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Molecular Aspects of Insulin Signaling

Renee Emkey, C. Ronald Kahn

10.1002/cphy.cp070212

Source: Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism

Originally published: 2001

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 The Insulin Receptor
2 Insulin Receptor Substrate 1
3 Role of Insulin Receptor Substrate 1 Sequence Polymorphisms in Humans and the Pathophysiology of Diabetes
4 Growing Family of Insulin Receptor Substrates
5 Complementary and Alternative Pathways in Insulin Signaling
6 A Polygenic Model of Non‐Insulin‐Dependent Diabetes Mellitus
7 Differential Subcellular Localization of Insulin Receptor Substrates 1 and 2
8 Insulin‐Stimulated Insulin Receptor Substrate Interactions
8.1 Src Homology‐2 Domain‐Mediated Interactions
8.2 Non‐Src Homology‐2 Domain‐Mediated Interactions
9 Serine/Threonine Protein Kinases and the Final Biological Effects of Insulin
10 Differential Regulation of Insulin Receptor Substrates 1 and 2 and Phosphatidylinositol‐3‐Kinase
11 Linking Early Steps in Insulin Action to Late Postreceptor Events
11.1 Insulin Stimulation of Glucose Transport
11.2 Coupling of Insulin Action to the Nucleus of the Cell
12 Cross‐Talk Between the Insulin‐Signaling Network and Other Hormonal Response Pathways
13 Future Perspectives
Figure 1. Figure 1.

Schematic diagram of the insulin signaling pathway. Insulin binding to the insulin receptor results in activation of receptor tyrosine kinase activity and, thus, autophosphorylation of the receptor, as well as phosphorylation of substrates of the insulin receptor (IRS) such as IRS proteins and Shc. Phosphorylation of IRS proteins results in recruitment of various signaling molecules which activate a variety of signaling pathways, including those of Ras/Raf/mitogen‐activated protein (MAP) kinase and phosphatidylinositol‐3‐kinase (PI 3‐kinase). The culmination of all of these signaling pathways results in insulin‐induced glucose uptake, protein synthesis, and cell proliferation. SOS, son of sevenless; MEK, MAP kinase kinase; SH2, Src homology‐2; GRB2, growth factor receptor‐binding protein‐2; SHP2, SH2 domain‐containing phosphotyrosine phosphatase.
Figure 2. Figure 2.

Schematic diagram of the insulin receptor. Insulin receptor α subunits are linked together and to a β subunit by disulfide bonds. The relative positions of the insulin‐binding domain, the cysteine‐rich region, the alternate exon 11, and the transmembrane‐spanning region are shown. A partial list of naturally‐occurring mutations in the insulin receptor is shown at the left. The numbering of amino acids pertains to the insulin receptor isoform that does not contain exon 11.
Figure 3. Figure 3.

Schematic diagram of insulin receptor substrate 1 (IRS‐1), highlighting its potential sites for tyrosine phosphorylation as well as proteins known to associate with it. Also included are two identified homology domains, the pleckstrin homology (PH) domain and the phosphotyrosine‐binding (PTB) domain, which are involved in interaction with the insulin receptor and potentially other molecules. PI‐3, phosphatidylinositol‐3, SHPTP2, Src homology‐2 domain‐containing phosphotyrosine phosphatase; GRB2, growth Factor receptor‐binding protein‐2; SERCA, sarco‐lendoplasmic reticular calcium ATPase.
Figure 4. Figure 4.

Schematic diagram of substrates of the insulin receptor (IRS), including the IRS family (IRS‐1, IRS‐2, IRS‐3, and IRS‐4), Grb2‐associated binder 1 (GAB‐1), and Shc. The conserved pleckstrin homology (PH) and phosphotyrosine‐binding (PTB) domains are illustrated. Note that GAB‐1 does not contain a PTB domain. Sites of interaction with various Src homology‐2 domain‐containing proteins are also indicated. GRB‐2 growth factor receptor‐binding protein‐2; PI 3‐K, phosphatidylinositol‐3‐kinase.
Figure 5. Figure 5.

