INSR_HUMAN » Insulin receptor

INSR_HUMAN » Insulin receptor
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Topology in Plasma membrane
Topologyextracellular side
cytoplasmic side
INSR_HUMAN » Insulin receptor » IR;
Hydrophobic Thickness 31.6 ± 2.0 Å
Tilt Angle 1 ± 0°
ΔGtransfer -37.3 kcal/mol
ΔGfold -20.0 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, Reactome, HMDB
Topology Out
TM Segments 951-979 (951-982)
Pathways

Adherens junction (KEGG)

Aldosterone-regulated sodium reabsorption (KEGG)

HIF-1 signaling pathway (KEGG)

Insulin signaling pathway (KEGG)

Insulin Signalling (SMPDB)

Ovarian steroidogenesis (KEGG)

PI3K-Akt signaling pathway (KEGG)

Signal Transduction (Reactome)

Type II diabetes mellitus (KEGG)

PDB 1i44 (1005-1310), 4ibm (1005-1310), 1irk (1005-1310), 1p14 (1005-1310), 3ekn (1005-1310), 3ekk (1005-1310), 2mfr (940-988), 1rqq (A/B=1005-1310), 3eta (A/B=1017-1322), 2hr7 (A/B=28-512), 3bu3 (A=1005-1310), 3bu6 (A=1005-1310), 3bu5 (A=1005-1310), 1gag (A=1005-1310), 2auh (A=1005-1310), 1ir3 (A=1005-1310), 2z8c (A=1008-1310), 2b4s (B/D=1005-1310), 3w14 (E/F=28-746), 3w13 (E=28-337, F=724-744), 3w11 (E=28-337, F=731-744), 3w12 (E=28-337, F=731-744), 4oga (E=28-337, F=731-744), 2dtg (E=28-955), 3loh (E=28-956)
OPM 2mfr
Complexes

INSR:INSR_HUMAN

Interactions

CEAM1, Complex: INSR:CEAM1, PubMed

ENPP1, Complex: ENPP1:INSR, PubMed

IGF1R, Complex: INSR:IGF1R, PubMed

INSRR, Complex: INSR:INSRR, PubMed

INSR, Complex: Homodimer of insulin receptor, PDBID: 2HR7

PTN2, Complex: INSR:PTN2, PubMed

PTPRB, Complex: INSR:PTPRB

PTPRC, Complex: PTPRC:INSR, PubMed

PTPRE, Complex: INSR:PTPRE, PubMed

PTPRF, Complex: PTPRF:INSR, PubMed

PTPRG, Complex: INSR:PTPRG

PTPRJ, Complex: INSR:PTPRJ

PTPRK, Complex: PTPRK:INSR

PTPRO, Complex: INSR:PTPRO

Domains

AA: 52-164, PDBID: 2HR7, Subunit A, Seq Identity:100%, Receptor L domain

AA: 179-340, PDBID: 2HR7, Subunit A, Seq Identity:100%, Furin-like cysteine rich region

AA: 359-473, PDBID: 2HR7, Subunit A, Seq Identity:100%, Receptor L domain

AA: 1023-1290, PDBID: 1GAG, Subunit A, Seq Identity:100%, Protein tyrosine kinase

UniProt annotation for INSR_HUMAN » Insulin receptor
FUNCTION: Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src- homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti- apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K- AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.

CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.

ENZYME REGULATION: Activated in response to insulin. Autophosphorylation activates the kinase activity. PTPN1, PTPRE and PTPRF dephosphorylate important tyrosine residues, thereby reducing INSR activity. Inhibited by ENPP1. GRB10 and GRB14 inhibit the catalytic activity of the INSR, they block access of substrates to the activated receptor. SOCS1 and SOCS3 act as negative regulators of INSR activity, they bind to the activated INRS and interfere with the phosphorylation of INSR substrates.

