Elsevier

Vitamins & Hormones

Volume 80, 2009, Pages 51-75
Vitamins & Hormones

Chapter 3 Molecular Mechanisms of Differential Intracellular Signaling From the Insulin Receptor

https://doi.org/10.1016/S0083-6729(08)00603-1Get rights and content

Abstract

Binding of insulin to the insulin receptor (IR) leads to a cascade of intracellular signaling events, which regulate multiple biological processes such as glucose and lipid metabolism, gene expression, protein synthesis, and cell growth, division, and survival. However, the exact mechanism of how the insulin‐IR interaction produces its own specific pattern of regulated cellular functions is not yet fully understood. Insulin analogs, anti‐IR antibodies as well as synthetic insulin mimetic peptides that target the two insulin‐binding regions of the IR, have been used to study the relationship between different aspects of receptor binding and function as well as providing new insights into the structure and function of the IR. This review focuses on the current knowledge of activation of the IR and how activation of the IR by different ligands initiates different cellular responses. Investigation of differential activation of the IR may provide clues to the molecular mechanisms of how the insulin‐receptor interaction controls the specificity of the downstream signaling response. Differences in the kinetics of ligand‐interaction with the IR, the magnitude of the signal as well as its subcelllar location all play important roles in determining/eliciting the different biological responses. Additional studies are nevertheless required to dissect the precise molecular mechanisms leading to the differential signaling from the IR.

Section snippets

Overview

Activation of the insulin receptor (IR) affects multiple biological processes such as glucose and lipid uptake/metabolism, gene expression, protein synthesis, and cell growth/division/survival (for a recent review, see Taniguchi et al., 2006). The diverse effects of IR activation are mediated through a multicomponent signaling complex that assembles upon binding of insulin. Activation of the IR leads to phosphorylation of several intracellular protein substrates. These include IRS1, IRS2, and

Organization of the IR

The IR is a member of the receptor tyrosine kinase superfamily. Apart from the IR itself, the IR family includes the insulin‐like growth factor‐1 receptor (IGF‐1R) and the IR related receptor (IRR) (Ebina et al., 1985, Seino et al., 1989). The IR is initially synthesized as a single‐chain prepro‐receptor. A 30‐residue signal peptide directs it to the endoplasmic reticulum (ER) where it is cotranslationally cleaved off (Ullrich et al., 1985). In the ER the precursor is glycosylated, folded, and

Modulation of signaling by different phosphorylation patterns on the IR

Activation of the IR tyrosine kinase and the phosphorylation of cellular substrates like IRS and Shc are essential for insulin signal transduction. The level and specific sites of autophosphorylation may regulate distinct but functionally coordinated aspects of IR functions as described below and summarized in Fig. 3.4.

The three tyrosine residues (Tyr1158, Tyr1162, and Tyr1163) in the regulatory loop are regarded as the autophosphorylation sites primarily responsible for activation of substrate

Differential Activation of the IR

Activation of the IR with different ligands can lead to different biological effects most likely due to differences in receptor interaction, internalization rates, and phosphorylation patterns of the IR. Studies investigating the effect of activating the IR with insulin and IGF‐2 (Frasca et al., 1999, Morrione et al., 1997, Pandini et al., 2003, Sciacca et al., 2002) found that insulin and IGF‐2 bind with a similar affinity to the IR‐A but whereas insulin led primarily to metabolic effects

Conclusions/Final Words

The details of the signal generated by the insulin–receptor interaction, which mediates the signaling and biological responses in the cell, remain unclear at the molecular level, although some aspects are beginning to emerge. The insulin–IR interaction might control the specificity of downstream signaling by a combination of several mechanisms. As such, the mitogenic and metabolic properties of IR action may result form a complex series of initial receptor/ligand interactions involving binding

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