Editing Insulin receptor

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{{short description|Cell receptor found in humans}}
{{Use dmy dates|date=August 2020}}
{{Infobox gene}}
The '''insulin receptor''' ('''IR''') is a [[transmembrane receptor]] that is activated by [[insulin]], [[IGF-I]], [[Insulin-like growth factor 2|IGF-II]] and belongs to the large class of [[receptor tyrosine kinase]].<ref name="pmid19274663">{{cite journal | vauthors = Ward CW, Lawrence MC | title = Ligand-induced activation of the insulin receptor: a multi-step process involving structural changes in both the ligand and the receptor | journal = BioEssays | volume = 31 | issue = 4 | pages = 422–34 | date = April 2009 | pmid = 19274663 | doi = 10.1002/bies.200800210 | s2cid = 27645596 }}</ref> Metabolically, the insulin receptor plays a key role in the regulation of [[glucose homeostasis]]; a functional process that under degenerate conditions may result in a range of clinical manifestations including [[diabetes]] and [[cancer]].<ref name="pmid2859121">{{cite journal | vauthors = Ebina Y, Ellis L, Jarnagin K, Edery M, Graf L, Clauser E, Ou JH, Masiarz F, Kan YW, Goldfine ID | title = The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling | journal = Cell | volume = 40 | issue = 4 | pages = 747–58 | date = April 1985 | pmid = 2859121 | doi = 10.1016/0092-8674(85)90334-4 | s2cid = 23230348 }}</ref><ref name="pmid22355074">{{cite journal | vauthors = Malaguarnera R, Sacco A, Voci C, Pandini G, Vigneri R, Belfiore A | title = Proinsulin binds with high affinity the insulin receptor isoform A and predominantly activates the mitogenic pathway | journal = Endocrinology | volume = 153 | issue = 5 | pages = 2152–63 | date = May 2012 | pmid = 22355074 | doi = 10.1210/en.2011-1843 | doi-access = free }}</ref> Insulin signalling controls access to blood glucose in body cells. When insulin falls, especially in those with high insulin sensitivity, body cells begin only to have access to lipids that do not require transport across the membrane. So, in this way, insulin is the key regulator of fat metabolism as well. Biochemically, the insulin receptor is encoded by a single [[gene]] {{gene|INSR}}, from which [[Alternative splicing|alternate splicing]] during transcription results in either IR-A or IR-B [[isoforms]].<ref name="pmid19752219">{{cite journal | vauthors = Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R | title = Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease | journal = Endocrine Reviews | volume = 30 | issue = 6 | pages = 586–623 | date = October 2009 | doi = 10.1210/er.2008-0047 | pmid = 19752219 | doi-access = free }}</ref> Downstream post-translational events of either isoform result in the formation of a proteolytically cleaved α and β subunit, which upon combination are ultimately capable of homo or hetero-dimerisation to produce the ≈320 kDa disulfide-linked transmembrane insulin receptor.<ref name="pmid19752219"/>

== Structure ==
Initially, [[transcription (genetics)|transcription]] of alternative splice variants derived from the ''INSR'' gene are [[translation (genetics)|translated]] to form one of two monomeric isomers; IR-A in which [[exon]] 11 is excluded, and IR-B in which exon 11 is included. Inclusion of exon 11 results in the addition of 12 amino acids upstream of the intrinsic [[furin]] proteolytic cleavage site. [[Image:Colour coded Schematic of the Insulin Receptor.png|left|thumbnail|350px|Colour-coded schematic of the insulin receptor]]

