InsR

The insulin receptor belongs to a subfamily of receptor tyrosine kinases that also includes the IGF-1 receptor and an orphan receptor called the insulin receptor-related receptor (IRR). It is a tetrameric protein consisting of two α- and two β-subunits encoded by the IR gene. The two subunits derived from a single chain proreceptor undergo post translational processing including cleavage by a furin-like enzyme and glycosylation, forming a single α-β subunit complex. Two of the α-β dimers are then cross linked by disulfide bonds to form the tetramer.

Ligand (insulin or IGF-1) binding to the α-subunit leads to activation of the kinase activity in the β-subunit. Following this initial activation, phosphorylation of one β-subunit by the other (transphosphorylation), leads to a conformational change and a further increase in activity of the kinase domain. Activation of the tyrosine kinase domain leads to autophosphorylation of tyrosine residues in several regions of the intracellular β-subunit, including Tyr⁹⁶⁰ in the juxtamembrane region, creating an NPXpY recognition motif for the PTB domain of the IRS proteins, Tyr¹¹⁴⁶, Tyr¹¹⁵⁰ and Tyr¹¹⁵¹ in the regulatory loop and Tyr¹³¹⁶ and Tyr¹³²² in the C-terminus.

The α-β heterodimers of the individual insulin, IGF-1 and the IRR receptors can form functional hybrids in which ligand binding to one receptor’s binding site leads to activation of the other receptor in the heterodimer by this transphosphorylation process.

Intracellular substrates of the insulin and IGF-1 receptor tyrosine kinases that have been identified include insulin receptor substrate (IRS) proteins 1-4, Gab-1, p62^dok, Cbl, APS and the various isoforms of Shc. Following insulin stimulation, the receptor directly phosphorylates most of these substrates on multiple tyrosine residues. These phosphorylated tyrosines occur in specific sequence motifs, which once phosphorylated serve as ‘docking sites’ for intracellular molecules that contain the SH2 (Src-homology) domain, transmitting the insulin signal downstream. A few proteins that bind to phosphotyrosines in the IRS proteins do not contain known SH2 domains; these include the calcium ATPases SERCA 1 and 2, and the SV40 large T antigen.

Negative regulation of insulin receptor signaling has been demonstrated by the tyrosine phosphatase PTP1B, which dephosphorylates the phosphotyrosine residues in the insulin receptor kinase and also through direct association of the novel PIR domain of the Grb14 adaptor protein with the insulin receptor.

Alterations in the function of the insulin receptor, both genetic and acquired, can lead to several different disease states including insulin resistance, diabetes and growth retardation. Insulin resistance at the level of the receptor may be the result of genetic alterations in receptor expression or structure, secondary changes in receptor activity due to serine phosphorylation, or due to down-regulation of receptor concentration. Insulin resistance is also closely linked to other common health problems, including obesity, polycystic ovarian disease, hyperlipidemia, hypertension and atherosclerosis.

The insulin receptor is widely distributed throughout the body, found in tissues classically regarded as both insulin 'responsive', for example muscle, liver and fat, and 'non-responsive', for example brain and the vascular system. It signals through two major signaling pathways, the IRS/PI 3-kinase pathway and the Ras-MAP kinase pathway, controlling processes including glucose transport, uptake and storage, glycogen synthesis, cell growth and differentiation, protein synthesis and gene expression.

Tissue specific knockouts of the insulin receptor have helped to define the role of the receptor in the classical insulin sensitive tissues and identified novel functions in other tissues. The Muscle specific Insulin Receptor Knockout (MIRKO) mouse model exhibits increased insulin stimulated glucose uptake in the fat, suggesting 'cross-talk' between muscle and fat in insulin resistant states. Fat specific knockout (FIRKO) mice have decreased fat mass, are resistant to diet induced obesity and have an extended lifespan, suggesting an interesting role for the insulin receptor in regulating longevity. The neuron specific insulin receptor knockout (NIRKO) has confirmed the importance of the receptor in brain and highlighted a role for it in appetite regulation.

