Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUXSHH7)

• DOT Name: Transmembrane emp24 domain-containing protein 10 (TMED10)
• Synonyms: Protein TMED10; 21 kDa transmembrane-trafficking protein; S31I125; S31III125; Tmp-21-I; Transmembrane protein Tmp21; p23; p24 family protein delta-1; p24delta1; p24delta
• Gene Name: TMED10
• Related Disease:
  Cryptosporidium infection
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Castration-resistant prostate carcinoma
  Childhood acute lymphoblastic leukemia
  Fibrosarcoma
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Intrahepatic cholestasis of pregnancy
  Lung adenocarcinoma
  Lyme disease
  Neoplasm
  Neoplasm of esophagus
  Parkinson disease
  Prostate cancer
  Prostate carcinoma
  Retinoblastoma
  Schizophrenia
  Systemic lupus erythematosus
  Acute myelogenous leukaemia
  Alzheimer disease
  Carcinoma
  Thyroid tumor
• UniProt ID: TMEDA_HUMAN
• Pfam ID: PF01105
• Sequence:
  MSGLSGPPARRGPFPLALLLLFLLGPRLVLAISFHLPINSRKCLREEIHKDLLVTGAYEI
  SDQSGGAGGLRSHLKITDSAGHILYSKEDATKGKFAFTTEDYDMFEVCFESKGTGRIPDQ
  LVILDMKHGVEAKNYEEIAKVEKLKPLEVELRRLEDLSESIVNDFAYMKKREEEMRDTNE
  STNTRVLYFSIFSMFCLIGLATWQVFYLRRFFKAKKLIE
• Function: Cargo receptor involved in protein vesicular trafficking and quality control in the endoplasmic reticulum (ER) and Golgi. The p24 protein family is a group of transmembrane proteins that bind coat protein complex I/COPI and coat protein complex II/COPII involved in vesicular trafficking between the membranes. Acts at the lumenal side for incorporation of secretory cargo molecules into transport vesicles and involved in vesicle coat formation at the cytoplasmic side. Mainly functions in the early secretory pathway and cycles between the ER, ER-Golgi intermediate compartment (ERGIC) and Golgi, mediating cargo transport through COPI and COPII-coated vesicles. In COPII vesicle-mediated anterograde transport, involved in the transport of GPI-anchored proteins by acting together with TMED2 as their cargo receptor; the function specifically implies SEC24C and SEC24D of the COPII vesicle coat and lipid raft-like microdomains of the ER. Recognizes GPI anchors structural remodeled in the ER by the GPI inositol-deacylase/PGAP1 and the metallophosphoesterase MPPE1/PGAP5. In COPI vesicle-mediated retrograde transport, involved in the biogenesis of COPI vesicles and vesicle coat recruitment. Involved in trafficking of amyloid beta A4 protein and soluble APP-beta release (independent from the modulation of gamma-secretase activity). Involved in the KDELR2-mediated retrograde transport of the toxin A subunit (CTX-A-K63)together with COPI and the COOH terminus of KDELR2. On Golgi membranes, acts as a primary receptor for ARF1-GDP, a GTP-binding protein involved in COPI-vesicle formation. Increases coatomer-dependent GTPase-activating activity of ARFGAP2 which mediates the hydrolysis of ARF1-bound GTP and therefore modulates protein trafficking from the Golgi apparatus. Involved in the exocytic trafficking of G protein-coupled receptors F2LR1/PAR2 (trypsin and tryspin-like enzyme receptor), OPRM1 (opioid receptor) and P2RY4 (UTD and UDP receptor) from the Golgi to the plasma membrane, thus contributing to receptor resensitization. In addition to its cargo receptor activity, may also act as a protein channel after oligomerization, facilitating the post-translational entry of leaderless cytoplasmic cargo into the ERGIC. Involved in the translocation into ERGIC, the vesicle entry and the secretion of leaderless cargos (lacking the secretion signal sequence), including the mature form of interleukin 1/IL-1 family members, the alpha-crystallin B chain HSPB5, the carbohydrate-binding proteins galectin-1/LGALS1 and galectin-3/LGALS3, the microtubule-associated protein Tau/MAPT, and the annexin A1/ANXA1; the translocation process is dependent on cargo protein unfolding and enhanced by chaperones HSP90AB1 and HSP90B1/GRP9. Could also associates with the presenilin-dependent gamma-secretase complex in order to regulate gamma-cleavages of the amyloid beta A4 protein to yield amyloid-beta 40/Abeta40.
• KEGG Pathway: Pathogenic Escherichia coli infection (hsa05130)
• Reactome Pathway:
  Cargo concentration in the ER (R-HSA-5694530)
  COPI-mediated anterograde transport (R-HSA-6807878)
  COPI-dependent Golgi-to-ER retrograde traffic (R-HSA-6811434)
  COPII-mediated vesicle transport (R-HSA-204005)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cryptosporidium infection	DISLBTU2	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[5]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[6]
Fibrosarcoma	DISWX7MU	Strong	Biomarker	[7]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[9]
Intrahepatic cholestasis of pregnancy	DISMHS5F	Strong	Genetic Variation	[10]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[11]
Lyme disease	DISO70G5	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Neoplasm of esophagus	DISOLKAQ	Strong	Genetic Variation	[13]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[14]
Prostate cancer	DISF190Y	Strong	Biomarker	[15]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[16]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[17]
Schizophrenia	DISSRV2N	Strong	Biomarker	[18]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[19]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[20]
Alzheimer disease	DISF8S70	Limited	Altered Expression	[14]
Carcinoma	DISH9F1N	Limited	Altered Expression	[21]
Thyroid tumor	DISLVKMD	Limited	Biomarker	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Transmembrane emp24 domain-containing protein 10 (TMED10).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Transmembrane emp24 domain-containing protein 10 (TMED10).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transmembrane emp24 domain-containing protein 10 (TMED10).	[23]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transmembrane emp24 domain-containing protein 10 (TMED10).	[24]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transmembrane emp24 domain-containing protein 10 (TMED10).	[25]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Transmembrane emp24 domain-containing protein 10 (TMED10).	[26]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Transmembrane emp24 domain-containing protein 10 (TMED10).	[27]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Transmembrane emp24 domain-containing protein 10 (TMED10).	[28]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Transmembrane emp24 domain-containing protein 10 (TMED10).	[29]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Transmembrane emp24 domain-containing protein 10 (TMED10).	[30]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Transmembrane emp24 domain-containing protein 10 (TMED10).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Transmembrane emp24 domain-containing protein 10 (TMED10).	[33]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Transmembrane emp24 domain-containing protein 10 (TMED10).	[34]

