Role of the time factor in signaling specificity: Application to mitogenic and metabolic signaling by the insulin and insulin-like growth factor-I receptor tyrosine kinases

Meyts, Pierre De; Christoffersen, Claus T.; Ursø, Birgitte; Wallach, Brenda; Grønskov, Karen; Yakushiji, Fumiatsu; Shymko, Ronald M.

doi:10.1016/0026-0495(95)90214-7

Cited by 54 publications

(28 citation statements)

References 65 publications

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“…Functional differences might arise from the kinetics of ligand association and dissociation, affecting the lifetime and/or intracellular itinerary of the activated receptors (35,36). Alternatively, the receptor intracellular domains might possess different signaling capacities, reflecting their differences in primary sequence (nonidentity, 16% in the tyrosine kinase domain, 39% in the juxtamembrane domain, and 56% in the carboxyl-terminal domain).…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…As both chimeras are identical in their extracellular regions and bind the same ligand, any differences observed between the two will be entirely due to differences in the sequence and function of their intracellular domains. If, as has been suggested, some of the differential signaling properties of the IR and IGF-1R relate to the residence time of the ligand on the receptor, with IGF-1R having more sustained activation (15,16), this real biological difference will not be observed in our system. However, we feel that our findings of consistent and repeatable differential biological responses using these chimeras, both herein and in previous reports (9 -11), adequately justifies their continued use for this purpose.…”

Section: Tigr-mediated Up-regulation Of Hb-egf Gene Transcription Doementioning

confidence: 94%

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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“…One interpretation of the dependence of signalling properties on dissociation rate and on the timing properties of signalling events in general is that there is a process downstream of the event that requires a certain minimal time to become activated [2,30] (e.g. nuclear translocation of MAPK in PC12 cells [29]).…”

Section: Scheme 1 Positive and Negative Signals In The Insulin Signalmentioning

confidence: 99%

“…For example, insulin, acting through its receptor, triggers a number of biological responses which can be divided into two broad categories. Metabolic processes, associated with uptake and subsequent storage of glucose, are generally taken to be the primary target of insulin receptor signalling, but mitogenic processes associated with DNA replication, cell growth and division are also activated to a lesser or greater degree (for reviews, see [1][2][3]). Both kinds of signalling begin with hormone binding, which results in receptor autophosphorylation and activation of the receptor tyrosine kinase, followed by a cascade of activation of intracellular signalling molecules (Scheme 1) [4,5].…”

Section: Introductionmentioning

confidence: 99%

“…Early events in the signalling cascade are shared by the metabolic and mitogenic signalling pathways, such as hormone binding and perhaps the binding of the tyrosinephosphorylated insulin receptor by insulin receptor substrate 1 (IRS-1) [4], IRS-2 [6][7][8] or Shc [4,9]. Moreover, many components of the known insulin receptor signalling pathways are shared by the predominantly mitogenic insulin-like growth factor I receptor [10][11][12][13] ; for review, see [2]. At some point along the various intracellular activation pathways, the signal diverges and the intracellular machinery for metabolic or mitogenic response is mobilized.…”

Section: Introductionmentioning

confidence: 99%

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Logical analysis of timing-dependent receptor signalling specificity: application to the insulin receptor metabolic and mitogenic signalling pathways

Shymko¹,

Meyts²,

Thomas

1997

Biochemical Journal

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We present a method for logical analysis of signal-transduction networks, focusing on metabolic and mitogenic signalling by the insulin receptor, with specific emphasis on dependence of the signalling properties on the timing of binding events. We discuss a basic model which demonstrates this dependence (hormone binding leads to activation of the receptor which can lead to a commitment to mitogenic signalling), and show how residence time of the hormone on the receptor can determine the specificity

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Role of the time factor in signaling specificity: Application to mitogenic and metabolic signaling by the insulin and insulin-like growth factor-I receptor tyrosine kinases

Cited by 54 publications

References 65 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 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

Logical analysis of timing-dependent receptor signalling specificity: application to the insulin receptor metabolic and mitogenic signalling pathways

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