-IR), which is, like IR, a member of the receptor tyrosine kinase family of growth factor receptors [105]. IGF-IR binds IGF-I and IGF-II with high affinity and insulin at a considerably lower affinity.…”

Section: Insulin Signaling Pathwaysmentioning

confidence: 99%

Insulin signaling and life span

Avogaro

Kreutzenberg

Fadini

2009

Pflugers Arch - Eur J Physiol

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Hyperinsulinemia and metabolic diseases are known to be associated with a reduction in life span. In the presence of insulin resistance, insulin signaling is selectively impaired, contributing to longevity shortening. Insulin indeed activates a complex web of intracellular downstream pathways, which are involved in mechanisms regulating longevity, primarily affecting cellular proliferation and apoptosis. Insulin resistance promotes reactive oxygen species (ROS) formation and favors a pro-inflammatory milieu, both these conditions playing a critical role in the reduction of life span. Insulin resistance/hyperinsulinemia also influences longevity regulating other intracellular signaling downstream in a direct or indirect manner, such as the phosphoinositide 3-kinase pathway that appears selectively impaired by insulin resistance. Decreased NAD-dependent deacetylase sirtuin (Sirt) 1 activity may mediate the shortened life span in conditions of insulin resistance. Furthermore, insulin resistance and diabetes may also associate with the telomere shortening, another important regulator of life span. This review will focus on the main intracellular pathways and mediators regulated by insulin and altered by hyperinsulinemia/insulin resistance; it summarizes the underlying mechanisms and provides evidence of these observations in experimental animal models and in human, giving further insight on the hypothesis that insulin signaling may play an important role in life span.

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Section: Insulin Signaling Pathwaysmentioning

confidence: 99%

Insulin signaling and life span

Avogaro

Kreutzenberg

Fadini

2009

Pflugers Arch - Eur J Physiol

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“…Insulin can also bind to the IGF-1 receptor and vice versa, albeit with a 10-to100-fold lower affinity (10). In addition, some IGF-1 and insulin receptors exist as heterodimer hybrids allowing crossphosphorylation of their intracellular kinase domains (11). Reflecting these mechanisms, the IGF-1R showed an early activation profile, similar to the insulin receptor, but with a fivefold lower activation.…”

Section: Analysis Of Temporal Activation Profiles Revealed Different mentioning

confidence: 99%

Dissection of the insulin signaling pathway via quantitative phosphoproteomics

Krüger

Kratchmarova

Blagoev

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

254

208

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The insulin signaling pathway is of pivotal importance in metabolic diseases, such as diabetes, and in cellular processes, such as aging. Insulin activates a tyrosine phosphorylation cascade that branches to create a complex network affecting multiple biological processes. To understand the full spectrum of the tyrosine phosphorylation cascade, we have defined the tyrosine-phosphoproteome of the insulin signaling pathway, using high resolution mass spectrometry in combination with phosphotyrosine immunoprecipitation and stable isotope labeling by amino acids in cell culture (SILAC) in differentiated brown adipocytes. Of 40 identified insulininduced effectors, 7 have not previously been described in insulin signaling, including SDR, PKC␦ binding protein, LRP-6, and PISP/ PDZK11, a potential calcium ATPase binding protein. A proteomic interaction screen with PISP/PDZK11 identified the calcium transporting ATPase SERCA2, supporting a connection to calcium signaling. The combination of quantitative phosphoproteomics with cell culture models provides a powerful strategy to dissect the insulin signaling pathways in intact cells.diabetes ͉ insulin action ͉ tyrosine phosphorylation R eversible phosphorylation is a major regulatory mechanism controlling the activity of proteins. Many signaling pathways, including the insulin/IGF-1 signaling pathway, transduce signals from the cell surface to downstream targets via tyrosine kinases and phosphatases (1). Insulin or IGF-1 binding initiates a complex cascade of events, starting with phosphorylation of specific tyrosine residues on the insulin and the IGF-1 receptors (2). Once activated, these receptors phosphorylate a number of docking proteins; the best characterized are the insulin receptor substrate (IRS) proteins 1-4 (3). IRS 1-4 interact with other intracellular signaling molecules primarily through SH2 domains leading to activation of several downstream pathways. These in turn coordinate and regulate vesicle trafficking, protein synthesis, and glucose uptake. The insulin receptor and its substrates, therefore, constitute the first critical node in the insulin signaling network (1) and thus define the full set of proteins that are tyrosine phosphorylated upon insulin stimulation and provide information that is central to determining the molecules involved in this signaling network.Mass spectrometry (MS)-based proteomics has become increasingly powerful not only to identify complex protein mixtures but also regulated protein modifications (4). We have studied tyrosine phosphorylated effectors and interactors in the EGF pathway (5, 6) and others have used MS to study tyrosine phosphorylation of the insulin pathway in white adipocytes (7). To quantify the time course of stimulation, we employ stable isotope labeling with amino acids in cell culture (SILAC) (8). Labeling three cell states by SILAC allows measuring a time course of activation of tyrosine phosphorylation by quantifying the relative protein amounts after antiphosphotyrosine immunoprecipitation. Here, we quanti...

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“…Insulin not only specifically activates its receptor, but it can also transactivate the IGF-I receptor, which is similar to the insulin receptor, a member of the receptor tyrosine kinase family of growth factor receptors 9. When insulin levels increase (as in the postprandial surge in insulin-resistant subjects or after insulin injection), insulin binds and activates the related IGF-I receptor which has a more potent mitogenic and transforming activity.…”

Section: Insulin Receptor/signalling and Irmentioning

confidence: 99%