Defining the key steps that lead to specificity in insulin signaling should offer therapeutic approaches for patients suffering from insulin resistant states, including type 2 diabetes.

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Related Products" section below.

Family Members	Insulin Receptor	Insulin-like Growth Factor I Receptor	IRR
Other Names	Insr IR	IGFR1 JTK13 Somatomedin receptor	INSRR Insulin receptor-related receptor IR-related receptor IRRR
Molecular Weight	α-subunit: 135 kDa β-subunit: 95 kDa	154 kDa	143 kDa
Structural Data	α-subunit: 719 aa β-subunit: 620 aa	1367 aa	1297 aa
Isoforms	Not Known	IGF1Ra IGF1Rb	Not Known
Species	Mammals Fish C. Elegans Xenopus	Human Bovine Mouse Pig Rat	Human Mouse Rat Guinea pig
Domain Organization	Tetramer of 2α and 2β subunits β-chain contains kinase domains 2 fibronectin type III-like domains	Tetramer of 2 α and 2 β chains α chain contains ligand-binding domain β chain contains kinase domain 3 fibronectin type-III domains	Probable tetramer of 2 α and 2 β chains α chain contains ligand-binding domain β chain contains kinase domain 4 fibronectin type-III domains
Phosphorylation Sites	Tyr¹¹⁴⁶ Tyr¹⁵⁰ Tyr¹¹⁵¹ Ser¹²⁷⁵ Ser¹³⁰⁹ Tyr⁹⁶⁰ Tyr¹³¹⁶ Tyr³²²	Tyr¹¹⁶⁵	Tyr¹¹⁴⁵
Tissue Distribution	Present in most tissues	Expressed in a variety of tissues	A subset of neuronal tissues Neuroblastomas Neural crest derived sensory and sympathetic neurons
Subcellular Localization	Plasma membrane	Plasma membrane	Plasma membrane
Binding Partner/ Associated Proteins	IRS1 IRS2 IRS3 IRS4 SHC ADS Sh2-B Grb10 Grb7 CAP p85 subunit of PI3K SHPTP2 (Syp) SOCS1-3 PC-1	SOCS1-3 14-3-3-ε/β/ζ SHC p85 IRS-1 IRS-2 IGF1R JAK-1 PIK3R3 IGF-I RACK1 PKCd β-1 integrin PKCμ CSK EHD1 NAG ACP AMP-PNP Src	Not Known
Upstream Activators	Insulin	IGF-I	Not Known
Downstream Activation	IRS1-4 Shc PTP1B cbl p62dok	IRS-1 IRS-2 Akt and p42/44 MAPKs PI3K	IRS-1 IRS-2 Ras
Activators	Not Known	Not Known	Not Known
Substrates	IRS 1-4 Gab-1 p62^dok Cbl APS Shc	Not Known	Not Known
Selective Inhibitors	Not Known	Not Known	Not Known
Non-Selective Inhibitors	Hydroxy-2-naphthalenylmethylphosphonic acid Quercetin (337951) Staurosporine (S4400)	Not Known	Not Known
Selective Activators	Not Known	Not Known	Not Known
Physiological Function	Insulin signaling	Binds insulin-like growth factor I (IGF I) with a high affinity and IGF II with a lower affinity	Embryonal development of dorsal root and trigeminal neurons Development of sympathetic neurons Male sexual differentiation
Disease Relevance	Type A syndrome of insulin resistance Leprechaunism Rabson-Medenhall syndrome Insulin resistance Type-2 diabetes mellitus	Gastrointestinal stromal tumors Crohn's disease Primary breast cancer Prostate cancer Graves' disease Pancreatic adenocarcinoma Thyroid carcinomas Colon cancer	Type-2 diabetes mellitus

References

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