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Critical nodes in signalling pathways: insights into insulin action

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.

Abstract

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.

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Figure 1: Evolution of our concepts on signalling pathways.
Figure 2: Critical nodes in the insulin-signalling network.
Figure 3: Structure and interacting partners of the insulin-receptor substrates.
Figure 4: Isoform-specific functions of IRS proteins.
Figure 5: PI3K as a critical node.
Figure 6: AKT/PKB as a critical node.

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Acknowledgements

This work was supported by National Institutes of Health grants, and a Joslin Diabetes and Endocrinology Research Center grant (to C.R.K.). C.M.T. acknowledges support from the American Diabetes Association Medical Scholars Award and the Medical Scientist Training Program (Harvard Medical School). B.E. was supported by a National Institutes of Health grant. We apologize to the authors whose work could not be cited in this review due to space limitations, but appreciate all of the many contributions to the large body of literature we have tried to summarize here.

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Glossary

Critical node

A point in a signalling network that is essential for the biological function of a ligand–receptor interaction, but also allows divergence of the signal to facilitate crosstalk between systems and/or to fine-tune the response to stimuli.

Insulin receptor substrate protein

(IRS protein). A large protein scaffold that serves as a docking platform for other signalling proteins that contain Src-homology-2 domains. The IRS proteins are required for a complete insulin signal.

Receptor tyrosine kinase

(RTK). A cell-surface receptor with an intracellular tyrosine kinase domain. The ligand-mediated activation of an RTK results in the activation of the intracellular kinase domain.

Insulin resistance

Insulin resistance is a condition in which normal concentrations of insulin produce a subnormal biological response. It is common in many physiological and pathological states, including obesity, type-2 diabetes, metabolic syndrome, polycystic ovarian disease, pregnancy and puberty.

Pleckstrin-homology domain

(PH domain). A protein domain of 100 amino acids with homology to pleckstrin that mediates the binding to membrane phospholipids, such as PIP3.

Phosphotyrosine-binding domain

(PTB domain). A domain that mediates the binding to specific phosphotyrosine residues. The affinity of a PTB domain for a phosphotyrosine depends on the residues that surround the phosphotyrosine. For instance, the PTB domain of the IRS proteins binds to an NPXpY motif.

Src-homology-2 domain

(SH2 domain). A domain of 100 amino acids that binds to phosphotyrosine residues in proteins. Every protein's SH2 domain might have a slightly different phosphotyrosine-binding motif.

Transphosphorylation

The transfer of a phosphate by a protein kinase to a residue within the same kinase molecule, or to a different kinase molecule of the same kind.

Phosphotyrosine motif

A phosphorylated tyrosine residue that is flanked by a few different amino-acid residues. Different phosphotyrosine-binding proteins have varying affinities for different phosphotyrosine motifs, which explains, in part, the specificity of phosphotyrosine-binding proteins.

AGC kinases

A large family of serine/threonine kinases that includes members as diverse as the cAMP-dependent protein kinases, and protein kinase C. The members of this AGC subgroup include AKT/PKB, serum/glucocorticoid kinases and the atypical PKCs.

Src-homology-3 domain

(SH3 domain). A protein sequence of 50 amino acids that facilitates the binding to proline-rich regions of proteins. Binding of an SH3 domain to a proline-rich region can occur in an intramolecular or intermolecular fashion.

Breakpoint-cluster region homology domain

A 150-residue region of p85a with homology to the breakpoint-cluster region gene and homology to Rho-GTPase activating proteins, which decrease the activity of small GTPases. Despite this homology, the breakpoint-cluster region homology domain has not been demonstrated to have GTPase activity.

Diacylglycerol

(DAG). DAG is a lipid second messenger that is produced by the cleavage of PIP2 by phospholipase C. DAG is involved in the activation of conventional and novel protein kinase Cs (PKCs).

GLUT4 translocation

Relocalization and fusion of an intracellular vesicle that contains the glucose transporter GLUT4 to the plasma membrane. It allows the uptake of extracellular glucose that is stimulated by insulin in muscle and adipose tissues.

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Taniguchi, C., Emanuelli, B. & Kahn, C. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7, 85–96 (2006). https://doi.org/10.1038/nrm1837

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