Upon receptor dimerisation, after [[Proteolysis|proteolytic cleavage]] into the α- and β-chains, the additional 12 amino acids remain present at the [[C-terminus]] of the α-chain (designated αCT) where they are predicted to influence receptor–[[ligand]] interaction.<ref name="pmid21838706">{{cite journal | vauthors = Knudsen L, De Meyts P, Kiselyov VV | title = Insight into the molecular basis for the kinetic differences between the two insulin receptor isoforms | journal = The Biochemical Journal | volume = 440 | issue = 3 | pages = 397–403 | date = December 2011 | pmid = 21838706 | doi = 10.1042/BJ20110550 | url = https://hal.archives-ouvertes.fr/hal-00658157/file/PEER_stage2_10.1042%252FBJ20110550.pdf }}</ref>

Each isometric [[monomer]] is structurally organized into 8 distinct domains consists of; a leucine-rich repeat domain (L1, residues 1–157), a cysteine-rich region (CR, residues 158–310), an additional leucine rich repeat domain (L2, residues 311–470), three [[fibronectin type III domain]]s; FnIII-1 (residues 471–595), FnIII-2 (residues 596–808) and FnIII-3 (residues 809–906). Additionally, an insert domain (ID, residues 638–756) resides within FnIII-2, containing the α/β furin cleavage site, from which proteolysis results in both IDα and IDβ domains. Within the β-chain, downstream of the FnIII-3 domain lies a transmembrane helix (TH) and intracellular juxtamembrane (JM) region, just upstream of the intracellular tyrosine kinase (TK) catalytic domain, responsible for subsequent intracellular signaling pathways.<ref name="pmid20348418">{{cite journal | vauthors = Smith BJ, Huang K, Kong G, Chan SJ, Nakagawa S, Menting JG, Hu SQ, Whittaker J, Steiner DF, Katsoyannis PG, Ward CW, Weiss MA, Lawrence MC | title = Structural resolution of a tandem hormone-binding element in the insulin receptor and its implications for design of peptide agonists | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 15 | pages = 6771–6 | date = April 2010 | pmid = 20348418 | pmc = 2872410 | doi = 10.1073/pnas.1001813107 | bibcode = 2010PNAS..107.6771S | doi-access = free }}</ref>

Upon cleavage of the monomer to its respective α- and β-chains, receptor hetero or homo-dimerisation is maintained covalently between chains by a single disulphide link and between monomers in the dimer by two disulphide links extending from each α-chain. The overall 3D [[ectodomain]] structure, possessing four ligand binding sites, resembles an inverted 'V', with the each monomer rotated approximately 2-fold about an axis running parallel to the inverted 'V' and L2 and FnIII-1 domains from each monomer forming the inverted 'V's apex.<ref name="pmid20348418"/><ref name="pmid16957736">{{cite journal | vauthors = McKern NM, Lawrence MC, Streltsov VA, Lou MZ, Adams TE, Lovrecz GO, Elleman TC, Richards KM, Bentley JD, Pilling PA, Hoyne PA, Cartledge KA, Pham TM, Lewis JL, Sankovich SE, Stoichevska V, Da Silva E, Robinson CP, Frenkel MJ, Sparrow LG, Fernley RT, Epa VC, Ward CW | title = Structure of the insulin receptor ectodomain reveals a folded-over conformation | journal = Nature | volume = 443 | issue = 7108 | pages = 218–21 | date = September 2006 | pmid = 16957736 | doi = 10.1038/nature05106 | bibcode = 2006Natur.443..218M | s2cid = 4381431 }}</ref>

