Insulin receptor
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In [[molecular biology]], the '''insulin receptor''' is a [[transmembrane receptor|transmembrane]] [[receptor (proteomics)|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 bond]]s. 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==
[[Image:insulin glucose metabolism.jpg|left|thumbnail|400px|'''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.
==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.<ref name="pmid12023989">{{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 }}</ref>
== 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.<ref name="pmid9793760">{{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 }}</ref>
==References==
{{reflist}}
==Further reading==
{{refbegin | 2}}
{{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}}
}}
{{refend}}
==External links==
* {{MeshName|Insulin+receptor}}
{{Clusters of differentiation}}
{{Receptor tyrosine kinases}}
[[Category:Clusters of differentiation]]
[[Category:Integral membrane proteins]]
[[Category:Receptors]]
[[Category:Tyrosine kinase receptors]]
[[es:Receptor de insulina]]
[[he:קולטן לאינסולין]]
[[oc:Receptor d'insulina]]
[[pl:Receptor insulinowy]]
[[ro:Receptorul pentru insulină]]
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