Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTOL40K)

DOT Name Insulin receptor substrate 4 (IRS4)
Synonyms IRS-4; 160 kDa phosphotyrosine protein; py160; Phosphoprotein of 160 kDa; pp160
Gene Name IRS4
Related Disease
Acute lymphocytic leukaemia ( )
Alzheimer disease ( )
Bone osteosarcoma ( )
Breast cancer ( )
Breast carcinoma ( )
Candidiasis ( )
Colon cancer ( )
Colon carcinoma ( )
Colorectal carcinoma ( )
Hepatocellular carcinoma ( )
Hyperplasia ( )
Hypothyroidism, congenital, nongoitrous, 9 ( )
Invasive candidiasis ( )
Osteosarcoma ( )
Squamous cell carcinoma ( )
Advanced cancer ( )
Non-insulin dependent diabetes ( )
Type-1/2 diabetes ( )
Lung cancer ( )
Lung carcinoma ( )
Melanoma ( )
Neoplasm ( )
T-cell acute lymphoblastic leukaemia ( )
UniProt ID
IRS4_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Pfam ID
PF02174
Sequence
MASCSFTRDQATRRLRGAAAAAAAALAAVVTTPLLSSGTPTALIGTGSSCPGAMWLSTAT
GSRSDSESEEEDLPVGEEVCKRGYLRKQKHGHRRYFVLKLETADAPARLEYYENARKFRH
SVRAAAAAAAAAASGAAIPPLIPPRRVITLYQCFSVSQRADARYRHLIALFTQDEYFAMV
AENESEQESWYLLLSRLILESKRRRCGTLGAQPDGEPAALAAAAAAEPPFYKDVWQVIVK
PRGLGHRKELSGVFRLCLTDEEVVFVRLNTEVASVVVQLLSIRRCGHSEQYFFLEVGRST
VIGPGELWMQVDDCVVAQNMHELFLEKMRALCADEYRARCRSYSISIGAHLLTLLSARRH
LGLVPLEPGGWLRRSRFEQFCHLRAIGDGEDEMLFTRRFVTPSEPVAHSRRGRLHLPRGR
RSRRAVSVPASFFRRLAPSPARPRHPAEAPNNGARLSSEVSGSGSGNFGEEGNPQGKEDQ
EGSGGDYMPMNNWGSGNGRGSGGGQGSNGQGSSSHSSGGNQCSGEGQGSRGGQGSNGQGS
GGNQCSRDGQGTAGGHGSGGGQRPGGGHGSGGGQGPGDGHGSGGGKNSGGGKGSGSGKGS
DGDGERGKSLKKRSYFGKLTQSKQQQMPPPPPPPPPPPPAGGTGGKGKSGGRFRLYFCVD
RGATKECKEAKEVKDAEIPEGAARGPHRARAFDEDEDDPYVPMRPGVATPLVSSSDYMPM
APQNVSASKKRHSRSPFEDSRGYMMMFPRVSPPPAPSPPKAPDTNKEDDSKDNDSESDYM
FMAPGAGAIPKNPRNPQGGSSSKSWSSYFSLPNPFRSSPLGQNDNSEYVPMLPGKFLGRG
LDKEVSYNWDPKDAASKPSGEGSFSKPGDGGSPSKPSDHEPPKNKAKRPNRLSFITKGYK
IKPKPQKPTHEQREADSSSDYVNMDFTKRESNTPAPSTQGLPDSWGIIAEPRQSAFSNYV
NVEFGVPFPNPANDLSDLLRAIPRANPLSLDSARWPLPPLPLSATGSNAIEEEGDYIEVI
FNSAMTPAMALADSAIRYDAETGRIYVVDPFSECCMDISLSPSRCSEPPPVARLLQEEEQ
ERRRPQSRSQSFFAAARAAVSAFPTDSLERDLSPSSAPAVASAAEPTLALSQVVAAASAL
AAAPGIGAAAAAAGFDSASARWFQPVANAADAEAVRGAQDVAGGSNPGAHNPSANLARGD
NQAGGAAAAAAAPEPPPRSRRVPRPPEREDSDNDDDTHVRMDFARRDNQFDSPKRGR
Function
Acts as an interface between multiple growth factor receptors possessing tyrosine kinase activity, such as insulin receptor, IGF1R and FGFR1, and a complex network of intracellular signaling molecules containing SH2 domains. Involved in the IGF1R mitogenic signaling pathway. Promotes the AKT1 signaling pathway and BAD phosphorylation during insulin stimulation without activation of RPS6KB1 or the inhibition of apoptosis. Interaction with GRB2 enhances insulin-stimulated mitogen-activated protein kinase activity. May be involved in nonreceptor tyrosine kinase signaling in myoblasts. Plays a pivotal role in the proliferation/differentiation of hepatoblastoma cell through EPHB2 activation upon IGF1 stimulation. May play a role in the signal transduction in response to insulin and to a lesser extent in response to IL4 and GH on mitogenesis. Plays a role in growth, reproduction and glucose homeostasis. May act as negative regulators of the IGF1 signaling pathway by suppressing the function of IRS1 and IRS2.
Tissue Specificity Expressed in myoblasts. Expressed in liver and hepatocellular carcinoma.
KEGG Pathway
cGMP-PKG sig.ling pathway (hsa04022 )
FoxO sig.ling pathway (hsa04068 )
Autophagy - animal (hsa04140 )
AMPK sig.ling pathway (hsa04152 )
Longevity regulating pathway (hsa04211 )
Longevity regulating pathway - multiple species (hsa04213 )
Insulin sig.ling pathway (hsa04910 )
Adipocytokine sig.ling pathway (hsa04920 )
Regulation of lipolysis in adipocytes (hsa04923 )
Type II diabetes mellitus (hsa04930 )
Growth hormone synthesis, secretion and action (hsa04935 )
Alzheimer disease (hsa05010 )
Reactome Pathway
IRS-related events triggered by IGF1R (R-HSA-2428928 )

