Target Information
Target General Infomation | |||||
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Target ID |
T85435
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Former ID |
TTDS00292
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Target Name |
Insulin receptor
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Gene Name |
INSR
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Synonyms |
CD220 antigen; IR; INSR
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Target Type |
Successful
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Disease | Autoimmune diabetes [ICD10: E08-E13] | ||||
Alzheimer disease [ICD9: 331; ICD10: G30] | |||||
Breast cancer [ICD9: 174, 175; ICD10: C50] | |||||
Crohn's disease [ICD9: 555; ICD10: K50] | |||||
Diabetes [ICD9: 253.5, 588.1; ICD10: E23.2, N25.1] | |||||
Hypoglycemia [ICD9: 250.8, 251.0, 251.1, 251.2, 270.3, 775.6, 962.3; ICD10: E16.0-E16.2] | |||||
Hunter syndrome [ICD10: E76.1] | |||||
Hyperlipidaemia [ICD9: 272.0-272.4; ICD10: E78] | |||||
Hyperglycaemia in type 2 diabetes [ICD9: 250, 790.29; ICD10: E11, R73.9] | |||||
Hypercholesterolemia [ICD10: E78] | |||||
Lymphoma [ICD9: 202.8, 208.9; ICD10: C81-C86] | |||||
Non-insulin dependent diabetes [ICD10: E11.9] | |||||
Pain [ICD9: 338, 356.0, 356.8,780; ICD10: G64, G90.0, R52, G89] | |||||
Type 2 diabetes [ICD9: 250; ICD10: E11] | |||||
Type 1 diabetes [ICD9: 250; ICD10: E10] | |||||
Type 1/2 diabetes [ICD9: 250, 278; ICD10: E08-E13] | |||||
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:12138094 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:16831875 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.
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BioChemical Class |
Kinase
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Target Validation |
T85435
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UniProt ID | |||||
EC Number |
EC 2.7.10.1
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Sequence |
MATGGRRGAAAAPLLVAVAALLLGAAGHLYPGEVCPGMDIRNNLTRLHELENCSVIEGHL
QILLMFKTRPEDFRDLSFPKLIMITDYLLLFRVYGLESLKDLFPNLTVIRGSRLFFNYAL VIFEMVHLKELGLYNLMNITRGSVRIEKNNELCYLATIDWSRILDSVEDNYIVLNKDDNE ECGDICPGTAKGKTNCPATVINGQFVERCWTHSHCQKVCPTICKSHGCTAEGLCCHSECL GNCSQPDDPTKCVACRNFYLDGRCVETCPPPYYHFQDWRCVNFSFCQDLHHKCKNSRRQG CHQYVIHNNKCIPECPSGYTMNSSNLLCTPCLGPCPKVCHLLEGEKTIDSVTSAQELRGC TVINGSLIINIRGGNNLAAELEANLGLIEEISGYLKIRRSYALVSLSFFRKLRLIRGETL EIGNYSFYALDNQNLRQLWDWSKHNLTITQGKLFFHYNPKLCLSEIHKMEEVSGTKGRQE RNDIALKTNGDQASCENELLKFSYIRTSFDKILLRWEPYWPPDFRDLLGFMLFYKEAPYQ NVTEFDGQDACGSNSWTVVDIDPPLRSNDPKSQNHPGWLMRGLKPWTQYAIFVKTLVTFS DERRTYGAKSDIIYVQTDATNPSVPLDPISVSNSSSQIILKWKPPSDPNGNITHYLVFWE RQAEDSELFELDYCLKGLKLPSRTWSPPFESEDSQKHNQSEYEDSAGECCSCPKTDSQIL KELEESSFRKTFEDYLHNVVFVPRKTSSGTGAEDPRPSRKRRSLGDVGNVTVAVPTVAAF PNTSSTSVPTSPEEHRPFEKVVNKESLVISGLRHFTGYRIELQACNQDTPEERCSVAAYV SARTMPEAKADDIVGPVTHEIFENNVVHLMWQEPKEPNGLIVLYEVSYRRYGDEELHLCV SRKHFALERGCRLRGLSPGNYSVRIRATSLAGNGSWTEPTYFYVTDYLDVPSNIAKIIIG PLIFVFLFSVVIGSIYLFLRKRQPDGPLGPLYASSNPEYLSASDVFPCSVYVPDEWEVSR EKITLLRELGQGSFGMVYEGNARDIIKGEAETRVAVKTVNESASLRERIEFLNEASVMKG FTCHHVVRLLGVVSKGQPTLVVMELMAHGDLKSYLRSLRPEAENNPGRPPPTLQEMIQMA AEIADGMAYLNAKKFVHRDLAARNCMVAHDFTVKIGDFGMTRDIYETDYYRKGGKGLLPV RWMAPESLKDGVFTTSSDMWSFGVVLWEITSLAEQPYQGLSNEQVLKFVMDGGYLDQPDN CPERVTDLMRMCWQFNPKMRPTFLEIVNLLKDDLHPSFPEVSFFHSEENKAPESEELEME FEDMENVPLDRSSHCQREEAGGRDGGSSLGFKRSYEEHIPYTHMNGGKKNGRILTLPRSN PS |
