Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7MYGYO)

DOT Name E3 ubiquitin-protein ligase SH3RF1 (SH3RF1)
Synonyms EC 2.3.2.27; Plenty of SH3s; Protein POSH; RING finger protein 142; RING-type E3 ubiquitin transferase SH3RF1; SH3 domain-containing RING finger protein 1; SH3 multiple domains protein 2
Gene Name SH3RF1
Related Disease
Alzheimer disease ( )
Breast neoplasm ( )
Lung adenocarcinoma ( )
Lung cancer ( )
Lung carcinoma ( )
Frontotemporal dementia ( )
Hereditary breast carcinoma ( )
Pick disease ( )
Parkinson disease ( )
Stroke ( )
UniProt ID
SH3R1_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
7NZC; 7NZD
EC Number
2.3.2.27
Pfam ID
PF00018 ; PF14604 ; PF13923
Sequence
MDESALLDLLECPVCLERLDASAKVLPCQHTFCKRCLLGIVGSRNELRCPECRTLVGSGV
EELPSNILLVRLLDGIKQRPWKPGPGGGSGTNCTNALRSQSSTVANCSSKDLQSSQGGQQ
PRVQSWSPPVRGIPQLPCAKALYNYEGKEPGDLKFSKGDIIILRRQVDENWYHGEVNGIH
GFFPTNFVQIIKPLPQPPPQCKALYDFEVKDKEADKDCLPFAKDDVLTVIRRVDENWAEG
MLADKIGIFPISYVEFNSAAKQLIEWDKPPVPGVDAGECSSAAAQSSTAPKHSDTKKNTK
KRHSFTSLTMANKSSQASQNRHSMEISPPVLISSSNPTAAARISELSGLSCSAPSQVHIS
TTGLIVTPPPSSPVTTGPSFTFPSDVPYQAALGTLNPPLPPPPLLAATVLASTPPGATAA
AAAAGMGPRPMAGSTDQIAHLRPQTRPSVYVAIYPYTPRKEDELELRKGEMFLVFERCQD
GWFKGTSMHTSKIGVFPGNYVAPVTRAVTNASQAKVPMSTAGQTSRGVTMVSPSTAGGPA
QKLQGNGVAGSPSVVPAAVVSAAHIQTSPQAKVLLHMTGQMTVNQARNAVRTVAAHNQER
PTAAVTPIQVQNAAGLSPASVGLSHHSLASPQPAPLMPGSATHTAAISISRASAPLACAA
AAPLTSPSITSASLEAEPSGRIVTVLPGLPTSPDSASSACGNSSATKPDKDSKKEKKGLL
KLLSGASTKRKPRVSPPASPTLEVELGSAELPLQGAVGPELPPGGGHGRAGSCPVDGDGP
VTTAVAGAALAQDAFHRKASSLDSAVPIAPPPRQACSSLGPVLNESRPVVCERHRVVVSY
PPQSEAELELKEGDIVFVHKKREDGWFKGTLQRNGKTGLFPGSFVENI
Function
Has E3 ubiquitin-protein ligase activity. In the absence of an external substrate, it can catalyze self-ubiquitination. Stimulates ubiquitination of potassium channel KCNJ1, enhancing it's dynamin-dependent and clathrin-independent endocytosis. Acts as a scaffold protein that coordinates with MAPK8IP1/JIP1 in organizing different components of the JNK pathway, including RAC1 or RAC2, MAP3K11/MLK3 or MAP3K7/TAK1, MAP2K7/MKK7, MAPK8/JNK1 and/or MAPK9/JNK2 into a functional multiprotein complex to ensure the effective activation of the JNK signaling pathway. Regulates the differentiation of CD4(+) and CD8(+) T-cells and promotes T-helper 1 (Th1) cell differentiation. Regulates the activation of MAPK8/JNK1 and MAPK9/JNK2 in CD4(+) T-cells and the activation of MAPK8/JNK1 in CD8(+) T-cells. Plays a crucial role in the migration of neocortical neurons in the developing brain. Controls proper cortical neuronal migration and the formation of proximal cytoplasmic dilation in the leading process (PCDLP) in migratory neocortical neurons by regulating the proper localization of activated RAC1 and F-actin assembly; (Microbial infection) Plays an essential role in the targeting of HIV-1 Gag to the plasma membrane, this function is dependent on it's RING domain, and hence it's E3 ligase activity.
Reactome Pathway
Antigen processing (R-HSA-983168 )
RHOV GTPase cycle (R-HSA-9013424 )

