Differential Signaling of Insulin and IGF-1 Receptors to Glycogen Synthesis in Murine Hepatocytes

Park, Byung‐Chul; Kido, Yoshiaki; Accili, Domenico

doi:10.1021/bi9830718

Cited by 43 publications

(36 citation statements)

References 29 publications

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“…Against this background, it is difficult to predict relative efficiency of IR and IGFR in mediating metabolic effects in other tissues based on the present data for glucose transport in 3T3-L1 adipocytes. Interestingly, in hepatocytes, as in 3T3-L1 fibroblasts, glycogen synthesis was more effectively stimulated via IR than IGFR, although both receptors mediated similar activation of PKB (52). The insulin-specific stimulation of glycogen synthesis in hepatocytes appeared to involve a rapamycin-sensitive pathway.…”

Section: Discussionmentioning

confidence: 89%

Differences in Signaling Properties of the Cytoplasmic Domains of the Insulin Receptor and Insulin-like Growth Factor Receptor in 3T3-L1 Adipocytes

Ursø

Cope

Kalloo-Hosein

et al. 1999

Journal of Biological Chemistry

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Insulin and insulin-like growth factors (IGFs) elicit distinct but overlapping biological effects in vivo. To investigate whether differences in intrinsic signaling capacity of receptors contribute to biological specificity, we constructed chimeric receptors containing the extracellular portion of the neurotrophin receptor TrkC fused to the intracellular portion of the insulin or IGF-I receptors. Chimeras were stably expressed in 3T3-L1 adipocytes at levels comparable to endogenous insulin receptors and were efficiently activated by neurotrophin-3. The wild-type insulin receptor chimera mediated approximately 2-fold greater phosphorylation of insulin receptor substrate 1 (IRS-1), association of IRS-1 with phosphoinositide 3-kinase, stimulation of glucose uptake, and GLUT4 translocation, compared with the IGF-I receptor chimera. In contrast, the IGF-I receptor chimera mediated more effective Shc phosphorylation, association of Shc with Grb2, and activation of mitogenactivated protein kinase compared with the insulin receptor chimera. The two receptors elicited similar activation of protein kinase B, p70S6 kinase, and glycogen synthesis. We conclude that the insulin receptor mediates some aspects of metabolic signaling in adipocytes more effectively than the IGF-I receptor, as a consequence of more efficient phosphorylation of IRS-1 and greater recruitment/activation of phosphoinositide 3-kinase. Insulin and insulin-like growth factors (IGFs)1 are structurally related polypeptides that exert diverse effects on mammalian tissues. The most prominent actions of insulin in vivo are concerned with the acute regulation of carbohydrate and lipid metabolism in liver, muscle, and fat, whereas IGFs act on skeletal and other tissues to promote growth, differentiation, and survival. The receptors for insulin and IGFs, which mediate these effects (IR and IGFR), are also structurally related and highly homologous, consisting of extracellular ␣-subunits responsible for ligand binding and transmembrane ␤-subunits possessing protein-tyrosine kinase activity, in a disulphide linked ␤-␣-␣-␤ configuration (1-3). Within the intracellular portion, the level of sequence identity between the receptors is greatest in the tyrosine kinase domain (84%) and somewhat less in the flanking juxtamembrane and carboxyl-terminal regions (61 and 44%, respectively). Not surprisingly, the signaling mechanisms of the insulin receptor (IR) and IGF-I receptor (IGFR) are broadly similar. Ligand binding activates tyrosine kinase activity, leading to phosphorylation of intracellular substrates, such as IRS and Shc proteins, and the recruitment and/or stimulation of signal transducing molecules, including phosphoinositide 3-kinase (PI 3-kinase) and Grb2⅐Sos (4, 5). These signal transducers in turn promote activation of proteinserine kinase cascades involving phosphoinositide-dependent kinase/PKB and MAPK/Erk kinase/MAPK, respectively, which modulate the activity of glucose transporters, enzymes, and transcription factors (6, 7).Given the similarity in structu...

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Section: Discussionmentioning

confidence: 89%

Differences in Signaling Properties of the Cytoplasmic Domains of the Insulin Receptor and Insulin-like Growth Factor Receptor in 3T3-L1 Adipocytes

Ursø

Cope

Kalloo-Hosein

et al. 1999

Journal of Biological Chemistry

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“…However, both PI3K and extracellular signal-regulated kinase (ERK) are involved in IGF-1-induced mitogenesis, whereas insulin stimulated mitogenesis through a PI3K-dependent and ERK-independent pathway (Svegliati- Baroni et al, 1999). Interestingly, glycogen synthesis was more effectively stimulated by the IR than by the IGF-1R, although both receptors mediated similar activation of the Akt/protein kinase B (PKB) protein kinase in hepatocytes and in 3T3-L1 fibroblasts (Park et al, 1999). The insulin-specific stimulation of glycogen synthesis appears to involve a rapamycin-sensitive pathway in hepatocytes (Park et al, 1999).…”

Section: Signaling Pathwaysmentioning

confidence: 99%

Microarray Analysis and Identification of Novel Molecules Involved in Insulin-like Growth Factor-1 Receptor Signaling and Gene Expression

