Protein–protein interaction in insulin signaling and the molecular mechanisms of insulin resistance

Abstract

Insulin is an anabolic hormone with powerful metabolic effects. The events after insulin binds to its receptor are highly regulated and specific. Defining the key steps that lead to the specificity in insulin signaling presents a major challenge to biochemical research, but the outcome should offer new therapeutic approaches for treatment of patients suffering from insulin-resistant states, including type 2 diabetes.The insulin receptor belongs to the large family of growth factor receptors with intrinsic tyrosine kinase activity. Following insulin binding, the receptor undergoes autophosphorylation on multiple tyrosine residues. This results in activation of the receptor kinase and tyrosine phosphorylation of a family of insulin receptor substrate (IRS) proteins. These substrates are commonly referred to as docking proteins, since several other intracellular proteins bind to the phosphorylated substrates, thereby transmitting the signal downstream. Like other growth factors, insulin uses phosphorylation and the resultant protein-protein interactions as essential tools to transmit and compartmentalize its signal. These intracellular protein-protein interactions are pivotal in transmitting the signal from the receptor to the final cellular effect, such as translocation of vesicles containing GLUT4 glucose transporters from the intracellular pool to the plasma membrane, activation of glycogen or protein synthesis, and initiation of specific gene transcription ( Figure 1). In this article, we review some of our current understanding about early insulin signal transduction through the network of IRS interacting proteins and the mechanisms that may modify insulin signal transduction in insulinresistant states, especially obesity and type 2 diabetes. Protein-protein interactionsSome of the best-characterized protein interaction domains involved in insulin signaling are the PH (pleckstrin homology), PTB (phosphotyrosine binding), SH2, and SH3 domains (1) ( Table 1). Other, less-characterized domains (e.g., LIM, PDZ, NOTCH, and WW) may also prove to be relevant (2).These interaction domains exist in the natural tertiary structure of proteins. In other cases, the domains for interaction are created by posttranslational covalent modification of the protein. The most common examples of the latter are the effects of phosphorylation of proteins on tyrosine or serine/threonine residues and the lipid modification by prenylation or fatty acid acylation Figure 2 illustrates how signal transduction is transmitted from the receptor downstream using different types of domains. PH domains, which are found in most of the proteins that interact with the insulin receptor, bind to charged headgroups of specific phosphatidylinositides and are thereby targeted preferentially to membrane structures. PH domains in the IRS proteins target the proteins to the membrane adjacent to the insulin receptor (3). PTB domains, also found in IRS proteins, recognize the phosphotyrosine in the amino acid sequence asparagine-proline-any amino acid-phospho...

5-Aminoimidazole-4-carboxamide ribonucleoside treatment improves glucose homeostasis in insulin-resistant diabetic (ob/ob) mice

“…Thus, our results suggest that AICAR-treatment was not effective in correcting the defective insulin signal transduction to glucose transport that is characteristic of ob/ob mice [28,34]. The PI 3-kinase is a necessary component of the insulin signal transduction pathway to glucose transport [35,36] and a site of insulin resistance in skeletal muscle in ob/ob mice [28,34]. AICAR-treatment did not restore insulin-stimulated phosphotyrosine-associated PI 3-kinase activity in soleus muscle from ob/ob mice.…”

“…Overexpression of either GLUT4 or hexokinase II in transgenic mice is associated with increased glucose uptake and metabolism in skeletal muscle [32,33]. Thus, our results suggest that AICAR-treatment was not effective in correcting the defective insulin signal transduction to glucose transport that is characteristic of ob/ob mice [28,34]. The PI 3-kinase is a necessary component of the insulin signal transduction pathway to glucose transport [35,36] and a site of insulin resistance in skeletal muscle in ob/ob mice [28,34].…”

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“…Shc is an IR adaptor substrate that is activated upon phosphorylation of IR ultimately leading to the activation of the Ras/MAPK pathway and concomitant stimulation of mitgogenic signaling pathways (Virkamaki et al, 1999;Leibiger et al, 2001). While insulin does stimulate Shc phosphorylation, other growth factor stimuli are stronger activators of this adaptor protein.…”

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“…High GI foods lead to rapid rises in blood glucose and insulin levels. Hyperinsulinemia, in turn, may downregulate insulin receptors and therefore reduce insulin efficiency, resulting in insulin resistance (Virkamaki et al, 1999). This condition may act in a vicious circle by increasing blood glucose concentrations and insulin secretion as shown in Figure 1.…”