Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTY341H)

• DOT Name: Insulin receptor (INSR)
• Synonyms: IR; EC 2.7.10.1; CD antigen CD220
• Gene Name: INSR
• Related Disease:
  Donohue syndrome
  Hyperinsulinism due to INSR deficiency
  Insulin-resistance syndrome type A
  Rabson-Mendenhall syndrome
• UniProt ID: INSR_HUMAN
• PDB ID: 1GAG ; 1I44 ; 1IR3 ; 1IRK ; 1P14 ; 1RQQ ; 2AUH ; 2B4S ; 2HR7 ; 2MFR ; 2Z8C ; 3BU3 ; 3BU5 ; 3BU6 ; 3EKK ; 3EKN ; 3ETA ; 3W11 ; 3W12 ; 3W13 ; 4IBM ; 4OGA ; 4XLV ; 4XSS ; 4XST ; 4ZXB ; 5E1S ; 5HHW ; 5J3H ; 5KQV ; 5U1M ; 6HN4 ; 6HN5 ; 6PXV ; 6PXW ; 6SOF ; 6VEP ; 6VEQ ; 7BW7 ; 7BW8 ; 7BWA ; 7KD6 ; 7MQO ; 7MQR ; 7MQS ; 7PG0 ; 7PG2 ; 7PG3 ; 7PG4 ; 7PHT ; 7QID ; 7S0Q ; 7S8V ; 7U6D ; 7U6E ; 7YQ3 ; 7YQ4 ; 7YQ5 ; 7YQ6 ; 8DWN ; 8GUY
• EC Number: 2.7.10.1
• Pfam ID: PF00041 ; PF00757 ; PF17870 ; PF07714 ; PF01030
• 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
• 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 phosphotyrosine 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. In adipocytes, inhibits lipolysis.
• 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.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  cGMP-PKG sig.ling pathway (hsa04022)
  HIF-1 sig.ling pathway (hsa04066)
  FoxO sig.ling pathway (hsa04068)
  Phospholipase D sig.ling pathway (hsa04072)
  mTOR sig.ling pathway (hsa04150)
  PI3K-Akt sig.ling pathway (hsa04151)
  AMPK sig.ling pathway (hsa04152)
  Longevity regulating pathway (hsa04211)
  Longevity regulating pathway - multiple species (hsa04213)
  Adherens junction (hsa04520)
  Insulin sig.ling pathway (hsa04910)
  Ovarian steroidogenesis (hsa04913)
  Regulation of lipolysis in adipocytes (hsa04923)
  Type II diabetes mellitus (hsa04930)
  Insulin resistance (hsa04931)
  Non-alcoholic fatty liver disease (hsa04932)
  Aldosterone-regulated sodium reabsorption (hsa04960)
  Alzheimer disease (hsa05010)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  IRS activation (R-HSA-74713)
  Signal attenuation (R-HSA-74749)
  Insulin receptor signalling cascade (R-HSA-74751)
  Signaling by Insulin receptor (R-HSA-74752)
  Insulin receptor recycling (R-HSA-77387)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Donohue syndrome	DISI822K	Strong	Autosomal recessive	[1]
Hyperinsulinism due to INSR deficiency	DISICZZL	Strong	Autosomal dominant	[1]
Insulin-resistance syndrome type A	DIS8NI3R	Strong	Autosomal dominant	[1]
Rabson-Mendenhall syndrome	DISTUI37	Strong	Autosomal recessive	[1]

20 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Insulin receptor (INSR).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Insulin receptor (INSR).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Insulin receptor (INSR).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Insulin receptor (INSR).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Insulin receptor (INSR).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Insulin receptor (INSR).	[7]
Testosterone	DM7HUNW	Approved	Testosterone affects the expression of Insulin receptor (INSR).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Insulin receptor (INSR).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Insulin receptor (INSR).	[11]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Insulin receptor (INSR).	[12]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Insulin receptor (INSR).	[10]
Phenytoin	DMNOKBV	Approved	Phenytoin increases the expression of Insulin receptor (INSR).	[14]
Sulfasalazine	DMICA9H	Approved	Sulfasalazine increases the expression of Insulin receptor (INSR).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Insulin receptor (INSR).	[17]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Insulin receptor (INSR).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Insulin receptor (INSR).	[19]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN affects the expression of Insulin receptor (INSR).	[23]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Insulin receptor (INSR).	[24]
Piceatannol	DMYOP45	Investigative	Piceatannol decreases the activity of Insulin receptor (INSR).	[27]
BAY11-7082	DMQNOFA	Investigative	BAY11-7082 increases the expression of Insulin receptor (INSR).	[15]

9 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the phosphorylation of Insulin receptor (INSR).	[8]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the phosphorylation of Insulin receptor (INSR).	[13]
Methamphetamine	DMPM4SK	Approved	Methamphetamine decreases the phosphorylation of Insulin receptor (INSR).	[13]
Insulin-glargine	DMR4HIW	Approved	Insulin-glargine increases the phosphorylation of Insulin receptor (INSR).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Insulin receptor (INSR).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Insulin receptor (INSR).	[21]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl affects the methylation of Insulin receptor (INSR).	[25]
Oleic acid	DM54O1Z	Investigative	Oleic acid decreases the phosphorylation of Insulin receptor (INSR).	[26]
methylglyoxal	DMRC3OZ	Investigative	methylglyoxal decreases the phosphorylation of Insulin receptor (INSR).	[28]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
D-glucose	DMMG2TO	Investigative	D-glucose decreases the degradation of Insulin receptor (INSR).	[22]

References

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