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Drugs and Mode of Action | |||||
Drug(s) | Insulin Lispro | Drug Info | Approved | Diabetes | [545337], [551871] |
Insulin Lyspro recombinant | Drug Info | Approved | Diabetes | [536361] | |
Insulin recombinant | Drug Info | Approved | Diabetes | [536361] | |
Insulin, porcine | Drug Info | Approved | Diabetes | [536361] | |
Insulin-glulisine | Drug Info | Approved | Diabetes | [527466] | |
Insulin-lispro | Drug Info | Approved | Diabetes | [536361] | |
Meglitinides | Drug Info | Approved | Hyperglycaemia in type 2 diabetes | [536873] | |
Metformin arginine-hemisuccinimide | Drug Info | Approved | Type 2 diabetes | [550096] | |
Ryzodeq | Drug Info | Approved | Type 2 diabetes | [551971] | |
NN5401 | Drug Info | Phase 3 | Diabetes | [522937] | |
Metformin glycinate | Drug Info | Phase 2/3 | Type 2 diabetes | [522727] | |
DM-71 | Drug Info | Phase 2 | Type 2 diabetes | [550601] | |
DM-99 | Drug Info | Phase 2 | Alzheimer disease | [548894] | |
EGS-21 | Drug Info | Phase 2 | Crohn's disease | [547959] | |
Mitoglitazone | Drug Info | Phase 2 | Type 2 diabetes | [523005] | |
MSDC-0602 | Drug Info | Phase 2 | Type 2 diabetes | [523326] | |
NP-01 | Drug Info | Phase 2 | Type 2 diabetes | [551121] | |
S-707106 | Drug Info | Phase 2 | Type 2 diabetes | [549034] | |
TAK-379 | Drug Info | Phase 2 | Type 2 diabetes | [522387] | |
Tesofensine | Drug Info | Phase 2 | Pain | [521678] | |
VVP-808 | Drug Info | Phase 2 | Type 2 diabetes | [548820] | |
DM-199 | Drug Info | Phase 1/2 | Autoimmune diabetes | [524275] | |
Insulin oral sublingual | Drug Info | Phase 1 | Type 1 diabetes | [549737] | |
Insulin transdermal | Drug Info | Phase 1 | Type 1/2 diabetes | [548362] | |
ISF-402 | Drug Info | Phase 1 | Type 2 diabetes | [551040] | |
NN-1218 | Drug Info | Phase 1 | Diabetes | [523039] | |
AKP-020 | Drug Info | Discontinued in Phase 2 | Type 2 diabetes | [548501] | |
DM-83 | Drug Info | Discontinued in Phase 2 | Type 2 diabetes | [548897] | |
EML-336 | Drug Info | Discontinued in Phase 2 | Type 2 diabetes | [547455] | |
KW-2450 | Drug Info | Discontinued in Phase 1/2 | Breast cancer | [548938] | |
CLX-0900 | Drug Info | Terminated | Hyperlipidaemia | [547166] | |
TER-16998 | Drug Info | Terminated | Diabetes | [546270] | |
Inhibitor | 4-((1H-indazol-6-ylamino)methyl)benzene-1,2-diol | Drug Info | [528746] | ||
4-((naphthalen-2-ylamino)methyl)benzene-1,2-diol | Drug Info | [528746] | |||
Adenosine-5'-[Beta, Gamma-Methylene]Triphosphate | Drug Info | [551393] | |||
compound 15 | Drug Info | [532801] | |||
GSK-1838705A | Drug Info | [530446] | |||
Metformin arginine-hemisuccinimide | Drug Info | [527070] | |||
Metformin glycinate | Drug Info | [544283] | |||
NVP-AEW541 | Drug Info | [530263] | |||
NVP-TAE684 | Drug Info | [528588] | |||
Tesofensine | Drug Info | [530847] | |||
