Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBF3DYK)

DOT Name VPS10 domain-containing receptor SorCS2 (SORCS2)
Gene Name SORCS2
Related Disease
Bipolar disorder ( )
Alcohol withdrawal ( )
Alzheimer disease ( )
Anorexia nervosa cachexia ( )
Attention deficit hyperactivity disorder ( )
Epilepsy ( )
Huntington disease ( )
Myocardial infarction ( )
Sickle-cell anaemia ( )
Acute myelogenous leukaemia ( )
UniProt ID
SORC2_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
1WGO
Pfam ID
PF18911 ; PF15902 ; PF15901
Sequence
MAHRGPSRASKGPGPTARAPSPGAPPPPRSPRSRPLLLLLLLLGACGAAGRSPEPGRLGP
HAQLTRVPRSPPAGRAEPGGGEDRQARGTEPGAPGPSPGPAPGPGEDGAPAAGYRRWERA
APLAGVASRAQVSLISTSFVLKGDATHNQAMVHWTGENSSVILILTKYYHADMGKVLESS
LWRSSDFGTSYTKLTLQPGVTTVIDNFYICPTNKRKVILVSSSLSDRDQSLFLSADEGAT
FQKQPIPFFVETLIFHPKEEDKVLAYTKESKLYVSSDLGKKWTLLQERVTKDHVFWSVSG
VDADPDLVHVEAQDLGGDFRYVTCAIHNCSEKMLTAPFAGPIDHGSLTVQDDYIFFKATS
ANQTKYYVSYRRNEFVLMKLPKYALPKDLQIISTDESQVFVAVQEWYQMDTYNLYQSDPR
GVRYALVLQDVRSSRQAEESVLIDILEVRGVKGVFLANQKIDGKVMTLITYNKGRDWDYL
RPPSMDMNGKPTNCKPPDCHLHLHLRWADNPYVSGTVHTKDTAPGLIMGAGNLGSQLVEY
KEEMYITSDCGHTWRQVFEEEHHILYLDHGGVIVAIKDTSIPLKILKFSVDEGLTWSTHN
FTSTSVFVDGLLSEPGDETLVMTVFGHISFRSDWELVKVDFRPSFSRQCGEEDYSSWELS
NLQGDRCIMGQQRSFRKRKSTSWCIKGRSFTSALTSRVCECRDSDFLCDYGFERSSSSES
STNKCSANFWFNPLSPPDDCALGQTYTSSLGYRKVVSNVCEGGVDMQQSQVQLQCPLTPP
RGLQVSIQGEAVAVRPGEDVLFVVRQEQGDVLTTKYQVDLGDGFKAMYVNLTLTGEPIRH
RYESPGIYRVSVRAENTAGHDEAVLFVQVNSPLQALYLEVVPVIGLNQEVNLTAVLLPLN
PNLTVFYWWIGHSLQPLLSLDNSVTTRFSDTGDVRVTVQAACGNSVLQDSRVLRVLDQFQ
VMPLQFSKELDAYNPNTPEWREDVGLVVTRLLSKETSVPQELLVTVVKPGLPTLADLYVL
LPPPRPTRKRSLSSDKRLAAIQQVLNAQKISFLLRGGVRVLVALRDTGTGAEQLGGGGGY
WAVVVLFVIGLFAAGAFILYKFKRKRPGRTVYAQMHNEKEQEMTSPVSHSEDVQGAVQGN
HSGVVLSINSREMHSYLVS
Function
The heterodimer formed by NGFR and SORCS2 functions as receptor for the precursor forms of NGF (proNGF) and BDNF (proBDNF). ProNGF and proBDNF binding both promote axon growth cone collapse (in vitro). Plays a role in the regulation of dendritic spine density in hippocampus neurons. Required for normal neurite branching and extension in response to BDNF. Plays a role in BDNF-dependent hippocampal synaptic plasticity. Together with NGFR and NTRK2, is required both for BDNF-mediated synaptic long-term depression and long-term potentiation. ProNGF binding promotes dissociation of TRIO from the heterodimer, which leads to inactivation of RAC1 and/or RAC2 and subsequent reorganization of the actin cytoskeleton. Together with the retromer complex subunit VPS35, required for normal expression of GRIN2A at synapses and dendritic cell membranes. Required for normal expression of the amino acid transporter SLC1A1 at the cell membrane, and thereby contributes to protect cells against oxidative stress; [SorCS2 122 kDa chain]: Does not promote Schwann cell apoptosis in response to proBDNF; SorCS2 104 kDa chain and SorCS2 18 kDa chain together promote Schwann cell apoptosis in response to proBDNF.
Tissue Specificity
Detected on neurons in the caudate region . Detected on neurons in the hippocampus (at protein level) . Highly expressed in brain and kidney. Detected at low levels in heart, liver, small intestine, skeletal muscle and thymus .