== Ligand binding ==
[[File:Insulin receptor conformation change upon binding-scheme.jpg|thumb|left|Ligand-induced conformation changes in the full-length human insulin receptor reconstituted in nanodiscs. Left - unactivated receptor conformation; right - insulin-activated receptor conformation. The changes are visualized with the electron microscopy of an individual molecule (upper panel) and schematically depicted as a cartoon (lower panel).<ref name="pmid29453311">{{cite journal | vauthors = Gutmann T, Kim KH, Grzybek M, Walz T, Coskun Ü | title = Visualization of ligand-induced transmembrane signaling in the full-length human insulin receptor | journal = The Journal of Cell Biology | volume = 217 | issue = 5 | pages = 1643–1649 | date = May 2018 | pmid = 29453311 | doi = 10.1083/jcb.201711047 | pmc = 5940312 }}</ref>]]
[[File:Ligand-saturated-cryoEM-IR-structure.png|thumb|left|Left - cryo-EM structure of the ligand-saturated IR ectodomain; right - 4 binding sites and IR structure upon binding schematically depicted as a cartoon.<ref name="pmid31727777">{{cite journal | vauthors = Gutmann T, Schäfer IB, Poojari C, Brankatschk B, Vattulainen I, Strauss M, Coskun Ü | title = Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain | journal = The Journal of Cell Biology | volume = 219 | issue = 1 | date = January 2020 | pmid = 31727777 | pmc = 7039211 | doi = 10.1083/jcb.201907210 | doi-access = free }}</ref>]]
The insulin receptor's endogenous ligands include [[insulin]], [[IGF-I]] and [[Insulin-like growth factor 2|IGF-II]]. Using a [[transmission electron cryomicroscopy|cryo-EM]], structural insight into conformational changes upon insulin binding was provided. Binding of ligand to the α-chains of the IR dimeric ectodomain shifts it from an inverted V-shape to a T-shaped conformation, and this change is propagated structurally to the transmembrane domains, which get closer, eventually leading to autophosphorylation of various tyrosine residues within the intracellular TK domain of the β-chain.<ref name="pmid29453311" /> These changes facilitate the recruitment of specific [[Signal transducing adaptor protein|adapter proteins]] such as the insulin receptor substrate proteins (IRS) in addition to [[SHB (gene)|SH2-B]] ([[Src (gene)|Src]] Homology 2 - B ), [[APS (gene)|APS]] and protein phosphatases, such as [[PTP1B]], eventually promoting downstream processes involving blood glucose homeostasis.<ref name="pmid19225456">{{cite journal | vauthors = Kiselyov VV, Versteyhe S, Gauguin L, De Meyts P | title = Harmonic oscillator model of the insulin and IGF1 receptors' allosteric binding and activation | journal = Molecular Systems Biology | volume = 5 | issue = 5 | pages = 243 | date = Feb 2009 | pmid = 19225456 | pmc = 2657531 | doi = 10.1038/msb.2008.78 }}</ref>

Strictly speaking the relationship between IR and ligand shows complex allosteric properties. This was indicated with the use of a [[Scatchard plot]]s which identified that the measurement of the ratio of IR bound ligand to unbound ligand does not follow a linear relationship with respect to changes in the concentration of IR bound ligand, suggesting that the IR and its respective ligand share a relationship of [[cooperative binding]].<ref name="pmid4361269">{{cite journal | vauthors = de Meyts P, Roth J, Neville DM, Gavin JR, Lesniak MA | title = Insulin interactions with its receptors: experimental evidence for negative cooperativity | journal = Biochemical and Biophysical Research Communications | volume = 55 | issue = 1 | pages = 154–61 | date = November 1973 | pmid = 4361269 | doi = 10.1016/S0006-291X(73)80072-5 }}</ref> Furthermore, the observation that the rate of IR-ligand dissociation is accelerated upon addition of unbound ligand implies that the nature of this cooperation is negative; said differently, that the initial binding of ligand to the IR inhibits further binding to its second active site - exhibition of allosteric inhibition.<ref name="pmid4361269"/>