VVP-100X | Drug Info | [543489] | |||
Agonist | AD10-1025 | Drug Info | [543489] | ||
DM-199 | Drug Info | [543489] | |||
DM-99 | Drug Info | [543489] | |||
NP-01 | Drug Info | [543489] | |||
Enhancer | AKP-020 | Drug Info | [526041] | ||
Modulator | CLX-0900 | Drug Info | [526150] | ||
DC-9703 | Drug Info | [543489] | |||
DM-71 | Drug Info | [543489] | |||
EGS-21 | Drug Info | [532546] | |||
EML-336 | Drug Info | [543489] | |||
FPT-038 | Drug Info | [543489] | |||
Insulin oral sublingual | Drug Info | [543489] | |||
Insulin transdermal | Drug Info | [526623] | |||
ISF-402 | Drug Info | [530158] | |||
KW-2450 | Drug Info | [1572591] | |||
Mitoglitazone | Drug Info | [532846] | |||
MSDC-0602 | Drug Info | [531918] | |||
NN-1218 | Drug Info | [544255] | |||
NN5401 | Drug Info | [543489] | |||
Quick-acting insulin | Drug Info | [543489] | |||
RHIIP | Drug Info | [529979] | |||
Ryzodeq | Drug Info | [543489] | |||
S-707106 | Drug Info | [543489] | |||
TAK-379 | Drug Info | [543489] | |||
VVP-808 | Drug Info | [543489] | |||
Stimulator | DM-83 | Drug Info | [543489] | ||
Meglitinides | Drug Info | [536873] | |||
Binder | Humulin (Human insulin isophane) | Drug Info | [535660] | ||
Insulin Lispro | Drug Info | [534941] | |||
Insulin Lyspro recombinant | Drug Info | [535660] | |||
Insulin recombinant | Drug Info | [535660] | |||
Insulin, porcine | Drug Info | [535465] | |||
Insulin-glulisine | Drug Info | [537423] | |||
Insulin-lispro | Drug Info | [534941] | |||
Activator | TER-16998 | Drug Info | [543489] | ||
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
Pathways | |||||
KEGG Pathway | Ras signaling pathway | ||||
Rap1 signaling pathway | |||||
cGMP-PKG signaling pathway | |||||
HIF-1 signaling pathway | |||||
FoxO signaling pathway | |||||
PI3K-Akt signaling pathway | |||||
AMPK signaling pathway | |||||
Adherens junction | |||||
Insulin signaling pathway | |||||
Ovarian steroidogenesis | |||||
Type II diabetes mellitus | |||||
Non-alcoholic fatty liver disease (NAFLD) | |||||
Aldosterone-regulated sodium reabsorption | |||||
NetPath Pathway | TGF_beta_Receptor Signaling Pathway | ||||
PANTHER Pathway | Insulin/IGF pathway-mitogen activated protein kinase kinase/MAP kinase cascade | ||||
Insulin/IGF pathway-protein kinase B signaling cascade | |||||
PI3 kinase pathway | |||||
Pathway Interaction Database | Insulin Pathway | ||||
Signaling events mediated by PTP1B | |||||
Signaling events mediated by TCPTP | |||||
Insulin-mediated glucose transport | |||||
PathWhiz Pathway | Insulin Signalling | ||||
Leucine Stimulation on Insulin Signaling | |||||
Reactome | IRS activation | ||||
Signal attenuation | |||||
Insulin receptor signalling cascade | |||||
Insulin receptor recycling | |||||
WikiPathways | DNA Damage Response (only ATM dependent) | ||||
Insulin Signaling | |||||
Nanoparticle triggered autophagic cell death | |||||
AGE/RAGE pathway | |||||
Signaling by Insulin receptor | |||||
Folate Metabolism | |||||
Type II diabetes mellitus | |||||
Vitamin B12 Metabolism | |||||
Selenium Micronutrient Network | |||||
AMPK Signaling | |||||