References

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• [4] High levels of Hsp90 cochaperone p23 promote tumor progression and poor prognosis in breast cancer by increasing lymph node metastases and drug resistance.Cancer Res. 2010 Nov 1;70(21):8446-56. doi: 10.1158/0008-5472.CAN-10-1590. Epub 2010 Sep 16.
• [5] Preclinical toxicology and toxicokinetic evaluation of ailanthone, a natural product against castration-resistant prostate cancer, in mice.Fitoterapia. 2019 Jul;136:104161. doi: 10.1016/j.fitote.2019.04.016. Epub 2019 Apr 30.
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• [7] Heterologous expression and characterization of the human R-ras gene product.Mol Cell Biol. 1987 Aug;7(8):2845-56. doi: 10.1128/mcb.7.8.2845-2856.1987.
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• [9] Depletion of three combined THOC5 mRNA export protein target genes synergistically induces human hepatocellular carcinoma cell death.Oncogene. 2016 Jul 21;35(29):3872-9. doi: 10.1038/onc.2015.433. Epub 2015 Nov 9.
• [10] Maternal susceptibility locus for obstetric cholestasis maps to chromosome region 2p13 in Finnish patients.Scand J Gastroenterol. 2001 Jul;36(7):766-70. doi: 10.1080/003655201300192049.
• [11] Docosahexaenoic Acid-mediated Inhibition of Heat Shock Protein 90-p23 Chaperone Complex and Downstream Client Proteins in Lung and Breast Cancer.Nutr Cancer. 2017 Jan;69(1):92-104. doi: 10.1080/01635581.2017.1247886. Epub 2016 Nov 23.
• [12] Molecular characterization and expression of p23 (OspC) from a North American strain of Borrelia burgdorferi.Infect Immun. 1993 Dec;61(12):5097-105. doi: 10.1128/iai.61.12.5097-5105.1993.
• [13] Germline sequence variants of the LZTS1 gene are associated with prostate cancer risk.Cancer Genet Cytogenet. 2002 Aug;137(1):1-7. doi: 10.1016/s0165-4608(02)00549-6.
• [14] Down-regulated TMED10 in Alzheimer disease induces autophagy via ATG4B activation.Autophagy. 2019 Sep;15(9):1495-1505. doi: 10.1080/15548627.2019.1586249. Epub 2019 Mar 19.
• [15] Identification of prognosis biomarkers of prostatic cancer in a cohort of 498 patients from TCGA.Curr Probl Cancer. 2019 Dec;43(6):100503. doi: 10.1016/j.currproblcancer.2019.100503. Epub 2019 Sep 20.
• [16] The co-chaperone p23 promotes prostate cancer motility and metastasis.Mol Oncol. 2015 Jan;9(1):295-308. doi: 10.1016/j.molonc.2014.08.014. Epub 2014 Sep 6.
• [17] pRb controls estrogen receptor alpha protein stability and activity.Oncotarget. 2013 Jun;4(6):875-83. doi: 10.18632/oncotarget.1036.
• [18] Abnormal ER quality control of neural GPI-anchored proteins via dysfunction in ER export processing in the frontal cortex of elderly subjects with schizophrenia.Transl Psychiatry. 2019 Jan 16;9(1):6. doi: 10.1038/s41398-018-0359-4.
• [19] Gene profiling involved in immature CD4+ T lymphocyte responsible for systemic lupus erythematosus.Mol Immunol. 2006 Mar;43(9):1497-507. doi: 10.1016/j.molimm.2005.07.039. Epub 2005 Sep 6.
• [20] del(2)(p23) as a sole abnormality in a case of acute myeloid leukemia.Cancer Genet Cytogenet. 2002 Apr 15;134(2):172-4. doi: 10.1016/s0165-4608(01)00631-8.
• [21] Function of HSP90 and p23 in the telomerase complex of thyroid tumors.Pathol Res Pract. 2003;199(9):573-9. doi: 10.1078/0344-0338-00464.
• [22] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [23] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [24] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [25] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [26] 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.
• [27] 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.
• [28] Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells. Int J Mol Sci. 2016 Dec 23;18(1):26. doi: 10.3390/ijms18010026.
• [29] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [30] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [31] 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.
• [32] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [33] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [34] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.