These models state that each IR monomer possesses 2 insulin binding sites; site 1, which binds to the 'classical' binding surface of [[insulin]]: consisting of L1 plus αCT domains and site 2, consisting of loops at the junction of FnIII-1 and FnIII-2 predicted to bind to the 'novel' hexamer face binding site of insulin.<ref name="pmid19274663"/> As each monomer contributing to the IR ectodomain exhibits 3D 'mirrored' complementarity, N-terminal site 1 of one monomer ultimately faces C-terminal site 2 of the second monomer, where this is also true for each monomers mirrored complement (the opposite side of the ectodomain structure). Current literature distinguishes the complement binding sites by designating the second monomer's site 1 and site 2 nomenclature as either site 3 and site 4 or as site 1' and site 2' respectively.<ref name="pmid19274663"/><ref name="pmid19225456" />
As such, these models state that each IR may bind to an insulin molecule (which has two binding surfaces) via 4 locations, being site 1, 2, (3/1') or (4/2'). As each site 1 proximally faces site 2, upon insulin binding to a specific site, [[Cross-link|'crosslinking']] via ligand between monomers is predicted to occur (i.e. as [monomer 1 Site 1 - Insulin - monomer 2 Site (4/2')] or as [monomer 1 Site 2 - Insulin - monomer 2 site (3/1')]). In accordance with current mathematical modelling of IR-insulin kinetics, there are two important consequences to the events of insulin crosslinking; 1. that by the aforementioned observation of negative cooperation between IR and its ligand that subsequent binding of ligand to the IR is reduced and 2. that the physical action of crosslinking brings the ectodomain into such a [[Conformational change|conformation]] that is required for intracellular tyrosine phosphorylation events to ensue (i.e. these events serve as the requirements for receptor activation and eventual maintenance of blood glucose homeostasis).<ref name="pmid19225456"/>

Visualization of full length IR complexes is not yet available due to many constrain. Visualization of full length IR–insulin complexes is not yet available due to flexible link of transmembrane (TM) domains  with extracellular domain and intracellular domain. The transmembrane (TM) domains are critical for activation and downstream signaling. Stabilization of TM domains may be result of phosphatidylinositol. Meanwhile, visualization of full length IR–downstream proteins is challenging because of transient nature of association, the phosphorylation receptor requirement, and the unfixed relative orientation.<ref>{{Cite journal | vauthors = Choi E, Bai XC | title = The Activation Mechanism of the Insulin Receptor: A Structural Perspective | journal = Annual Review of Biochemistry | volume = 92 | pages = 247–272 | date = 2023-06-20 | pmid = 37001136 | pmc = 10398885 | doi = 10.1146/annurev-biochem-052521-033250 | language = en | issn = 0066-4154 }}</ref>

Applying cryo-EM and [[molecular dynamics]] simulations of receptor reconstituted in [[nanodisc]]s, the structure of the entire dimeric insulin receptor ectodomain with four insulin molecules bound was visualized, therefore confirming and directly showing biochemically predicted 4 binding locations.<ref name="pmid31727777" />

===Agonists===
* [[4548-G05]]
* [[Insulin]]
* [[Insulin-like growth factor 1]]
* [[Mecasermin]]

A number of [[small-molecule]] insulin receptor agonists have been identified.<ref name="pmid34907529">{{cite journal | vauthors = Kumar L, Vizgaudis W, Klein-Seetharaman J | title = Structure-based survey of ligand binding in the human insulin receptor | journal = Br J Pharmacol | volume = 179 | issue = 14 | pages = 3512–3528 | date = July 2022 | pmid = 34907529 | doi = 10.1111/bph.15777 | s2cid = 245242018 | url = | doi-access = free }}</ref>

