Epidermal growth factor-induced activation of the insulin-like growth factor I receptor in rat hepatocytes

Hallak, Hazem; Moehren, Giesla; Tang, Jei; Kaou, Mohamad; Addas, Mouhamad; Hoek, Jan B.; Rubin, Raphael

doi:10.1002/hep.1840360628

Cited by 6 publications

(10 citation statements)

References 44 publications

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“…Confocal immunofluorescence microscopy shows surface association of IGFBP-3 on isolated primary hepatocytes (33). These observations also suggest that IGFBP-3's modulation of hepatic metabolism may occur through IGF-independent mechanisms.…”

Section: Discussionmentioning

confidence: 66%

Evidence of a Role for Insulin-Like Growth Factor Binding Protein (IGFBP)-3 in Metabolic Regulation

et al. 2010

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IGF-binding protein (IGFBP)-3 is a metabolic regulator that has been shown to inhibit insulin-stimulated glucose uptake in murine models. This finding contrasts with epidemiological evidence of decreased serum IGFBP-3 in patients with type 2 diabetes. The purpose of this study was to clarify the role of IGFBP-3 in metabolism. Four-week-old male IGFBP-3(-/-) and control mice were subjected to a high-fat diet (HFD) for 12 wk. IGFBP-3(-/-) mice were heavier before the initiation of HFD and at the end of the study period. Resting metabolic rate was significantly decreased in knockout mice; however, respiratory exchange ratio was not significantly different. Fasting blood glucose and insulin levels were significantly elevated in IGFBP-3(-/-) mice. However, IGFBP-3(-/-) mice had relatively normal glucose tolerance because the relative glucose excursion over time was not different between the groups. During hyperinsulinemic clamps, IGFBP-3(-/-) mice had increased basal hepatic glucose production, but after insulin stimulation, no differences in hepatic glucose production were observed. A second cohort of older IGFBP-3(-/-) mice on HFD displayed unexpected evidence of hepatic steatosis. In summary, glucose tolerance and clamp testing indicate that IGFBP-3(-/-) mice preserve insulin sensitivity despite evidence of increased basal glucose turnover and hepatic steatosis. We provide evidence that genetic deletion of IGFBP-3 modulates hepatic carbohydrate and lipid metabolism.

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Section: Discussionmentioning

confidence: 66%

Evidence of a Role for Insulin-Like Growth Factor Binding Protein (IGFBP)-3 in Metabolic Regulation

et al. 2010

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“…It has been shown that IGF-1 receptor cross-talks with several other receptors such as angiotensin II, endothelin-1, estrogen or EGF [30]–[36]. We examined whether IGF-1 receptor is involved in AGEs-mediated Akt activation in 3T3-L1 cells.…”

Section: Resultsmentioning

confidence: 99%

“…Besides stimulating its own signaling pathways, IGF-1 receptor can be transactivated by a variety of receptors such as angiotensin II, endothelin-1, estrogen, and epidermal growth factor [30]-[36]. IGF-1 receptor is ubiquitously expressed and also present in 3T3-L1 cells [41].…”

Section: Discussionmentioning

confidence: 99%

“…Both groups found that Ang II or endothelin-1 induces the tyrosine phosphorylation levels of IGF-1Rβ and a Src inhibitor PP1 or PP2 weakens the phosphorylation of IGF-1 receptor. Src is also a mediator of IGF-1 receptor transactivation in response to EGF [36]. Thus, activation of Src appears to be essential for the transactivation of IGF-1 receptor by Ang II, endothelin-1, EGF and AGEs.…”

Section: Discussionmentioning

confidence: 99%

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Activation of Akt by Advanced Glycation End Products (AGEs): Involvement of IGF-1 Receptor and Caveolin-1

