Journal Article

Critical nodes in signalling pathways: insights into insulin action

Kahn, C. Ronald, Taniguchi, Cullen M., Emanuelli, Brice

2006

Overview

The concept of 'critical nodes' has been used to define the main junctions in physiologically important, complex signalling networks. Several critical nodes of the insulin network have been identified and shown to have important roles in normal physiology and disease states. Key Points Cell-signalling networks are complex systems that allow for the specific biological response to a defined stimulus. We argue that it is possible to qualitatively identify the important mediators of any ligand–receptor system through a method that conceptualizes the most important genes as critical nodes. A 'critical node' is defined as a group of related proteins (for example, gene isoforms) that are essential for the receptor-mediated signal, and in which two or more of these related proteins might have unique biological roles within a signalling network and therefore serve as a source of divergence within the signalling system. The node is highly regulated, both positively and negatively, and is a junction for potential crosstalk with other signalling systems. Here, we use the insulin-signalling pathway as a model system. Three groups of genes are used as examples of 'critical nodes': the insulin receptor and its substrates (IR/IRS), phosphatidylinositol 3-kinase (PI3K) and AKT/protein kinase B (PKB). Although many proteins could be considered to be significant players in insulin signalling, only these three have attained sufficient in vivo and in vitro evidence to be considered 'critical nodes'. The IRSs are a critical node because six isoforms exist, with most of insulin's signal being mediated by IRS1 and IRS2. These IRS proteins, and others, have been shown, through knockout and RNAi studies, to have different biological functions in vivo . These proteins are regulated, both positively by the insulin receptor, and negatively through serine phosphorylation and downregulation of protein levels. The IRS proteins also mediate crosstalk with other signalling systems, particularly with the inflammation pathways. PI3K is also a critical node because both of its subunits, p85 and p110, have many different isoforms, many of which have unique biological functions. The p85α isoform is of particular interest because it negatively regulates insulin action independently of its function in the PI3K holoenzyme. This p85α subunit might also mediate crosstalk with the inflammatory pathways through the activation of c-Jun N-terminal kinase (JNK). AKT/PKB is a critical node because it has been shown to be crucial for glucose homeostasis. AKT comes in three isoforms, and is subject to considerable positive and negative regulation, both by other kinases and by proteins that bind to and inhibit AKT. Many of insulin's downstream functions are mediated by AKT, including the activation of glycogen synthesis, the suppression of gluconeogenesis and the regulation of cell growth and cell size. Physiologically important cell-signalling networks are complex, and contain several points of regulation, signal divergence and crosstalk with other signalling cascades. Here, we use the concept of 'critical nodes' to define the important junctions in these pathways and illustrate their unique role using insulin signalling as a model system.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Biochemistry / Biomedical and Life Sciences / Cancer Research / Cell Biology / Developmental Biology / Diabetes / Humans / Insulin / Insulin - physiology / Kinases / Life Sciences / Ligands / Metabolism / Phosphatidylinositol 3-Kinases - metabolism / Proteins / Proto-Oncogene Proteins c-akt - metabolism / Receptor, Insulin - physiology / review-article / Signal Transduction / Stem Cells