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BIOMD0000000423
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creator:
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    orgname: EMBL-EBI
  n:
    given: Vijayalakshmi
    family: Chelliah
reaction: 898110
reaction: 898398
is described by: http://identifiers.org/pubmed/22248283
name: Nyman2012_InsulinSignalling
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area units: area
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substance units: substance
is derived from: BIOMD0000000343
created:
  W3 CDTF: Fri Jul 27 13:02:12 BST 2012
parameter: 897678
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modified:
  W3 CDTF: Thu Aug 09 16:53:40 BST 2012
time units: time
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occurs in: http://identifiers.org/taxonomy/39107
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creator:
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    orgname: Linkoping University
  n:
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    family: Nyman
reaction: 898350
type: SBMLModel
notes: This model is from the article: Mechanistic explanations for counter-intuitive phosphorylation dynamics of the insulin receptor and insulin receptor substrate-1 in response to insulin in murine adipocytes. Nyman E, Fagerholm S, Jullesson D, Strålfors P, Cedersund G. FEBS J. 2012 Jan 16. 22248283 , Abstract: Insulin signaling through insulin receptor (IR) and insulin receptor substrate-1 (IRS1) is important for insulin control of target cells. We have previously demonstrated a rapid and simultaneous overshoot behavior in the phosphorylation dynamics of IR and IRS1 in human adipocytes. Herein, we demonstrate that in murine adipocytes a similar overshoot behavior is not simultaneous for IR and IRS1. The peak of IRS1 phosphorylation, which is a direct consequence of the phosphorylation and the activation of IR, occurs earlier than the peak of IR phosphorylation. We used a conclusive modeling framework to unravel the mechanisms behind this counter-intuitive order of phosphorylation. Through a number of rejections, we demonstrate that two fundamentally different mechanisms may create the reversed order of peaks: (i) two pools of phosphorylated IR, where a large pool of internalized IR peaks late, but phosphorylation of IRS1 is governed by a small plasma membrane-localized pool of IR with an early peak, or (ii) inhibition of the IR-catalyzed phosphorylation of IRS1 by negative feedback. Although (i) may explain the reversed order, this two-pool hypothesis alone requires extensive internalization of IR, which is not supported by experimental data. However, with the additional assumption of limiting concentrations of IRS1, (i) can explain all data. Also, (ii) can explain all available data. Our findings illustrate how modeling can potentiate reasoning, to help draw nontrivial conclusions regarding competing mechanisms in signaling networks. Our work also reveals new differences between human and murine insulin signaling. Database The mathematical model described here has bee…
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898026
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898374
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