References | |||||
Ref 521678 | ClinicalTrials.gov (NCT00153010) An Evaluation of Three Doses of NS 2330 in Patients With Mild to Moderate Dementia of the Alzheimer's Type. U.S. National Institutes of Health. | ||||
Ref 522387 | ClinicalTrials.gov (NCT00722917) Efficacy and Safety of TAK-379 in Adult Subjects With Type 2 Diabetes Mellitus. U.S. National Institutes of Health. | ||||
Ref 522727 | ClinicalTrials.gov (NCT00940472) Study on DMMET-01 Versus Metformin on Improvement of Metabolic Control in Naive Type 2 Diabetes Patients. U.S. National Institutes of Health. | ||||
Ref 522937 | ClinicalTrials.gov (NCT01059812) A Pan Asian Trial Comparing Efficacy and Safety of NN5401 and Biphasic Insulin Aspart 30 in Type 2 Diabetes. U.S. National Institutes of Health. | ||||
Ref 523005 | ClinicalTrials.gov (NCT01103414) Study to Evaluate the Safety, Tolerability and Efficacy of Three Dose Levels of Mitoglitazone in Type 2 Diabetic Patients. U.S. National Institutes of Health. | ||||
Ref 523039 | ClinicalTrials.gov (NCT01121289) A Trial Investigating NN1218 in Subjects With Type 1 Diabetes. U.S. National Institutes of Health. | ||||
Ref 523326 | ClinicalTrials.gov (NCT01280695) A Randomized, Double-Blind, Comparator- and Placebo-Controlled, Multiple-Dose Study to Evaluate the Safety, Tolerability and Efficacy of Three Dose Levels of MSDC-0602 in Type 2 Diabetic Patients. U.S. National Institutes of Health. | ||||
Ref 524275 | ClinicalTrials.gov (NCT01845064) A Study to Evaluate the Safety and Effectiveness of DM199 in Healthy Subjects and Type 2 Diabetes Patients. U.S. National Institutes of Health. | ||||
Ref 536361 | Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77. Epub 2007 Feb 20. | ||||
Ref 536873 | New drugs for type 2 diabetes mellitus: what is their place in therapy? Drugs. 2008;68(15):2131-62. | ||||
Ref 545337 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002887) | ||||
Ref 546270 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007187) | ||||
Ref 547166 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800013573) | ||||
Ref 547455 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800016521) | ||||
Ref 547959 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020751) | ||||
Ref 548362 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024972) | ||||
Ref 548501 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026051) | ||||
Ref 548820 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029155) | ||||
Ref 548894 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800030024) | ||||
Ref 548897 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800030050) | ||||
Ref 548938 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800030562) | ||||
Ref 549034 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031641) | ||||
Ref 550096 | Clinical pipeline report, company report or official report of Boehringer Ingelheim Pharmaceuticals. | ||||
Ref 526041 | Effect of vanadium on insulin and leptin in Zucker diabetic fatty rats. Mol Cell Biochem. 2001 Feb;218(1-2):93-6. | ||||
Ref 526623 | Transdermal drug delivery of insulin with ultradeformable carriers. Clin Pharmacokinet. 2003;42(5):461-74. | ||||