SUBUNIT: Tetramer of 2 alpha and 2 beta chains linked by disulfide bonds. The alpha chains carry the insulin-binding regions, while the beta chains carry the kinase domain. Forms a hybrid receptor with IGF1R, the hybrid is a tetramer consisting of 1 alpha chain and 1 beta chain of INSR and 1 alpha chain and 1 beta chain of IGF1R. Interacts with SORBS1 but dissociates from it following insulin stimulation. Binds SH2B2. Activated form of INSR interacts (via Tyr-999) with the PTB/PID domains of IRS1 and SHC1. The sequences surrounding the phosphorylated NPXY motif contribute differentially to either IRS1 or SHC1 recognition. Interacts (via tyrosines in the C-terminus) with IRS2 (via PTB domain and 591-786 AA); the 591-786 would be the primary anchor of IRS2 to INSR while the PTB domain would have a stabilizing action on the interaction with INSR. Interacts with the SH2 domains of the 85 kDa regulatory subunit of PI3K (PIK3R1) in vitro, when autophosphorylated on tyrosine residues. Interacts with SOCS7. Interacts (via the phosphorylated Tyr-999), with SOCS3. Interacts (via the phosphorylated Tyr-1185, Tyr-1189, Tyr-1190) with SOCS1. Interacts with CAV2 (tyrosine-phosphorylated form); the interaction is increased with "Tyr-27"phosphorylation of CAV2 (By similarity). Interacts with ARRB2 (By similarity). Interacts with GRB10; this interaction blocks the association between IRS1/IRS2 and INSR, significantly reduces insulin-stimulated tyrosine phosphorylation of IRS1 and IRS2 and thus decreases insulin signaling. Interacts with GRB7. Interacts with PDPK1. Interacts (via Tyr-1190) with GRB14 (via BPS domain); this interaction protects the tyrosines in the activation loop from dephosphorylation, but promotes dephosphorylation of Tyr-999, this results in decreased interaction with, and phosphorylation of, IRS1. Interacts (via subunit alpha) with ENPP1 (via 485-599 AA); this interaction blocks autophosphorylation. Interacts with PTPRE; this interaction is dependent of Tyr-1185, Tyr-1189 and Tyr-1190 of the INSR. Interacts with STAT5B (via SH2 domain). Interacts with PTPRF.

TISSUE SPECIFICITY: Isoform Long and isoform Short are predominantly expressed in tissue targets of insulin metabolic effects: liver, adipose tissue and skeletal muscle but are also expressed in the peripheral nerve, kidney, pulmonary alveoli, pancreatic acini, placenta vascular endothelium, fibroblasts, monocytes, granulocytes, erythrocytes and skin. Isoform Short is preferentially expressed in fetal cells such as fetal fibroblasts, muscle, liver and kidney. Found as a hybrid receptor with IGF1R in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Overexpressed in several tumors, including breast, colon, lung, ovary, and thyroid carcinomas.

DOMAIN: The tetrameric insulin receptor binds insulin via non- identical regions from two alpha chains, primarily via the C- terminal region of the first INSR alpha chain. Residues from the leucine-rich N-terminus of the other INSR alpha chain also contribute to this insulin binding site. A secondary insulin- binding site is formed by residues at the junction of fibronectin type-III domain 1 and 2.

DISEASE: Rabson-Mendenhall syndrome (RMS) OMIM: Severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive. mutations affecting the gene represented in this entry.

DISEASE: Leprechaunism (LEPRCH) OMIM: Represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive. mutations affecting the gene represented in this entry.

DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM) OMIM: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body"s own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. gene represented in this entry may be involved in disease pathogenesis.

DISEASE: Familial hyperinsulinemic hypoglycemia 5 (HHF5) OMIM: Familial hyperinsulinemic hypoglycemia OMIM, also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels. disease is caused by mutations affecting the gene represented in this entry.

DISEASE: Insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) OMIM: Characterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor. disease is caused by mutations affecting the gene represented in this entry.