== Signal transduction pathway ==
The insulin receptor is a type of [[tyrosine kinase receptor]], in which the binding of an agonistic ligand triggers [[autophosphorylation]] of the tyrosine residues, with each subunit phosphorylating its partner. The addition of the phosphate groups generates a binding site for the [[insulin receptor substrate]] (IRS-1), which is subsequently activated via phosphorylation. The activated IRS-1 initiates the signal transduction pathway and binds to [[phosphoinositide 3-kinase]] (PI3K), in turn causing its activation. This then catalyses the conversion of [[Phosphatidylinositol 4,5-bisphosphate]] into [[Phosphatidylinositol (3,4,5)-trisphosphate|Phosphatidylinositol 3,4,5-trisphosphate]] (PIP<sub>3</sub>). PIP<sub>3</sub> acts as a secondary messenger and induces the activation of phosphatidylinositol dependent protein kinase, which then activates several other kinases – most notably [[protein kinase B]], (PKB, also known as Akt). PKB triggers the translocation of glucose transporter ([[GLUT4]]) containing vesicles to the cell membrane, via the activation of [[SNARE (protein)|SNARE]] proteins, to facilitate the diffusion of glucose into the cell. PKB also phosphorylates and inhibits [[Glycogen synthase kinase 3|glycogen synthase kinase]], which is an enzyme that inhibits [[glycogen synthase]]. Therefore, PKB acts to start the process of glycogenesis, which ultimately reduces blood-glucose concentration.<ref>{{Cite book |last=Berg JM, Tymoczko JL, Gatto GJ, Stryer L |title=Biochemistry |publisher=W H Freeman/Macmillan International |year=2019 |isbn=978-1-319-11465-7 |edition=9th |page=897}}</ref>

{{Gallery
|title=Signal transduction of Insulin
|width=700 | height=230
|align=center
|File:insulin glucose metabolism.jpg
 |'''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).
|File:Signal Transduction Diagram- Insulin.svg
 |'''Signal transduction of Insulin:''' At the end of the transduction process, the activated protein binds to the [[c|'''PIP<sub>2</sub>''']] phospholipids embedded in the membrane.
}}

== Function ==

=== 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|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 [[Phosphoinositide 3-kinase|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|phosphatidylinositol 4,5-bisphosphate]] (PIP<sub>2</sub>) to [[Phosphatidylinositol (3,4,5)-trisphosphate|phosphatidylinositol 3,4,5-triphosphate]] (PIP<sub>3</sub>).  This indirectly activates a protein kinase, PKB ([[Akt]]), 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 | vauthors = Duckworth WC, Bennett RG, Hamel FG | title = Insulin degradation: progress and potential | journal = Endocrine Reviews | volume = 19 | issue = 5 | pages = 608–24 | date = October 1998 | pmid = 9793760 | doi = 10.1210/edrv.19.5.0349 | doi-access = free }}</ref>

=== Immune system ===
Besides the metabolic function, insulin receptors are also expressed on immune cells, such as macrophages, B cells, and T cells. On T cells, the expression of insulin receptors is undetectable during the resting state but up-regulated upon [[T-cell receptor]] (TCR) activation. Indeed, [[insulin]] has been shown when supplied exogenously to promote ''in vitro'' T cell proliferation in animal models. Insulin receptor signalling is important for maximizing the potential effect of T cells during acute infection and inflammation.<ref>{{cite journal | vauthors = Tsai S, Clemente-Casares X, Zhou AC, Lei H, Ahn JJ, Chan YT, Choi O, Luck H, Woo M, Dunn SE, Engleman EG, Watts TH, Winer S, Winer DA | display-authors = 6 | title = Insulin Receptor-Mediated Stimulation Boosts T Cell Immunity during Inflammation and Infection | journal = Cell Metabolism | volume = 28 | issue = 6 | pages = 922–934.e4 | date = August 2018 | pmid = 30174303 | doi = 10.1016/j.cmet.2018.08.003 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Fischer HJ, Sie C, Schumann E, Witte AK, Dressel R, van den Brandt J, Reichardt HM | title = The Insulin Receptor Plays a Critical Role in T Cell Function and Adaptive Immunity | journal = Journal of Immunology | volume = 198 | issue = 5 | pages = 1910–1920 | date = March 2017 | pmid = 28115529 | doi = 10.4049/jimmunol.1601011 | doi-access = free }}</ref>