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Acute lymphocytic leukaemia DISPX75S Strong Altered Expression [1]
Alzheimer disease DISF8S70 Strong Genetic Variation [2]
Bone osteosarcoma DIST1004 Strong Altered Expression [3]
Breast cancer DIS7DPX1 Strong Biomarker [4]
Breast carcinoma DIS2UE88 Strong Biomarker [4]
Candidiasis DISIRYMU Strong Biomarker [5]
Colon cancer DISVC52G Strong Biomarker [6]
Colon carcinoma DISJYKUO Strong Biomarker [6]
Colorectal carcinoma DIS5PYL0 Strong Altered Expression [7]
Hepatocellular carcinoma DIS0J828 Strong Biomarker [8]
Hyperplasia DISK4DFB Strong Genetic Variation [9]
Hypothyroidism, congenital, nongoitrous, 9 DISYAJH6 Strong X-linked [10]
Invasive candidiasis DIS5EI0L Strong Biomarker [5]
Osteosarcoma DISLQ7E2 Strong Altered Expression [3]
Squamous cell carcinoma DISQVIFL Strong Biomarker [11]
Advanced cancer DISAT1Z9 moderate Altered Expression [3]
Non-insulin dependent diabetes DISK1O5Z moderate Genetic Variation [12]
Type-1/2 diabetes DISIUHAP moderate Biomarker [12]
Lung cancer DISCM4YA Limited Altered Expression [13]
Lung carcinoma DISTR26C Limited Altered Expression [13]
Melanoma DIS1RRCY Limited Biomarker [14]
Neoplasm DISZKGEW Limited Altered Expression [7]
T-cell acute lymphoblastic leukaemia DIS17AI2 Limited Altered Expression [15]
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⏷ Show the Full List of 23 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
2 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of Insulin receptor substrate 4 (IRS4). [16]
Trichostatin A DM9C8NX Investigative Trichostatin A decreases the expression of Insulin receptor substrate 4 (IRS4). [17]
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References

1 Effect of IRS4 levels on PI 3-kinase signalling.PLoS One. 2013 Sep 10;8(9):e73327. doi: 10.1371/journal.pone.0073327. eCollection 2013.
2 Clustering of transcriptional profiles identifies changes to insulin signaling as an early event in a mouse model of Alzheimer's disease.BMC Genomics. 2013 Nov 25;14:831. doi: 10.1186/1471-2164-14-831.
3 Phosphorylation of IRS4 by CK12 promotes its degradation by CHIP through the ubiquitin/lysosome pathway.Theranostics. 2018 Jun 7;8(13):3643-3653. doi: 10.7150/thno.26021. eCollection 2018.
4 IRS4 induces mammary tumorigenesis and confers resistance to HER2-targeted therapy through constitutive PI3K/AKT-pathway hyperactivation.Nat Commun. 2016 Nov 23;7:13567. doi: 10.1038/ncomms13567.
5 Candida albicans IRS4 contributes to hyphal formation and virulence after the initial stages of disseminated candidiasis.Microbiology (Reading). 2005 Sep;151(Pt 9):2923-2931. doi: 10.1099/mic.0.27998-0.
6 Insulin receptor substrate-4 is overexpressed in colorectal cancer and promotes retinoblastoma-cyclin-dependent kinase activation.J Gastroenterol. 2018 Aug;53(8):932-944. doi: 10.1007/s00535-018-1432-8. Epub 2018 Jan 20.
7 Overexpression of insulin receptor substrate-4 is correlated with clinical staging in colorectal cancer patients.J Mol Histol. 2018 Feb;49(1):39-49. doi: 10.1007/s10735-017-9745-0. Epub 2017 Nov 28.
8 In vitro studies of water-stable cationic carbosilane dendrimers as delivery vehicles for gene therapy against HIV and hepatocarcinoma.Curr Med Chem. 2012;19(29):5052-61. doi: 10.2174/0929867311209025052.
9 Selective alterations in insulin receptor substrates-1, -2 and -4 in theca but not granulosa cells from polycystic ovaries.Mol Hum Reprod. 2004 Jul;10(7):473-9. doi: 10.1093/molehr/gah066. Epub 2004 May 21.
10 Mutations in IRS4 are associated with central hypothyroidism. J Med Genet. 2018 Oct;55(10):693-700. doi: 10.1136/jmedgenet-2017-105113. Epub 2018 Jul 30.
11 Interaction between Brk kinase and insulin receptor substrate-4.Oncogene. 2005 Aug 25;24(36):5656-64. doi: 10.1038/sj.onc.1208721.
12 Common amino acid substitutions in insulin receptor substrate-4 are not associated with Type II diabetes mellitus or insulin resistance.Diabetologia. 1998 Aug;41(8):969-74. doi: 10.1007/s001250051015.
13 Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking.Nat Genet. 2017 Jan;49(1):65-74. doi: 10.1038/ng.3722. Epub 2016 Nov 21.
14 Downregulation of miR-493 promoted melanoma proliferation by suppressing IRS4 expression.Tumour Biol. 2017 May;39(5):1010428317701640. doi: 10.1177/1010428317701640.
15 The t(X;7)(q22;q34) in paediatric T-cell acute lymphoblastic leukaemia results in overexpression of the insulin receptor substrate 4 gene through illegitimate recombination with the T-cell receptor beta locus.Br J Haematol. 2009 Feb;144(4):546-51. doi: 10.1111/j.1365-2141.2008.07453.x. Epub 2008 Nov 13.
16 Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
17 From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.