Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNJ9IFS)

DOT Name Short transient receptor potential channel 4-associated protein (TRPC4AP)
Synonyms Trp4-associated protein; Trpc4-associated protein; Protein TAP1; TNF-receptor ubiquitous scaffolding/signaling protein; Protein TRUSS
Gene Name TRPC4AP
Related Disease
Advanced cancer ( )
Alcohol dependence ( )
Alzheimer disease ( )
Fatty liver disease ( )
Metabolic disorder ( )
Non-alcoholic fatty liver disease ( )
Non-alcoholic steatohepatitis ( )
Venous thromboembolism ( )
Bipolar disorder ( )
Hypothyroidism ( )
Prostate cancer ( )
Prostate carcinoma ( )
UniProt ID
TP4AP_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Pfam ID
PF12463
Sequence
MAAAPVAAGSGAGRGRRSAATVAAWGGWGGRPRPGNILLQLRQGQLTGRGLVRAVQFTET
FLTERDKQSKWSGIPQLLLKLHTTSHLHSDFVECQNILKEISPLLSMEAMAFVTEERKLT
QETTYPNTYIFDLFGGVDLLVEILMRPTISIRGQKLKISDEMSKDCLSILYNTCVCTEGV
TKRLAEKNDFVIFLFTLMTSKKTFLQTATLIEDILGVKKEMIRLDEVPNLSSLVSNFDQQ
QLANFCRILAVTISEMDTGNDDKHTLLAKNAQQKKSLSLGPSAAEINQAALLSIPGFVER
LCKLATRKVSESTGTASFLQELEEWYTWLDNALVLDALMRVANEESEHNQASIVFPPPGA
SEENGLPHTSARTQLPQSMKIMHEIMYKLEVLYVLCVLLMGRQRNQVHRMIAEFKLIPGL
NNLFDKLIWRKHSASALVLHGHNQNCDCSPDITLKIQFLRLLQSFSDHHENKYLLLNNQE
LNELSAISLKANIPEVEAVLNTDRSLVCDGKRGLLTRLLQVMKKEPAESSFRFWQARAVE
SFLRGTTSYADQMFLLKRGLLEHILYCIVDSECKSRDVLQSYFDLLGELMKFNVDAFKRF
NKYINTDAKFQVFLKQINSSLVDSNMLVRCVTLSLDRFENQVDMKVAEVLSECRLLAYIS
QVPTQMSFLFRLINIIHVQTLTQENVSCLNTSLVILMLARRKERLPLYLRLLQRMEHSKK
YPGFLLNNFHNLLRFWQQHYLHKDKDSTCLENSSCISFSYWKETVSILLNPDRQSPSALV
SYIEEPYMDIDRDFTEE
Function
Substrate-recognition component of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex required for cell cycle control. The DCX(TRPC4AP) complex specifically mediates the polyubiquitination and subsequent degradation of MYC as part of the DesCEND (destruction via C-end degrons) pathway. The DesCEND (destruction via C-end degrons) pathway recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation. The DCX(TRPC4AP) complex specifically recognizes proteins with an arginine at the minus 3 position (R-3 motif) at the C-terminus, such as MYC, leading to their ubiquitination and degradation. Also participates in the activation of NFKB1 in response to ligation of TNFRSF1A, possibly by linking TNFRSF1A to the IKK signalosome. Involved in JNK activation via its interaction with TRAF2. Also involved in elevation of endoplasmic reticulum Ca(2+) storage reduction in response to CHRM1.
Reactome Pathway
TRP channels (R-HSA-3295583 )

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Advanced cancer DISAT1Z9 Strong Altered Expression [1]
Alcohol dependence DIS4ZSCO Strong Genetic Variation [2]
Alzheimer disease DISF8S70 Strong Genetic Variation [3]
Fatty liver disease DIS485QZ Strong Biomarker [4]
Metabolic disorder DIS71G5H Strong Biomarker [5]
Non-alcoholic fatty liver disease DISDG1NL Strong Biomarker [5]
Non-alcoholic steatohepatitis DIST4788 Strong Altered Expression [5]
Venous thromboembolism DISUR7CR Strong Genetic Variation [6]
Bipolar disorder DISAM7J2 moderate Genetic Variation [7]
Hypothyroidism DISR0H6D Limited Autosomal dominant [8]
Prostate cancer DISF190Y Limited Biomarker [9]
Prostate carcinoma DISMJPLE Limited Biomarker [9]
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⏷ Show the Full List of 12 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
Tretinoin DM49DUI Approved Tretinoin increases the expression of Short transient receptor potential channel 4-associated protein (TRPC4AP). [10]
Temozolomide DMKECZD Approved Temozolomide decreases the expression of Short transient receptor potential channel 4-associated protein (TRPC4AP). [11]
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3 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene affects the methylation of Short transient receptor potential channel 4-associated protein (TRPC4AP). [12]
TAK-243 DM4GKV2 Phase 1 TAK-243 increases the sumoylation of Short transient receptor potential channel 4-associated protein (TRPC4AP). [13]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the methylation of Short transient receptor potential channel 4-associated protein (TRPC4AP). [14]
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References

1 Myc protein is stabilized by suppression of a novel E3 ligase complex in cancer cells.Genes Dev. 2010 Jun 15;24(12):1236-41. doi: 10.1101/gad.1920310.
2 A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53.Mol Psychiatry. 2013 Nov;18(11):1218-24. doi: 10.1038/mp.2012.143. Epub 2012 Oct 23.
3 Genome screen of late-onset Alzheimer's extended pedigrees identifies TRPC4AP by haplotype analysis.Am J Med Genet B Neuropsychiatr Genet. 2009 Jan 5;150B(1):50-5. doi: 10.1002/ajmg.b.30767.
4 TRUSS inhibition protects against high fat diet (HFD)-stimulated brain injury by alleviation of inflammatory response.Biochem Biophys Res Commun. 2019 Mar 26;511(1):41-48. doi: 10.1016/j.bbrc.2019.01.058. Epub 2019 Feb 11.
5 TRUSS Exacerbates NAFLD Development by Promoting IB Degradation in Mice.Hepatology. 2018 Nov;68(5):1769-1785. doi: 10.1002/hep.30066. Epub 2018 Oct 4.
6 Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.Blood. 2019 Nov 7;134(19):1645-1657. doi: 10.1182/blood.2019000435.
7 Replication of bipolar disorder susceptibility alleles and identification of two novel genome-wide significant associations in a new bipolar disorder case-control sample.Mol Psychiatry. 2013 Dec;18(12):1302-7. doi: 10.1038/mp.2012.142. Epub 2012 Oct 16.
8 Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
9 Identification of a candidate prognostic gene signature by transcriptome analysis of matched pre- and post-treatment prostatic biopsies from patients with advanced prostate cancer.BMC Cancer. 2014 Dec 18;14:977. doi: 10.1186/1471-2407-14-977.
10 Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
11 Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
12 Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
13 Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
14 DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.