Yang¹,

Chen

Chang

et al. 2013

PLoS ONE

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Diabetes is characterized by chronic hyperglycemia, which in turn facilitates the formation of advanced glycation end products (AGEs). AGEs activate signaling proteins such as Src, Akt and ERK1/2. However, the mechanisms by which AGEs activate these kinases remain unclear. We examined the effect of AGEs on Akt activation in 3T3-L1 preadipocytes. Addition of AGEs to 3T3-L1 cells activated Akt in a dose- and time-dependent manner. The AGEs-stimulated Akt activation was blocked by a PI3-kinase inhibitor LY 294002, Src inhibitor PP2, an antioxidant NAC, superoxide scavenger Tiron, or nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase inhibitor DPI, suggesting the involvement of Src and NAD(P)H oxidase in the activation of PI3-kinase-Akt pathway by AGEs. AGEs-stimulated Src tyrosine phosphorylation was inhibited by NAC, suggesting that Src is downstream of NAD(P)H oxidase. The AGEs-stimulated Akt activity was sensitive to Insulin-like growth factor 1 receptor (IGF-1R) kinase inhibitor AG1024. Furthermore, AGEs induced phosphorylation of IGF-1 receptorβsubunit (IGF-1Rβ) on Tyr1135/1136, which was sensitive to PP2, indicating that AGEs stimulate Akt activity by transactivating IGF-1 receptor. In addition, the AGEs-stimulated Akt activation was attenuated by β-methylcyclodextrin that abolishes the structure of caveolae, and by lowering caveolin-1 (Cav-1) levels with siRNAs. Furthermore, addition of AGEs enhanced the interaction of phospho-Cav-1 with IGF-1Rβ and transfection of 3T3-L1 cells with Cav-1 Y14F mutants inhibited the activation of Akt by AGEs. These results suggest that AGEs activate NAD(P)H oxidase and Src which in turn phosphorylates IGF-1 receptor and Cav-1 leading to activation of IGF-1 receptor and the downstream Akt in 3T3-L1 cells. AGEs treatment promoted the differentiation of 3T3-L1 preadipocytes and addition of AG1024, LY 294002 or Akt inhibitor attenuated the promoting effect of AGEs on adipogenesis, suggesting that IGF-1 receptor, PI3-Kinase and Akt are involved in the facilitation of adipogenesis by AGEs.

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“…The kinase inhibitors of Group III occupied the anchors of the ATP site, and only showed the competitive inhibitions for ATP. The pocket environment of ATP is generally conserved in kinase family, and the inhibitors of Group III also have the broadband inhibition for multiple kinases, including AG538 ( 5 ), which is observed on insulin-like growth factor-1 receptor (IGF-1R) [25], IR, EGFR [26], and Src kinases [27].…”

Section: Resultsmentioning

confidence: 99%

Core Site-Moiety Maps Reveal Inhibitors and Binding Mechanisms of Orthologous Proteins by Screening Compound Libraries

et al. 2012

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Members of protein families often share conserved structural subsites for interaction with chemically similar moieties despite low sequence identity. We propose a core site-moiety map of multiple proteins (called CoreSiMMap) to discover inhibitors and mechanisms by profiling subsite-moiety interactions of immense screening compounds. The consensus anchor, the subsite-moiety interactions with statistical significance, of a CoreSiMMap can be regarded as a “hot spot” that represents the conserved binding environments involved in biological functions. Here, we derive the CoreSiMMap with six consensus anchors and identify six inhibitors (IC50<8.0 µM) of shikimate kinases (SKs) of Mycobacterium tuberculosis and Helicobacter pylori from the NCI database (236,962 compounds). Studies of site-directed mutagenesis and analogues reveal that these conserved interacting residues and moieties contribute to pocket-moiety interaction spots and biological functions. These results reveal that our multi-target screening strategy and the CoreSiMMap can increase the accuracy of screening in the identification of novel inhibitors and subsite-moiety environments for elucidating the binding mechanisms of targets.

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Epidermal growth factor-induced activation of the insulin-like growth factor I receptor in rat hepatocytes

Cited by 6 publications

References 44 publications

Evidence of a Role for Insulin-Like Growth Factor Binding Protein (IGFBP)-3 in Metabolic Regulation

Evidence of a Role for Insulin-Like Growth Factor Binding Protein (IGFBP)-3 in Metabolic Regulation

Activation of Akt by Advanced Glycation End Products (AGEs): Involvement of IGF-1 Receptor and Caveolin-1

Core Site-Moiety Maps Reveal Inhibitors and Binding Mechanisms of Orthologous Proteins by Screening Compound Libraries

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