Target General Infomation
Target ID
T85435
Former ID
TTDS00292
Target Name
Insulin receptor
Gene Name
INSR
Synonyms
CD220 antigen; IR; INSR
Target Type
Successful
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.
BioChemical Class
Kinase
Target Validation
T85435
UniProt ID
EC Number
EC 2.7.10.1
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
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)
TEP EXP Info
DRM DRM Info
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 521678ClinicalTrials.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 522387ClinicalTrials.gov (NCT00722917) Efficacy and Safety of TAK-379 in Adult Subjects With Type 2 Diabetes Mellitus. U.S. National Institutes of Health.
Ref 522727ClinicalTrials.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 522937ClinicalTrials.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 523005ClinicalTrials.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 523039ClinicalTrials.gov (NCT01121289) A Trial Investigating NN1218 in Subjects With Type 1 Diabetes. U.S. National Institutes of Health.
Ref 523326ClinicalTrials.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 524275ClinicalTrials.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 5274662004 approvals: the demise of the blockbuster. Nat Rev Drug Discov. 2005 Feb;4(2):93-4.
Ref 536361Natural 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 536873New drugs for type 2 diabetes mellitus: what is their place in therapy? Drugs. 2008;68(15):2131-62.
Ref 545337Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002887)
Ref 546270Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007187)
Ref 547166Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800013573)
Ref 547455Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800016521)
Ref 547959Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020751)
Ref 548362Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024972)
Ref 548501Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026051)
Ref 548820Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029155)
Ref 548894Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800030024)
Ref 548897Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800030050)
Ref 548938Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800030562)
Ref 549034Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031641)
Ref 549737Clinical pipeline report, company report or official report of Biodel.
Ref 550096Clinical pipeline report, company report or official report of Boehringer Ingelheim Pharmaceuticals.
Ref 550601Clinical pipeline report, company report or official report of DiaMedica Inc.
Ref 551040Clinical pipeline report, company report or official report of Dia-B Tech.
Ref 551121Clinical pipeline report, company report or official report of Medesis Pharma SA.
Ref 551871Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
Ref 551971Clinical pipeline report, company report or official report of Novo nordisk.
Ref
Ref 526041Effect of vanadium on insulin and leptin in Zucker diabetic fatty rats. Mol Cell Biochem. 2001 Feb;218(1-2):93-6.
Ref 526150CLX-0901 (Calyx Therapeutics). Curr Opin Investig Drugs. 2001 May;2(5):650-3.
Ref 526623Transdermal drug delivery of insulin with ultradeformable carriers. Clin Pharmacokinet. 2003;42(5):461-74.
Ref 527070Metformin (Glucophage) inhibits tyrosine phosphatase activity to stimulate the insulin receptor tyrosine kinase. Biochem Pharmacol. 2004 Jun 1;67(11):2081-91.
Ref 528588Proc 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 528746Eur 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 529979PROMAXX inhaled insulin: safe and efficacious administration with a commercially available dry powder inhaler. Diabetes Obes Metab. 2009 May;11(5):455-9.
Ref 530158Ability 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 530263J 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 530446GSK1838705A 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 530847The 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 531918Insulin 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 532546Ceramides and glucosylceramides are independent antagonists of insulin signaling. J Biol Chem. 2014 Jan 10;289(2):723-34.
Ref 532801Discovery 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 532846An 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 534941Hope for insulin mimetic oral antidiabetic drugs. Eur J Endocrinol. 1999 Dec;141(6):561-2.
Ref 535465Acidic 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 535660Knockouts model the 100 best-selling drugs--will they model the next 100? Nat Rev Drug Discov. 2003 Jan;2(1):38-51.
Ref 536873New drugs for type 2 diabetes mellitus: what is their place in therapy? Drugs. 2008;68(15):2131-62.
Ref 537423Insulin 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 544255Ultrafast-Acting Insulins: State of the Art. J Diabetes Sci Technol. 2012 July; 6(4): 728-742.
Ref 544283Effect of Metformin Glycinate on Glycated Hemoglobin A1c Concentration and Insulin Sensitivity in Drug-Naive Adult Patients with Type 2 Diabetes Mellitus. Diabetes Technol Ther. 2012 December; 14(12): 1140-1144.
Ref 551393How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
Ref 1572591Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.