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

Abstract

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

Inquiring into the Differential Action of Interferons (IFNs): an IFN-α2 Mutant with Enhanced Affinity to IFNAR1 Is Functionally Similar to IFN-β

“…A second example of differential activation would be the activities of insulin and insulin-like growth factor. It was shown that, depending on their concentrations, insulin and insulin-like growth factor can bind to either their homologous or heterologous receptors and trigger different biological responses, which also depend on the surface receptor concentration (10,47).…”

A logical analysis of T cell activation and anergy

“…Our logical description is based on the approach developed by Thomas and D'Ari, which emphasizes the importance of feedback loops and asynchronous switching for the dynamic properties of regulatory networks (9). This formalism already has been applied to other biological examples such as the decision between lysis and lysogenization in bacteriophage (21), the choice between memory and paralysis in the humoral immune response (22), or the influence of hormone residence time on the insulin receptor for metabolic versus mitogenic signaling (10).…”

International Union of Basic and Clinical Pharmacology. XCV. Recent Advances in the Understanding of the Pharmacology and Biological Roles of Relaxin Family Peptide Receptors 1–4, the Receptors for Relaxin Family Peptides

“…Two consequences of this are an increase in the functional concentration range of the ligand and a decrease in ligand residence time corresponding to an increase in free ligand concentration, potentially allowing selective activation of different signaling pathways (Shymko et al, 1997). This may provide one explanation for the observation that in many experimental and clinical situations the concentration-response curves for relaxin acting at RXFP1 are bell shaped (also see section III.A.4).…”

“…It should be borne in mind, however, that such behavior does not necessarily reflect the formation of dimers (Chabre et al, 2009), and studies are required using receptors that retain function but are unable to form dimers or on receptors expressed in model phospholipid bilayers that allow examination of their functional characteristics when in monomeric form (Whorton et al, 2007;Velez-Ruiz and Sunahara, 2011). Nevertheless, there are two intriguing, functionally relevant consequences of negative cooperativity: an increased functional range of the ligand over a wider concentration range and a decrease in ligand residence time at the receptor as the free ligand concentration increases, potentially allowing selective activation of different signaling pathways (Shymko et al, 1997). The negative cooperativity concentration-response curve for relaxin binding to RXFP1 is linear, although the absence of a protein structure precludes conclusions regarding the functional consequences of this observation (Svendsen et al, 2008b).…”