UniProt features for INSR_HUMAN » Insulin receptor
SIGNAL 1 27
CHAIN 28 758 Insulin receptor subunit alpha.
CHAIN 763 1382 Insulin receptor subunit beta.
DOMAIN 622 695 Fibronectin type-III 1.
DOMAIN 757 842 Fibronectin type-III 2.
DOMAIN 850 946 Fibronectin type-III 3.
DOMAIN 1023 1298 Protein kinase.
REGION 733 741 Insulin-binding.
REGION 999 999 Important for interaction with IRS1, SHC1 and STAT5B.
REGION 1361 1364 PIK3R1-binding.
ACT_SITE 1159 1159 Proton donor/acceptor.
SITE 66 66 Insulin-binding (Probable).
DISULFID 35 53
DISULFID 153 182
DISULFID 186 209
DISULFID 196 215
DISULFID 219 228
DISULFID 223 234
DISULFID 235 243
DISULFID 239 252
DISULFID 255 264
DISULFID 268 280
DISULFID 286 311
DISULFID 293 301
DISULFID 315 328
DISULFID 331 335
DISULFID 339 360
DISULFID 462 495
DISULFID 551 551 Interchain.
DISULFID 674 899
DISULFID 825 834
Amino Acid Sequence for INSR_HUMAN » Insulin receptor
MGTGGRRGAA AAPLLVAVAA LLLGAAGHLY PGEVCPGMDI RNNLTRLHEL ENCSVIEGHL QILLMFKTRP EDFRDLSFPK LIMITDYLLL FRVYGLESLK DLFPNLTVIR GSRLFFNYAL VIFEMVHLKE LGLYNLMNIT RGSVRIEKNN ELCYLATIDW SRILDSVEDN YIVLNKDDNE ECGDICPGTA KGKTNCPATV INGQFVERCW THSHCQKVCP TICKSHGCTA EGLCCHSECL GNCSQPDDPT KCVACRNFYL DGRCVETCPP PYYHFQDWRC VNFSFCQDLH HKCKNSRRQG CHQYVIHNNK CIPECPSGYT MNSSNLLCTP CLGPCPKVCH LLEGEKTIDS VTSAQELRGC TVINGSLIIN IRGGNNLAAE LEANLGLIEE ISGYLKIRRS YALVSLSFFR KLRLIRGETL EIGNYSFYAL DNQNLRQLWD WSKHNLTITQ GKLFFHYNPK LCLSEIHKME EVSGTKGRQE RNDIALKTNG DQASCENELL KFSYIRTSFD KILLRWEPYW PPDFRDLLGF MLFYKEAPYQ NVTEFDGQDA CGSNSWTVVD IDPPLRSNDP KSQNHPGWLM RGLKPWTQYA IFVKTLVTFS DERRTYGAKS DIIYVQTDAT NPSVPLDPIS VSNSSSQIIL KWKPPSDPNG NITHYLVFWE RQAEDSELFE LDYCLKGLKL PSRTWSPPFE SEDSQKHNQS EYEDSAGECC SCPKTDSQIL KELEESSFRK TFEDYLHNVV FVPRKTSSGT GAEDPRPSRK RRSLGDVGNV TVAVPTVAAF PNTSSTSVPT SPEEHRPFEK VVNKESLVIS GLRHFTGYRI ELQACNQDTP EERCSVAAYV SARTMPEAKA DDIVGPVTHE IFENNVVHLM WQEPKEPNGL IVLYEVSYRR YGDEELHLCV SRKHFALERG CRLRGLSPGN YSVRIRATSL AGNGSWTEPT YFYVTDYLDV PSNIAKIIIG PLIFVFLFSV VIGSIYLFLR KRQPDGPLGP LYASSNPEYL SASDVFPCSV YVPDEWEVSR EKITLLRELG QGSFGMVYEG NARDIIKGEA ETRVAVKTVN ESASLRERIE FLNEASVMKG FTCHHVVRLL GVVSKGQPTL VVMELMAHGD LKSYLRSLRP EAENNPGRPP PTLQEMIQMA AEIADGMAYL NAKKFVHRDL AARNCMVAHD FTVKIGDFGM TRDIYETDYY RKGGKGLLPV RWMAPESLKD GVFTTSSDMW SFGVVLWEIT SLAEQPYQGL SNEQVLKFVM DGGYLDQPDN CPERVTDLMR MCWQFNPKMR PTFLEIVNLL KDDLHPSFPE VSFFHSEENK APESEELEME FEDMENVPLD RSSHCQREEA GGRDGGSSLG FKRSYEEHIP YTHMNGGKKN GRILTLPRSN PS