Ref 527070 | Metformin (Glucophage) inhibits tyrosine phosphatase activity to stimulate the insulin receptor tyrosine kinase. Biochem Pharmacol. 2004 Jun 1;67(11):2081-91. | ||||
Ref 528588 | Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):270-5. Epub 2006 Dec 21.Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. | ||||
Ref 528746 | Eur J Pharmacol. 2007 May 7;562(1-2):1-11. Epub 2007 Feb 3.ATP non-competitive IGF-1 receptor kinase inhibitors as lead anti-neoplastic and anti-papilloma agents. | ||||
Ref 529979 | PROMAXX inhaled insulin: safe and efficacious administration with a commercially available dry powder inhaler. Diabetes Obes Metab. 2009 May;11(5):455-9. | ||||
Ref 530158 | Ability of GHTD-amide and analogs to enhance insulin activity through zinc chelation and dispersal of insulin oligomers. Peptides. 2009 Jun;30(6):1088-97. | ||||
Ref 530263 | J Med Chem. 2009 Aug 27;52(16):4981-5004.Inhibition of the insulin-like growth factor-1 receptor (IGF1R) tyrosine kinase as a novel cancer therapy approach. | ||||
Ref 530446 | GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers. Mol Cancer Ther. 2009 Oct;8(10):2811-20. | ||||
Ref 530847 | The novel triple monoamine reuptake inhibitor tesofensine induces sustained weight loss and improves glycemic control in the diet-induced obese rat: comparison to sibutramine and rimonabant. Eur J Pharmacol. 2010 Jun 25;636(1-3):88-95. | ||||
Ref 531918 | Insulin resistance and metabolic derangements in obese mice are ameliorated by a novel peroxisome proliferator-activated receptor gamma-sparing thiazolidinedione. J Biol Chem. 2012 Jul 6;287(28):23537-48. | ||||
Ref 532546 | Ceramides and glucosylceramides are independent antagonists of insulin signaling. J Biol Chem. 2014 Jan 10;289(2):723-34. | ||||
Ref 532801 | Discovery of a potent inhibitor of anaplastic lymphoma kinase with in vivo antitumor activity. ACS Med Chem Lett. 2010 Sep 1;1(9):493-8. | ||||
Ref 532846 | An evaluation of MSDC-0160, a prototype mTOT modulating insulin sensitizer, in patients with mild Alzheimer's disease. Curr Alzheimer Res. 2014;11(6):564-73. | ||||
Ref 534941 | Hope for insulin mimetic oral antidiabetic drugs. Eur J Endocrinol. 1999 Dec;141(6):561-2. | ||||
Ref 535465 | Acidic residues on the N-terminus of proinsulin C-Peptide are important for the folding of insulin precursor. J Biochem. 2002 Jun;131(6):855-9. | ||||
Ref 535660 | Knockouts model the 100 best-selling drugs--will they model the next 100? Nat Rev Drug Discov. 2003 Jan;2(1):38-51. | ||||
Ref 536873 | New drugs for type 2 diabetes mellitus: what is their place in therapy? Drugs. 2008;68(15):2131-62. | ||||
Ref 537423 | Insulin glulisine: a review of its use in the management of diabetes mellitus. Drugs. 2009;69(8):1035-57. doi: 10.2165/00003495-200969080-00006. | ||||
Ref 543489 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1800). | ||||
Ref 544255 | Ultrafast-Acting Insulins: State of the Art. J Diabetes Sci Technol. 2012 July; 6(4): 728-742. |
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