Insulin binding to the insulin receptor results in tyrosine phosphorylation of insulin receptor substrate (IRS) proteins and recruitment and activation of phosphatidylinositol‐3‐kinase (PI‐3K). The catalytic 110 kd subunit of PI‐3K catalyzes the phosphorylation of phosphatidylinositol (PI), PI‐4‐P, and PI‐4,5‐P2 on the D‐3 position of the inositol ring to produce PI‐3‐P, PI‐3,4‐P2, and PI‐3,4,5‐P3. The phosphorylation of phosphatidylinositol to produce PI‐3‐P is illustrated here.
Figure 6. Figure 6.

Comparison of the various regulatory subunits of phosphatidylinositol‐3‐kinase, depicting the conserved structural domains: breakpoint cluster region (BCR) homology domain, Src homology‐2 (SH2) domains, and proline‐rich regions. p85α, AS53/p55α, and p50α are splicing variants of the same gene, whereas p55PIK/p50γ is the unique product of a different gene. The three products of the p85α gene, p85α, AS53/p55α, and p50α, undergo an alternative splicing event, which results in the insertion of nine amino acids in the inter‐SH2 domain, which encodes for two potential sites of serine phosphorylation. The serine labbeled 1 is the site of phosphorylation by the catalytic subunit of phosphatidylinositol‐3‐kinase. Phosphorylation of this residue creates a consensus sequence for phosphorylation by casein kinase II 1. Similarly, phosphorylation of this second serine results in a consensus sequence for glycogen synthase kinase‐3 2. The unique amino terminus of the AS53/p55α, p50α, and p55PIK/p50γ subunits is also depicted.
Figure 7. Figure 7.

Schematic model of insulin‐induced glucose transport. Insulin‐induced glucose uptake occurs by the specific recruitment of GLUT‐4 glucose transporters from an intracellular vesicular pool to the plasma membrane. These intracellular GLUT‐4‐containing vesicles also contain a number of accessory proteins, which play a role in the trafficking of these vesicles and are recycled following translocation of GLUT‐4 to the plasma membrane. Note that GLUT‐1 transporters are constitutively found in the plasma membrane and are not recycled in an insulin‐sensitive manner. VAMP‐2, vesicle‐associated membrane protein 2; SNARE, soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor.
Figure 8. Figure 8.

Schematic model of the glucose transporter illustrating the 12 membrane‐spanning α‐helical domains. Both the amino and carboxy termini are on the intracellular side of the plasma membrane.


Figure 1.

Schematic diagram of the insulin signaling pathway. Insulin binding to the insulin receptor results in activation of receptor tyrosine kinase activity and, thus, autophosphorylation of the receptor, as well as phosphorylation of substrates of the insulin receptor (IRS) such as IRS proteins and Shc. Phosphorylation of IRS proteins results in recruitment of various signaling molecules which activate a variety of signaling pathways, including those of Ras/Raf/mitogen‐activated protein (MAP) kinase and phosphatidylinositol‐3‐kinase (PI 3‐kinase). The culmination of all of these signaling pathways results in insulin‐induced glucose uptake, protein synthesis, and cell proliferation. SOS, son of sevenless; MEK, MAP kinase kinase; SH2, Src homology‐2; GRB2, growth factor receptor‐binding protein‐2; SHP2, SH2 domain‐containing phosphotyrosine phosphatase.



Figure 2.

Schematic diagram of the insulin receptor. Insulin receptor α subunits are linked together and to a β subunit by disulfide bonds. The relative positions of the insulin‐binding domain, the cysteine‐rich region, the alternate exon 11, and the transmembrane‐spanning region are shown. A partial list of naturally‐occurring mutations in the insulin receptor is shown at the left. The numbering of amino acids pertains to the insulin receptor isoform that does not contain exon 11.



