Insulin receptor

Insulin receptor

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 (gene|INSR). The insulin receptor has also recently been designated CD220 (cluster of differentiation 220).

Function

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.

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.cite journal | author = Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, Giannella-Neto D | title = Genotype-phenotype correlation in inherited severe insulin resistance | journal = Hum. Mol. Genet. | volume = 11 | issue = 12 | pages = 1465–75 | year = 2002 | pmid = 12023989 | doi = 10.1093/hmg/11.12.1465 ]

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).

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.

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.cite journal | author = Duckworth WC, Bennett RG, Hamel FG | title = Insulin degradation: progress and potential | journal = Endocr. Rev. | volume = 19 | issue = 5 | pages = 608–24 | year = 1998 | pmid = 9793760 | doi = 10.1210/er.19.5.608 ]

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Pearson RB, Kemp BE |title=Protein kinase phosphorylation site sequences and consensus specificity motifs: tabulations |journal=Meth. Enzymol. |volume=200 |issue= |pages= 62–81 |year= 1991 |pmid= 1956339 |doi=
*cite journal | author=Joost HG |title=Structural and functional heterogeneity of insulin receptors |journal=Cell. Signal. |volume=7 |issue= 2 |pages= 85–91 |year= 1995 |pmid= 7794689| doi=10.1016/0898-6568(94)00071-I
*cite journal | author=O'Dell SD, Day IN |title=Insulin-like growth factor II (IGF-II) |journal=Int. J. Biochem. Cell Biol. |volume=30 |issue= 7 |pages= 767–71 |year= 1998 |pmid= 9722981| doi=10.1016/S1357-2725(98)00048-X
*cite journal | author=Lopaczynski W |title=Differential regulation of signaling pathways for insulin and insulin-like growth factor I |journal=Acta Biochim. Pol. |volume=46 |issue= 1 |pages= 51–60 |year= 1999 |pmid= 10453981 |doi=
*cite journal | author=Sasaoka T, Kobayashi M |title=The functional significance of Shc in insulin signaling as a substrate of the insulin receptor |journal=Endocr. J. |volume=47 |issue= 4 |pages= 373–81 |year= 2000 |pmid= 11075717| doi=10.1507/endocrj.47.373
*cite journal | author=Perz M, Torlińska T |title=Insulin receptor--structural and functional characteristics |journal=Med. Sci. Monit. |volume=7 |issue= 1 |pages= 169–77 |year= 2001 |pmid= 11208515 |doi=
*cite journal | author=Benaim G, Villalobo A |title=Phosphorylation of calmodulin. Functional implications |journal=Eur. J. Biochem. |volume=269 |issue= 15 |pages= 3619–31 |year= 2002 |pmid= 12153558| doi=10.1046/j.1432-1033.2002.03038.x

External links

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