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Bipolar disorder DISAM7J2 Definitive Biomarker [1]
Alcohol withdrawal DIS7INCX Strong Biomarker [2]
Alzheimer disease DISF8S70 Strong Genetic Variation [3]
Anorexia nervosa cachexia DISFO5RQ Strong Genetic Variation [4]
Attention deficit hyperactivity disorder DISL8MX9 Strong Genetic Variation [5]
Epilepsy DISBB28L Strong Biomarker [6]
Huntington disease DISQPLA4 Strong Biomarker [7]
Myocardial infarction DIS655KI Strong Genetic Variation [8]
Sickle-cell anaemia DIS5YNZB Strong Genetic Variation [9]
Acute myelogenous leukaemia DISCSPTN Limited Genetic Variation [10]
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⏷ Show the Full List of 10 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
13 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate decreases the expression of VPS10 domain-containing receptor SorCS2 (SORCS2). [11]
Tretinoin DM49DUI Approved Tretinoin increases the expression of VPS10 domain-containing receptor SorCS2 (SORCS2). [13]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide affects the expression of VPS10 domain-containing receptor SorCS2 (SORCS2). [15]
Testosterone DM7HUNW Approved Testosterone increases the expression of VPS10 domain-containing receptor SorCS2 (SORCS2). [16]
Triclosan DMZUR4N Approved Triclosan increases the expression of VPS10 domain-containing receptor SorCS2 (SORCS2). [17]
Panobinostat DM58WKG Approved Panobinostat decreases the expression of VPS10 domain-containing receptor SorCS2 (SORCS2). [18]
Urethane DM7NSI0 Phase 4 Urethane decreases the expression of VPS10 domain-containing receptor SorCS2 (SORCS2). [19]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of VPS10 domain-containing receptor SorCS2 (SORCS2). [20]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 decreases the expression of VPS10 domain-containing receptor SorCS2 (SORCS2). [21]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 decreases the expression of VPS10 domain-containing receptor SorCS2 (SORCS2). [22]
Trichostatin A DM9C8NX Investigative Trichostatin A decreases the expression of VPS10 domain-containing receptor SorCS2 (SORCS2). [24]
Formaldehyde DM7Q6M0 Investigative Formaldehyde increases the expression of VPS10 domain-containing receptor SorCS2 (SORCS2). [25]
Sulforaphane DMQY3L0 Investigative Sulforaphane decreases the expression of VPS10 domain-containing receptor SorCS2 (SORCS2). [26]
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⏷ Show the Full List of 13 Drug(s)
3 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Ciclosporin DMAZJFX Approved Ciclosporin decreases the methylation of VPS10 domain-containing receptor SorCS2 (SORCS2). [12]
Arsenic DMTL2Y1 Approved Arsenic affects the methylation of VPS10 domain-containing receptor SorCS2 (SORCS2). [14]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the methylation of VPS10 domain-containing receptor SorCS2 (SORCS2). [23]
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References

1 Genetics of long-term treatment outcome in bipolar disorder.Prog Neuropsychopharmacol Biol Psychiatry. 2016 Feb 4;65:17-24. doi: 10.1016/j.pnpbp.2015.08.008. Epub 2015 Aug 20.
2 Reduced Alcohol Seeking and Withdrawal Symptoms in Mice Lacking the BDNF Receptor SorCS2.Front Pharmacol. 2019 May 17;10:499. doi: 10.3389/fphar.2019.00499. eCollection 2019.
3 Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP).Transl Psychiatry. 2013 May 14;3(5):e256. doi: 10.1038/tp.2013.13.
4 Significant Locus and Metabolic Genetic Correlations Revealed in Genome-Wide Association Study of Anorexia Nervosa.Am J Psychiatry. 2017 Sep 1;174(9):850-858. doi: 10.1176/appi.ajp.2017.16121402. Epub 2017 May 12.
5 New suggestive genetic loci and biological pathways for attention function in adult attention-deficit/hyperactivity disorder.Am J Med Genet B Neuropsychiatr Genet. 2015 Sep;168(6):459-470. doi: 10.1002/ajmg.b.32341. Epub 2015 Jul 14.
6 SorCS2 Controls Functional Expression of Amino Acid Transporter EAAT3 and Protects Neurons from Oxidative Stress and Epilepsy-Induced Pathology.Cell Rep. 2019 Mar 5;26(10):2792-2804.e6. doi: 10.1016/j.celrep.2019.02.027.
7 SorCS2-mediated NR2A trafficking regulates motor deficits in Huntington's disease.JCI Insight. 2017 May 4;2(9):e88995. doi: 10.1172/jci.insight.88995. eCollection 2017 May 4.
8 Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations.Atherosclerosis. 2011 Mar;215(1):145-52. doi: 10.1016/j.atherosclerosis.2010.12.005. Epub 2010 Dec 15.
9 Genome-wide association study of erythrocyte density in sickle cell disease patients.Blood Cells Mol Dis. 2017 Jun;65:60-65. doi: 10.1016/j.bcmd.2017.05.005. Epub 2017 May 13.
10 Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
11 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
12 Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
13 Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
14 Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
15 Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
16 The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
17 Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
18 A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
19 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
20 Inter- and intra-laboratory study to determine the reproducibility of toxicogenomics datasets. Toxicology. 2011 Nov 28;290(1):50-8.
21 Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
22 Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
23 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.
24 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.
25 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
26 Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.