Dupont

Se²,

Jc³

et al. 2003

Recent Progress in Hormone Research

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The insulin receptor (IR) and the insulin-like growth factor-1 receptor (IGF-1R) are members of the same subfamily of receptor tyrosine kinases. The two receptors phosphorylate many of the same substrates and activate the same signaling modules, including the mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3Ј kinase (PI3K) signaling pathways. Although the IR and IGF-1R share some redundant functions in metabolism, cell growth, differentiation, and apoptosis, they also exhibit distinct physiological roles. Some of these may be due to differences in tissue distribution, receptor structure, formation of hybrid receptors, or mechanisms of ligand binding. However, the divergent effects of insulin and IGF-1 also may be explained by specificity in the intracellular signals generated by insulin and IGF-1. In particular, the IR and IGF-1R are capable of triggering their own biological responses by using specific or preferential substrates, molecular adapters, or signaling pathways. In a recent study, we used cDNA microarray analysis to identify genes differentially regulated by insulin and IGF-1. Mouse NIH-3T3 fibroblasts expressing either the wild-type human IGF-1R or IR were stimulated with either IGF-1 or insulin, respectively. We identified 39 genes differentially regulated by insulin and IGF-1. Most of these genes had not been reported previously to be responsive to insulin or IGF-1. The genes induced by IGF-1 generally were involved in mitogenesis or differentiation, while the genes found to be induced by insulin did not conform to any particular category. In a separate study, immortalized breast epithelial cells were stimulated with IGF-1 and a cDNA microarray analysis was used to generate a profile of IGF-1-regulated genes. A number of genes known to be involved in angiogenesis were found to be regulated by IGF-1. These results strongly suggest that this technology may be extremely useful in identifying groups of genes that are specifically regulated by different ligands and their activated receptors.

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“…The majority of these studies indicate that activation of the IGF-1R is more mitogenic than the IR (4 -6), although others (7) have failed to demonstrate such differences. In addition, glycogen synthesis has been shown to be coupled more strongly to the IR than the IGF-1R (6,8). However, there are several problems associated with the use of these systems, including the formation of hybrid IR/IGF-1Rs and cross-reactivity (ligand binding to non-cognate endogenous receptors, which is likely to occur at the concentrations usually used in ex vivo experiments), all of which may obscure any signaling specificity.…”

mentioning

confidence: 99%

Microarray Analysis of Insulin and Insulin-like Growth Factor-1 (IGF-1) Receptor Signaling Reveals the Selective Up-regulation of the Mitogen Heparin-binding EGF-like Growth Factor by IGF-1

Mulligan

Rochford

Denyer

et al. 2002

Journal of Biological Chemistry

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Insulin and insulin-like growth factor-1 (IGF-1) act through highly homologous receptors that engage similar intracellular signaling pathways, yet these hormones serve largely distinct physiological roles in the control of metabolism and growth, respectively. In an attempt to uncover the molecular mechanisms underlying their divergent functions, we compared insulin receptor (IR) and IGF-1 receptor (IGF-1R) regulation of gene expression by microarray analysis, using 3T3-L1 cells expressing either TrkC/IR or TrkC/IGF-1R chimeric receptors to ensure the highly selective activation of each receptor tyrosine kinase. Following stimulation of the chimeric receptors for 4 h, we detected 11 genes to be differentially regulated, of which 10 were up-regulated to a greater extent by the IGF-1R. These included genes involved in adhesion, transcription, transport, and proliferation. The expression of mRNA encoding heparin-binding epidermal growth factor-like growth factor (HB-EGF), a potent mitogen, was markedly increased by IGF-1R but not IR activation. This effect was dependent on MAPK, but not phosphatidylinositol 3-kinase, and did not require an autocrine loop through the epidermal growth factor receptor. HB-EGF mitogenic activity was detectable in the medium of 3T3-L1 preadipocytes expressing activated IGF-1R but not IR, indicating that the transcriptional response is accompanied by a parallel increase in mature HB-EGF protein. The differential abilities of the IR and IGF-1R tyrosine kinases to stimulate the synthesis and release of a growth factor may provide, at least in part, an explanation for the greater role of the IGF-1R in the control of cellular proliferation.

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Differential Signaling of Insulin and IGF-1 Receptors to Glycogen Synthesis in Murine Hepatocytes

Cited by 43 publications

References 29 publications

Differences in Signaling Properties of the Cytoplasmic Domains of the Insulin Receptor and Insulin-like Growth Factor Receptor in 3T3-L1 Adipocytes

Differences in Signaling Properties of the Cytoplasmic Domains of the Insulin Receptor and Insulin-like Growth Factor Receptor in 3T3-L1 Adipocytes

Microarray Analysis and Identification of Novel Molecules Involved in Insulin-like Growth Factor-1 Receptor Signaling and Gene Expression

Microarray Analysis of Insulin and Insulin-like Growth Factor-1 (IGF-1) Receptor Signaling Reveals the Selective Up-regulation of the Mitogen Heparin-binding EGF-like Growth Factor by IGF-1

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