Insulin receptor

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Insulin receptor
PDB rendering based on 1gag.
Available structures: 1gag, 1i44, 1ir3, 1irk, 1p14, 1rqq, 2auh, 2b4s, 2dtg, 2hr7
Identifiers
Symbol(s)	INSR; CD220; HHF5
External IDs	OMIM: 147670 MGI: 96575 HomoloGene: 20090
Gene ontology Molecular Function: • nucleotide binding • receptor signaling protein tyrosine kinase activity • receptor activity • epidermal growth factor receptor activity • insulin receptor activity • transmembrane receptor protein tyrosine kinase signaling protein activity • ATP binding • transferase activity • SH2 domain binding • phosphoinositide 3-kinase binding • insulin binding • insulin receptor substrate binding • PTB domain binding Cellular Component: • plasma membrane • integral to plasma membrane • membrane Biological Process: • carbohydrate metabolic process • generation of precursor metabolites and energy • protein amino acid phosphorylation • signal transduction • transmembrane receptor protein tyrosine kinase signaling pathway • insulin receptor signaling pathway • organ morphogenesis • male sex determination • protein amino acid autophosphorylation • protein heterotetramerization
RNA expression pattern
More reference expression data
Orthologs
	Human	Mouse
Entrez	3643	16337
Ensembl	ENSG00000171105	ENSMUSG00000005534
Uniprot	P06213	O35466
Refseq	NM_000208 (mRNA) NP_000199 (protein)	XM_972939 (mRNA) XP_978033 (protein)
Location	Chr 19: 7.07 - 7.25 Mb	Chr 8: 3.16 - 3.28 Mb
Pubmed search	[1]	[2]

In molecular biology, the insulin receptor is a transmembrane receptor that is activated by insulin. It belongs to the large class of tyrosine kinase receptors.

Two alpha subunits and two beta subunits make up the insulin receptor. The beta subunits pass through the cellular membrane and are linked by disulfide bonds. The alpha and beta subunits are encoded by a single gene (INSR). The insulin receptor has also recently been designated CD220 (cluster of differentiation 220).

[edit] Function

Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1) which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).

Tyrosine kinase receptors, including the insulin receptor, mediate their activity by causing the addition of a phosphate group to particular tyrosines on certain proteins within a cell. The "substrate" proteins which are phosphorylated by the Insulin Receptor include a protein called "IRS-1" for "insulin receptor substrate 1". IRS-1 binding and phosphorylation eventually leads to an increase in the high affinity glucose transporter (Glut4) molecules on the outer membrane of insulin-responsive tissues, including muscle cells and adipose tissue, and therefore to an increase in the uptake of glucose from blood into these tissues. Briefly, the glucose transporter (Glut4), is transported from cellular vesicles to the cell surface, where it then can mediate the transport of glucose into the cell.

[edit] Pathology

The main activity of activation of the insulin receptor is inducing glucose uptake. For this reason "insulin insensitivity", or a decrease in insulin receptor signaling, leads to diabetes mellitus type 2 - the cells are unable to take up glucose, and the result is hyperglycemia (an increase in circulating glucose), and all the sequelae which result from diabetes.

Patients with insulin resistance may display acanthosis nigricans.

A few patients with homozygous mutations in the INSR gene have been described, which causes Donohue syndrome or Leprechaunism. This autosomal recessive disorder results in a totally non-functional insulin receptor. These patients have low set, often protruberant, ears, flared nostrils, thickened lips, and severe growth retardation. In most cases, the outlook for these patients is extremely poor with death occurring within the first year of life. Other mutations of the same gene cause the less severe Rabson-Mendenhall syndrome, in which patients have characteristically abnormal teeth, hypertrophic gingiva (gums) and enlargement of the pineal gland. Both diseases present with fluctuations of the glucose level: after a meal the glucose is initially very high, and then falls rapidly to abnormally low levels.^[1]

[edit] Regulation of gene expression

The activated IRS-1 acts as a secondary messenger within the cell to stimulate the transcription of insulin-regulated genes. First, the protein Grb2 binds the P-Tyr residue of IRS-1 in its SH2 domain. Grb2 is then able to bind SOS, which in turn catalyzes the replacement of bound GDP with GTP on Ras, a G protein. This protein then begins a phosphorylation cascade, culminating in the activation of mitogen-activated protein kinase (MAPK), which enters the nucleus and phosphorylates various nuclear transcription factors (such as Elk1).

[edit] Stimulation of glycogen synthesis

Glycogen synthesis is also stimulated by the insulin receptor via IRS-1. In this case, it is the SH2 domain of PI-3 kinase (PI-3K) that binds the P-Tyr of IRS-1. Now activated, PI-3K can convert the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3). This indirectly activates a protein kinase, PKB, via phosphorylation. PKB then phosphorylates several target proteins, including glycogen synthase kinase 3 (GSK-3). GSK-3 is responsible for phosphorylating (and thus deactivating) glycogen synthase. When GSK-3 is phosphorylated, it is deactivated, and prevented from deactivating glycogen synthase. In this roundabout manner, insulin increases glycogen synthesis.

[edit] Degradation of insulin

Once an insulin molecule has docked onto the receptor and effected its action, it may be released back into the extracellular environment or it may be degraded by the cell. Degradation normally involves endocytosis of the insulin-receptor complex followed by the action of insulin degrading enzyme. Most insulin molecules are degraded by liver cells. It has been estimated that a typical insulin molecule is finally degraded about 71 minutes after its initial release into circulation.^[2]

[edit] References

[edit] Further reading

[edit] External links

• MeSH Insulin+receptor