Figure 3.

Schematic diagram of insulin receptor substrate 1 (IRS‐1), highlighting its potential sites for tyrosine phosphorylation as well as proteins known to associate with it. Also included are two identified homology domains, the pleckstrin homology (PH) domain and the phosphotyrosine‐binding (PTB) domain, which are involved in interaction with the insulin receptor and potentially other molecules. PI‐3, phosphatidylinositol‐3, SHPTP2, Src homology‐2 domain‐containing phosphotyrosine phosphatase; GRB2, growth Factor receptor‐binding protein‐2; SERCA, sarco‐lendoplasmic reticular calcium ATPase.



Figure 4.

Schematic diagram of substrates of the insulin receptor (IRS), including the IRS family (IRS‐1, IRS‐2, IRS‐3, and IRS‐4), Grb2‐associated binder 1 (GAB‐1), and Shc. The conserved pleckstrin homology (PH) and phosphotyrosine‐binding (PTB) domains are illustrated. Note that GAB‐1 does not contain a PTB domain. Sites of interaction with various Src homology‐2 domain‐containing proteins are also indicated. GRB‐2 growth factor receptor‐binding protein‐2; PI 3‐K, phosphatidylinositol‐3‐kinase.



Figure 5.

Insulin binding to the insulin receptor results in tyrosine phosphorylation of insulin receptor substrate (IRS) proteins and recruitment and activation of phosphatidylinositol‐3‐kinase (PI‐3K). The catalytic 110 kd subunit of PI‐3K catalyzes the phosphorylation of phosphatidylinositol (PI), PI‐4‐P, and PI‐4,5‐P2 on the D‐3 position of the inositol ring to produce PI‐3‐P, PI‐3,4‐P2, and PI‐3,4,5‐P3. The phosphorylation of phosphatidylinositol to produce PI‐3‐P is illustrated here.



Figure 6.

Comparison of the various regulatory subunits of phosphatidylinositol‐3‐kinase, depicting the conserved structural domains: breakpoint cluster region (BCR) homology domain, Src homology‐2 (SH2) domains, and proline‐rich regions. p85α, AS53/p55α, and p50α are splicing variants of the same gene, whereas p55PIK/p50γ is the unique product of a different gene. The three products of the p85α gene, p85α, AS53/p55α, and p50α, undergo an alternative splicing event, which results in the insertion of nine amino acids in the inter‐SH2 domain, which encodes for two potential sites of serine phosphorylation. The serine labbeled 1 is the site of phosphorylation by the catalytic subunit of phosphatidylinositol‐3‐kinase. Phosphorylation of this residue creates a consensus sequence for phosphorylation by casein kinase II 1. Similarly, phosphorylation of this second serine results in a consensus sequence for glycogen synthase kinase‐3 2. The unique amino terminus of the AS53/p55α, p50α, and p55PIK/p50γ subunits is also depicted.



Figure 7.

Schematic model of insulin‐induced glucose transport. Insulin‐induced glucose uptake occurs by the specific recruitment of GLUT‐4 glucose transporters from an intracellular vesicular pool to the plasma membrane. These intracellular GLUT‐4‐containing vesicles also contain a number of accessory proteins, which play a role in the trafficking of these vesicles and are recycled following translocation of GLUT‐4 to the plasma membrane. Note that GLUT‐1 transporters are constitutively found in the plasma membrane and are not recycled in an insulin‐sensitive manner. VAMP‐2, vesicle‐associated membrane protein 2; SNARE, soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor.



Figure 8.

Schematic model of the glucose transporter illustrating the 12 membrane‐spanning α‐helical domains. Both the amino and carboxy termini are on the intracellular side of the plasma membrane.

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Article Title: Molecular Aspects of Insulin Signaling
 

How to Cite

Renee Emkey, C. Ronald Kahn. Molecular Aspects of Insulin Signaling. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 413-433. First published in print 2001. doi: 10.1002/cphy.cp070212