== 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 that 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 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 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 | vauthors = Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, Giannella-Neto D | title = Genotype-phenotype correlation in inherited severe insulin resistance | journal = Human Molecular Genetics | volume = 11 | issue = 12 | pages = 1465–75 | date = June 2002 | pmid = 12023989 | doi = 10.1093/hmg/11.12.1465 | s2cid = 15924838 | doi-access = free }}</ref> Other genetic mutations to the insulin receptor gene can cause Severe Insulin Resistance.<ref>{{Cite journal| vauthors = Melvin A, Stears A |title=Severe insulin resistance: pathologies|url=https://www.practicaldiabetes.com/article/severe-insulin-resistance-pathologies/|access-date=2020-10-31|journal=Practical Diabetes|year=2017|volume=34|issue=6|pages=189–194a|doi=10.1002/pdi.2116|s2cid=90238599|language=en-US|doi-access=free}}</ref>

== Interactions ==
Insulin receptor has been shown to [[protein–protein interaction|interact]] with 
{{div col|colwidth=20em}}
* [[Ectonucleotide pyrophosphatase/phosphodiesterase 1|ENPP1]],<ref name=pmid10615944>{{cite journal | vauthors = Maddux BA, Goldfine ID | title = Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit | journal = Diabetes | volume = 49 | issue = 1 | pages = 13–9 | date = January 2000 | pmid = 10615944 | doi = 10.2337/diabetes.49.1.13 | doi-access = free }}</ref>
* [[GRB10]],<ref name=pmid10871840>{{cite journal | vauthors = Langlais P, Dong LQ, Hu D, Liu F | title = Identification of Grb10 as a direct substrate for members of the Src tyrosine kinase family | journal = Oncogene | volume = 19 | issue = 25 | pages = 2895–903 | date = June 2000 | pmid = 10871840 | doi = 10.1038/sj.onc.1203616 | s2cid = 25923169 | doi-access =  }}</ref><ref name=pmid8621530>{{cite journal | vauthors = Hansen H, Svensson U, Zhu J, Laviola L, Giorgino F, Wolf G, Smith RJ, Riedel H | title = Interaction between the Grb10 SH2 domain and the insulin receptor carboxyl terminus | journal = The Journal of Biological Chemistry | volume = 271 | issue = 15 | pages = 8882–6 | date = April 1996 | pmid = 8621530 | doi = 10.1074/jbc.271.15.8882 | doi-access = free }}</ref><ref name=pmid7479769>{{cite journal | vauthors = Liu F, Roth RA | title = Grb-IR: a SH2-domain-containing protein that binds to the insulin receptor and inhibits its function | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 22 | pages = 10287–91 | date = October 1995 | pmid = 7479769 | pmc = 40781 | doi = 10.1073/pnas.92.22.10287 | bibcode = 1995PNAS...9210287L | doi-access = free }}</ref><ref name=pmid9506989>{{cite journal | vauthors = He W, Rose DW, Olefsky JM, Gustafson TA | title = Grb10 interacts differentially with the insulin receptor, insulin-like growth factor I receptor, and epidermal growth factor receptor via the Grb10 Src homology 2 (SH2) domain and a second novel domain located between the pleckstrin homology and SH2 domains | journal = The Journal of Biological Chemistry | volume = 273 | issue = 12 | pages = 6860–7 | date = March 1998 | pmid = 9506989 | doi = 10.1074/jbc.273.12.6860 | doi-access = free }}</ref><ref name=pmid9006901>{{cite journal | vauthors = Frantz JD, Giorgetti-Peraldi S, Ottinger EA, Shoelson SE | title = Human GRB-IRbeta/GRB10. Splice variants of an insulin and growth factor receptor-binding protein with PH and SH2 domains | journal = The Journal of Biological Chemistry | volume = 272 | issue = 5 | pages = 2659–67 | date = January 1997 | pmid = 9006901 | doi = 10.1074/jbc.272.5.2659 | doi-access = free }}</ref>
* [[GRB7]],<ref name=pmid10803466>{{cite journal | vauthors = Kasus-Jacobi A, Béréziat V, Perdereau D, Girard J, Burnol AF | title = Evidence for an interaction between the insulin receptor and Grb7. A role for two of its binding domains, PIR and SH2 | journal = Oncogene | volume = 19 | issue = 16 | pages = 2052–9 | date = April 2000 | pmid = 10803466 | doi = 10.1038/sj.onc.1203469 | s2cid = 10955124 | doi-access =  }}</ref>
