Structural Basis for Inhibition of the Insulin Receptor by the Adaptor Protein Grb14

Depetris, Rafael S.; Hu, Junjie; Gimpelevich, I.; Holt, Lowenna J; Daly, Roger J.; Hubbard, Stevan R.

doi:10.1016/j.molcel.2005.09.001

Cited by 101 publications

(128 citation statements)

References 24 publications

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“…The phosphorylated activation loop represents an atypical SH2-domain binding site, in that the loop is multiply phosphorylated and is stabilized in a turn-containing (rather than an extended) conformation. Indeed, these SH2 domains possess unique features that allow them to bind efficiently to the phosphorylated activation loop of InsR (Hu et al 2003;Stein et al 2003;Depetris et al 2005). First, they are dimeric.…”

Section: Structure and Mechanism Of The Insulin Receptormentioning

confidence: 99%

“…The BPS a helix ends near the kinase N lobe, which positions the carboxy-terminal SH2 domain for interaction with pY1158 and pY1162 in the activation loop . The SH2 domain of Grb14/10 is dimeric Depetris et al 2005), like the SH2B2 SH2 domain (Hu et al 2003), but each protomer possesses a prototypical SH2-domain architecture. Binding of canonical phosphotyrosine sequences (with Pþ3 hydrophobic residues) are selected against by a valine in the BG loop (glycine in Src and Abl), which effectively seals off the Pþ3 binding pocket .…”

Section: Recruitment Of Negative Regulators To the Activated Insrmentioning

confidence: 99%

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The Insulin Receptor: Both a Prototypical and Atypical Receptor Tyrosine Kinase

Hubbard

2013

Cold Spring Harbor Perspectives in Biology

120

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Unlike prototypical receptor tyrosine kinases (RTKs), which are single-chain polypeptides, the insulin receptor (InsR) is a preformed, covalently linked tetramer with two extracellular a subunits and two membrane-spanning, tyrosine kinase-containing b subunits. A single molecule of insulin binds asymmetrically to the ectodomain, triggering a conformational change that is transmitted to the cytoplasmic kinase domains, which facilitates their trans-phosphorylation. As in prototypical RTKs, tyrosine phosphorylation in the juxtamembrane region of InsR creates recruitment sites for downstream signaling proteins (IRS [InsR substrate] proteins, Shc) containing a phosphotyrosine-binding (PTB) domain, and tyrosine phosphorylation in the kinase activation loop stimulates InsR's catalytic activity. For InsR, phosphorylation of the activation loop, which contains three tyrosine residues, also creates docking sites for adaptor proteins (Grb10/14, SH2B2) that possess specialized Src homology-2 (SH2) domains, which are dimeric and engage two phosphotyrosines in the activation loop.

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Section: Structure and Mechanism Of The Insulin Receptormentioning

confidence: 99%

Section: Recruitment Of Negative Regulators To the Activated Insrmentioning

confidence: 99%

The Insulin Receptor: Both a Prototypical and Atypical Receptor Tyrosine Kinase

Hubbard

2013

Cold Spring Harbor Perspectives in Biology

120

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“…These Grb7 family proteins each have an N-terminal region harboring a conserved proline-rich motif, a central region containing a pleckstrin homology (PH) domain and a C-terminal SH2 domain. A novel domain has also been identified in these proteins, termed the BPS (between PH and SH2) domain, which can contribute to receptor interactions (17,25,30). Originally identified through its ability to bind to the epidermal growth factor receptor, Grb10 has been shown to bind both the Insr and the related type 1 insulin-like growth factor receptor (IGF1R), as well as a number of other receptor tyrosine kinases (27).…”

mentioning

confidence: 99%

Mice with a Disruption of the Imprinted Grb10 Gene Exhibit Altered Body Composition, Glucose Homeostasis, and Insulin Signaling during Postnatal Life

