In
molecular biologyMolecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...
, the
insulin receptor is a transmembrane receptor that is activated by
insulinInsulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
. 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 bondIn chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
s. The alpha and beta subunits are encoded by a single
geneA gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. The insulin receptor has also recently been designated
CD220 (
cluster of differentiationThe cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on white blood cells, providing targets for immunophenotyping of cells...
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 that 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 transporterGlucose transporters are a wide group of membrane proteins that facilitate the transport of glucose over a plasma membrane. Because glucose is a vital source of energy for all life these transporters are present in all phyla...
(
Glut4Glucose transporter type 4, also known as GLUT4, is a protein that in humans is encoded by the GLUT4 gene. GLUT4 is the insulin-regulated glucose transporter found in adipose tissues and striated muscle that is responsible for insulin-regulated glucose translocation into the cell...
) molecules on the outer membrane of insulin-responsive tissues, including
muscleMuscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
cells and adipose tissue, and therefore to an increase in the uptake of
glucoseGlucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
from blood into these tissues. In other words, the glucose transporter
Glut4Glucose transporter type 4, also known as GLUT4, is a protein that in humans is encoded by the GLUT4 gene. GLUT4 is the insulin-regulated glucose transporter found in adipose tissues and striated muscle that is responsible for insulin-regulated glucose translocation into the cell...
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 2Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...
– the cells are unable to take up glucose, and the result is hyperglycemia (an increase in circulating glucose), and all the sequelae that result from diabetes.
Patients with
insulin resistanceInsulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
may display
acanthosis nigricansAcanthosis nigricans is a brown to black, poorly defined, velvety hyperpigmentation of the skin. It is usually found in body folds, such as the posterior and lateral folds of the neck, the axilla, groin, umbilicus, forehead, and other areas.-Causes:...
.
A few patients with homozygous mutations in the
INSR gene have been described, which causes
Donohue syndromeDonohue syndrome is an extremely rare and severe genetic disorder. Leprechaunism derives its name from the fact that those afflicted with the disease often have elfin features and are smaller than usual...
or Leprechaunism. This autosomal recessive disorder results in a totally non-functional insulin receptor. These patients have low-set, often protuberant, 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 syndromeRabson–Mendenhall syndrome is a rare insulin receptor disorder characterized by severe insulin resistance, developmental abnormalities, and acanthosis nigricans...
, in which patients have characteristically abnormal teeth, hypertrophic
gingivaThe gingiva , or gums, consists of the mucosal tissue that lies over the mandible and maxilla inside the mouth.-General description:...
(gums), and enlargement of the
pineal glandThe pineal gland is a small endocrine gland in the vertebrate brain. It produces the serotonin derivative melatonin, a hormone that affects the modulation of wake/sleep patterns and seasonal functions...
. Both diseases present with fluctuations of the
glucoseGlucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
level: After a meal the glucose is initially very high, and then falls rapidly to abnormally low levels.
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 domainThe SH2 domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins...
. Grb2 is then able to bind SOS, which in turn catalyzes the replacement of bound GDP with GTP on Ras, a
G proteinG proteins are a family of proteins involved in transmitting chemical signals outside the cell, and causing changes inside the cell. They communicate signals from many hormones, neurotransmitters, and other signaling factors. G protein-coupled receptors are transmembrane receptors...
. 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 domainThe SH2 domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins...
of
PI-3 kinasePhosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
(PI-3K) that binds the P-Tyr of IRS-1. Now activated, PI-3K can convert the membrane lipid
phosphatidylinositol 4,5-bisphosphatePhosphatidylinositol 4,5-bisphosphate or PtdInsP2, also known simply as PIP2, is a minor phospholipid component of cell membranes...
(PIP
2) to
phosphatidylinositol 3,4,5-triphosphatePhosphatidylinositol -triphosphate , abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases phosphorylation on phosphatidylinositol -bisphosphate .-Discovery:...
(PIP
3). This indirectly activates a protein kinase, PKB (
AktAkt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
), 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
endocytosisEndocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
of the insulin-receptor complex followed by the action of
insulin degrading enzymeInsulin-degrading enzyme, also known as IDE is a human enzyme.Known alternatively as insulysin or insulin protease, Insulin Degrading Enzyme is a large zinc-binding protease of the M16A metalloprotease subfamily known to cleave multiple short polypeptides that vary considerably in sequence...
. Most insulin molecules are degraded by
liverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
cells. It has been estimated that a typical insulin molecule is finally degraded about 71 minutes after its initial release into circulation.
Interactions
Insulin receptor has been shown to
interactProtein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with
Ectonucleotide pyrophosphatase/phosphodiesterase 1Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 is an enzyme that in humans is encoded by the ENPP1 gene.-Interactions:Ectonucleotide pyrophosphatase/phosphodiesterase 1 has been shown to interact with Insulin receptor....
,
PTPN11Tyrosine-protein phosphatase non-receptor type 11 also known as protein-tyrosine phosphatase 1D or protein-tyrosine phosphatase 2C is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase Shp2.PTPN11 is a member of the protein tyrosine phosphatase ...
,
GRB10Growth factor receptor-bound protein 10 also known as insulin receptor-binding protein Grb-IR is a protein that in humans is encoded by the GRB10 gene.- Function :...
,
GRB7Growth factor receptor-bound protein 7, also known as GRB7, is a protein which in humans is encoded by the GRB7 gene.- Function :The product of this gene belongs to a small family of adaptor proteins that are known to interact with a number of receptor tyrosine kinases and signaling molecules...
,
PRKCDProtein kinase C delta type is an enzyme that in humans is encoded by the PRKCD gene.- Function :Protein kinase C is a family of serine- and threonine-specific protein kinases that can be activated by calcium and the second messenger diacylglycerol...
,
IRS1Insulin receptor substrate 1 is a protein that in humans is encoded by the IRS-1 gene.-Function:Insulin receptor substrate 1 plays a key role in transmitting signals from the insulin and insulin-like growth factor-1 receptors to intracellular pathways PI3K / Akt and Erk MAP kinase...
,
SH2B1SH2B adapter protein 1 is a protein that in humans is encoded by the SH2B1 gene.-Interactions:SH2B1 has been shown to interact with Insulin receptor, Grb2, TrkA and Janus kinase 2.- Clinical significance :...
and
Mothers against decapentaplegic homolog 2Mothers against decapentaplegic homolog 2 also known as SMAD family member 2 or SMAD2 is a protein that in humans is encoded by the SMAD2 gene. MAD homolog 2 belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' and the C....
.
External links