* [[IRS1]],<ref name=pmid11606564>{{cite journal | vauthors = Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF | title = Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action | journal = The Journal of Biological Chemistry | volume = 277 | issue = 2 | pages = 1531–7 | date = January 2002 | pmid = 11606564 | doi = 10.1074/jbc.M101521200 | doi-access = free }}</ref><ref name=pmid8626379>{{cite journal | vauthors = Sawka-Verhelle D, Tartare-Deckert S, White MF, Van Obberghen E | title = Insulin receptor substrate-2 binds to the insulin receptor through its phosphotyrosine-binding domain and through a newly identified domain comprising amino acids 591-786 | journal = The Journal of Biological Chemistry | volume = 271 | issue = 11 | pages = 5980–3 | date = March 1996 | pmid = 8626379 | doi = 10.1074/jbc.271.11.5980  |doi-access=free }}</ref>
* [[MAD2L1]],<ref name=pmid9092546>{{cite journal | vauthors = O'Neill TJ, Zhu Y, Gustafson TA | title = Interaction of MAD2 with the carboxyl terminus of the insulin receptor but not with the IGFIR. Evidence for release from the insulin receptor after activation | journal = The Journal of Biological Chemistry | volume = 272 | issue = 15 | pages = 10035–40 | date = April 1997 | pmid = 9092546 | doi = 10.1074/jbc.272.15.10035 | doi-access = free }}</ref>
* [[PRKCD]],<ref name=pmid11266508>{{cite journal | vauthors = Braiman L, Alt A, Kuroki T, Ohba M, Bak A, Tennenbaum T, Sampson SR | title = Insulin induces specific interaction between insulin receptor and protein kinase C delta in primary cultured skeletal muscle | journal = Molecular Endocrinology | volume = 15 | issue = 4 | pages = 565–74 | date = April 2001 | pmid = 11266508 | doi = 10.1210/mend.15.4.0612 | doi-access = free }}</ref><ref name=pmid12031982>{{cite journal | vauthors = Rosenzweig T, Braiman L, Bak A, Alt A, Kuroki T, Sampson SR | title = Differential effects of tumor necrosis factor-alpha on protein kinase C isoforms alpha and delta mediate inhibition of insulin receptor signaling | journal = Diabetes | volume = 51 | issue = 6 | pages = 1921–30 | date = June 2002 | pmid = 12031982 | doi = 10.2337/diabetes.51.6.1921 | doi-access = free }}</ref>
* [[PTPN11]],<ref name=pmid8135823>{{cite journal | vauthors = Maegawa H, Ugi S, Adachi M, Hinoda Y, Kikkawa R, Yachi A, Shigeta Y, Kashiwagi A | title = Insulin receptor kinase phosphorylates protein tyrosine phosphatase containing Src homology 2 regions and modulates its PTPase activity in vitro | journal = Biochemical and Biophysical Research Communications | volume = 199 | issue = 2 | pages = 780–5 | date = March 1994 | pmid = 8135823 | doi = 10.1006/bbrc.1994.1297 }}</ref><ref name=pmid7493946>{{cite journal | vauthors = Kharitonenkov A, Schnekenburger J, Chen Z, Knyazev P, Ali S, Zwick E, White M, Ullrich A | title = Adapter function of protein-tyrosine phosphatase 1D in insulin receptor/insulin receptor substrate-1 interaction | journal = The Journal of Biological Chemistry | volume = 270 | issue = 49 | pages = 29189–93 | date = December 1995 | pmid = 7493946 | doi = 10.1074/jbc.270.49.29189 | doi-access = free }}</ref> and
* [[SH2B1]].<ref name=pmid9742218>{{cite journal | vauthors = Kotani K, Wilden P, Pillay TS | title = SH2-Balpha is an insulin-receptor adapter protein and substrate that interacts with the activation loop of the insulin-receptor kinase | journal = The Biochemical Journal | volume = 335 | issue = 1 | pages = 103–9 | date = October 1998 | pmid = 9742218 | pmc = 1219757 | doi = 10.1042/bj3350103 }}</ref><ref name=pmid10594240>{{cite journal | vauthors = Nelms K, O'Neill TJ, Li S, Hubbard SR, Gustafson TA, Paul WE | title = Alternative splicing, gene localization, and binding of SH2-B to the insulin receptor kinase domain | journal = Mammalian Genome | volume = 10 | issue = 12 | pages = 1160–7 | date = December 1999 | pmid = 10594240 | doi = 10.1007/s003359901183 | s2cid = 21060861 | url = https://zenodo.org/record/1232697 }}</ref>
{{Div col end}}