Smith

Holt

Garfield

et al. 2007

Molecular and Cellular Biology

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113

153

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The Grb10 adapter protein is capable of interacting with a variety of receptor tyrosine kinases, including, notably, the insulin receptor. Biochemical and cell culture experiments have indicated that Grb10 might act as an inhibitor of insulin signaling. We have used mice with a disruption of the Grb10 gene (Grb10⌬2-4 mice) to assess whether Grb10 might influence insulin signaling and glucose homeostasis in vivo. Adult Grb10⌬2-4 mice were found to have improved whole-body glucose tolerance and insulin sensitivity, as well as increased muscle mass and reduced adiposity. Tissue-specific changes in insulin receptor tyrosine phosphorylation were consistent with a model in which Grb10, like the closely related Grb14 adapter protein, prevents specific protein tyrosine phosphatases from accessing phosphorylated tyrosines within the kinase activation loop. Furthermore, insulin-induced IRS-1 tyrosine phosphorylation was enhanced in Grb10⌬2-4 mutant animals, supporting a role for Grb10 in attenuation of signal transmission from the insulin receptor to IRS-1. We have previously shown that Grb10 strongly influences growth of the fetus and placenta. Thus, Grb10 forms a link between fetal growth and glucose-regulated metabolism in postnatal life and is a candidate for involvement in the process of fetal programming of adult metabolic health.Insulin controls glucose homeostasis by regulating protein, lipid, and carbohydrate metabolism. Cellular responses to insulin in target tissues, such as skeletal muscle, adipose tissue, and liver, are mediated via the insulin receptor (Insr) (reviewed in reference 51). Activation of the Insr results in tyrosine phosphorylation of intracellular docking proteins such as Shc and IRS-1 through IRS-4, which then bind specific Src homology 2 (SH2) domain-containing enzymes and adapters, leading to the activation of downstream signaling cascades. A critical event mediating insulin regulation of metabolic endpoints is the activation of phosphatidylinositol 3-kinase (PI3K). This stimulates the synthesis of phosphatidylinositol 3,4,5-triphosphate, which induces plasma membrane recruitment and subsequent phosphorylation of protein kinase B (also known as Akt), a key player in the regulation of glucose uptake and glycogen synthesis. Activation of the Insr and downstream signaling results in increased glucose uptake, utilization, and storage in adipose tissue and skeletal muscle, while decreased gluconeogenesis and glycogenolysis and increased glycogen synthesis occur in the liver (reviewed in reference 51). Resistance to these effects of insulin is a defining feature of type 2 diabetes, a polygenic disease afflicting over 110 million people worldwide. Impaired insulin action is also a feature of obesity and predisposes people to arteriosclerosis and cardiovascular diseases, facts which highlight its importance in human health. The fundamental role of the Insr in insulin action was demonstrated following targeted disruption of the receptor (1, 29). To dissect the contribution of individual tissues to gl...

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“…A role for Grb14 as a physiological modulator of insulin action was first suggested by its inhibitory effect on the catalytic activity of the insulin receptor and by the metabolic phenotype of Grb14 Ϫ/Ϫ mice, which displayed improved glucose tolerance and insulin signaling in the liver and skeletal muscle (11,36,37). However, the regulation by Grb14 of hepatic metabolism likely involves additional molecular mechanisms besides its role as a pseudo-substrate inhibitor of the insulin receptor.…”

Section: Discussionmentioning

confidence: 99%

Novel Grb14-Mediated Cross Talk between Insulin and p62/Nrf2 Pathways Regulates Liver Lipogenesis and Selective Insulin Resistance

Popineau

Morzyglod

Carré

et al. 2016

Molecular and Cellular Biology

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A long-standing paradox in the pathophysiology of metabolic diseases is the selective insulin resistance of the liver. It is characterized by a blunted action of insulin to reduce glucose production, contributing to hyperglycemia, while de novo lipogenesis remains insulin sensitive, participating in turn to hepatic steatosis onset. The underlying molecular bases of this conundrum are not yet fully understood. Here, we established a model of selective insulin resistance in mice by silencing an inhibitor of insulin receptor catalytic activity, the growth factor receptor binding protein 14 (Grb14) in liver. Indeed, Grb14 knockdown enhanced hepatic insulin signaling but also dramatically inhibited de novo fatty acid synthesis. In the liver of obese and insulin-resistant mice, downregulation of Grb14 markedly decreased blood glucose and improved liver steatosis. Mechanistic analyses showed that upon Grb14 knockdown, the release of p62/sqstm1, a partner of Grb14, activated the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), which in turn repressed the lipogenic nuclear liver X receptor (LXR). Our study reveals that Grb14 acts as a new signaling node that regulates lipogenesis and modulates insulin sensitivity in the liver by acting at a crossroad between the insulin receptor and the p62-Nrf2-LXR signaling pathways.

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Structural Basis for Inhibition of the Insulin Receptor by the Adaptor Protein Grb14

Cited by 101 publications

References 24 publications

The Insulin Receptor: Both a Prototypical and Atypical Receptor Tyrosine Kinase

The Insulin Receptor: Both a Prototypical and Atypical Receptor Tyrosine Kinase

Mice with a Disruption of the Imprinted Grb10 Gene Exhibit Altered Body Composition, Glucose Homeostasis, and Insulin Signaling during Postnatal Life

Novel Grb14-Mediated Cross Talk between Insulin and p62/Nrf2 Pathways Regulates Liver Lipogenesis and Selective Insulin Resistance

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