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Alzheimer disease DISF8S70 Strong Genetic Variation [1]
Breast neoplasm DISNGJLM Strong Genetic Variation [2]
Lung adenocarcinoma DISD51WR Strong Genetic Variation [3]
Lung cancer DISCM4YA Strong Genetic Variation [4]
Lung carcinoma DISTR26C Strong Genetic Variation [4]
Frontotemporal dementia DISKYHXL moderate Biomarker [5]
Hereditary breast carcinoma DISAEZT5 moderate Genetic Variation [6]
Pick disease DISP6X50 moderate Biomarker [5]
Parkinson disease DISQVHKL Limited Biomarker [7]
Stroke DISX6UHX Limited Biomarker [8]
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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
19 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 E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [9]
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [10]
Tretinoin DM49DUI Approved Tretinoin increases the expression of E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [11]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [12]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [13]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [14]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [15]
Estradiol DMUNTE3 Approved Estradiol decreases the expression of E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [16]
Quercetin DM3NC4M Approved Quercetin increases the expression of E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [18]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [19]
Azathioprine DMMZSXQ Approved Azathioprine increases the expression of E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [20]
SNDX-275 DMH7W9X Phase 3 SNDX-275 decreases the expression of E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [21]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [22]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 increases the expression of E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [23]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide increases the expression of E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [24]
Trichostatin A DM9C8NX Investigative Trichostatin A decreases the expression of E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [21]
Formaldehyde DM7Q6M0 Investigative Formaldehyde decreases the expression of E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [25]
Milchsaure DM462BT Investigative Milchsaure increases the expression of E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [26]
Coumestrol DM40TBU Investigative Coumestrol decreases the expression of E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [28]
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⏷ Show the Full List of 19 Drug(s)
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Arsenic DMTL2Y1 Approved Arsenic affects the methylation of E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [17]
Coumarin DM0N8ZM Investigative Coumarin increases the phosphorylation of E3 ubiquitin-protein ligase SH3RF1 (SH3RF1). [27]
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References

1 Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.Mol Psychiatry. 2016 Nov;21(11):1608-1612. doi: 10.1038/mp.2015.218. Epub 2016 Feb 2.
2 A novel HER2-positive breast cancer phenotype arising from germline TP53 mutations.J Med Genet. 2010 Nov;47(11):771-4. doi: 10.1136/jmg.2010.078113. Epub 2010 Aug 30.
3 Expression profiling of ubiquitin-related genes in LKB1 mutant lung adenocarcinoma.Sci Rep. 2018 Sep 5;8(1):13221. doi: 10.1038/s41598-018-31592-2.
4 Imputation-based association analyses identify new lung cancer susceptibility variants in CDK6 and SH3RF1 and their interactions with smoking in Chinese populations.Carcinogenesis. 2013 Sep;34(9):2010-6. doi: 10.1093/carcin/bgt145. Epub 2013 May 3.
5 The pro-apoptotic JNK scaffold POSH/SH3RF1 mediates CHMP2BIntron5-associated toxicity in animal models of frontotemporal dementia.Hum Mol Genet. 2018 Apr 15;27(8):1382-1395. doi: 10.1093/hmg/ddy048.
6 A genome wide meta-analysis study for identification of common variation associated with breast cancer prognosis.PLoS One. 2014 Dec 19;9(12):e101488. doi: 10.1371/journal.pone.0101488. eCollection 2014.
7 Proapoptotic Nix activates the JNK pathway by interacting with POSH and mediates death in a Parkinson disease model.J Biol Chem. 2007 Jan 12;282(2):1288-95. doi: 10.1074/jbc.M607038200. Epub 2006 Nov 9.
8 TAT-PEP Enhanced Neurobehavioral Functional Recovery by Facilitating Axonal Regeneration and Corticospinal Tract Projection After Stroke.Mol Neurobiol. 2018 Jan;55(1):652-667. doi: 10.1007/s12035-016-0301-9. Epub 2016 Dec 16.
9 Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
10 Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
11 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.
12 Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
13 Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
14 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
15 Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
16 High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
17 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.
18 Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
19 Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
20 A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
21 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.
22 Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
23 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.
24 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
25 Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
26 Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
27 Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
28 Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.