== References ==
{{reflist}}

== Further reading ==
{{refbegin|30em}}
* {{cite book | vauthors = Pearson RB, Kemp BE | title = Protein kinase phosphorylation site sequences and consensus specificity motifs: tabulations | chapter = &#91;3&#93; Protein kinase phosphorylation site sequences and consensus specificity motifs: Tabulations | series = Methods in Enzymology | volume = 200 | pages = 62–81 | year = 1991 | pmid = 1956339 | doi = 10.1016/0076-6879(91)00127-I | isbn = 9780121821012 }}
* {{cite journal | vauthors = Joost HG | title = Structural and functional heterogeneity of insulin receptors | journal = Cellular Signalling | volume = 7 | issue = 2 | pages = 85–91 | date = February 1995 | pmid = 7794689 | doi = 10.1016/0898-6568(94)00071-I }}
* {{cite journal | vauthors = O'Dell SD, Day IN | title = Insulin-like growth factor II (IGF-II) | journal = The International Journal of Biochemistry & Cell Biology | volume = 30 | issue = 7 | pages = 767–71 | date = July 1998 | pmid = 9722981 | doi = 10.1016/S1357-2725(98)00048-X }}
* {{cite journal | vauthors = Lopaczynski W | title = Differential regulation of signaling pathways for insulin and insulin-like growth factor I | journal = Acta Biochimica Polonica | volume = 46 | issue = 1 | pages = 51–60 | year = 1999 | doi = 10.18388/abp.1999_4183 | pmid = 10453981 | doi-access = free }}
* {{cite journal | vauthors = Sasaoka T, Kobayashi M | title = The functional significance of Shc in insulin signaling as a substrate of the insulin receptor | journal = Endocrine Journal | volume = 47 | issue = 4 | pages = 373–81 | date = August 2000 | pmid = 11075717 | doi = 10.1507/endocrj.47.373 | doi-access = free }}
* {{cite journal | vauthors = Perz M, Torlińska T | title = Insulin receptor--structural and functional characteristics | journal = Medical Science Monitor | volume = 7 | issue = 1 | pages = 169–77 | year = 2001 | pmid = 11208515 }}
* {{cite journal | vauthors = Benaim G, Villalobo A | title = Phosphorylation of calmodulin. Functional implications | journal = European Journal of Biochemistry | volume = 269 | issue = 15 | pages = 3619–31 | date = August 2002 | pmid = 12153558 | doi = 10.1046/j.1432-1033.2002.03038.x | hdl = 10261/79981 | hdl-access = free }}
{{refend}}

== External links ==
* {{MeshName|Insulin+receptor}}
* {{PDBe-KB2|P06213|Insulin receptor}}

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[[Category:Clusters of differentiation]]
[[Category:EC 2.7.10]]
[[Category:Single-pass transmembrane proteins]]
[[Category:Tyrosine kinase receptors]]