Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8CLQ1W)

DOT Name	Stromal interaction molecule 1 (STIM1)
Gene Name	STIM1
Related Disease	Adult glioblastoma ( ) Amelogenesis imperfecta ( ) Ectodermal dysplasia ( ) Glioblastoma multiforme ( ) Myopathy, tubular aggregate, 1 ( ) Tubular aggregate myopathy ( ) Advanced cancer ( ) Alzheimer disease ( ) Autoimmune disease ( ) B-cell neoplasm ( ) Breast cancer ( ) Breast carcinoma ( ) Breast neoplasm ( ) Cardiac failure ( ) Cervical cancer ( ) Cervical carcinoma ( ) Childhood kidney Wilms tumor ( ) Coagulation defect ( ) Colorectal carcinoma ( ) Combined immunodeficiency due to STIM1 deficiency ( ) Congestive heart failure ( ) Gastric cancer ( ) Hepatocellular carcinoma ( ) Immune system disorder ( ) Juvenile idiopathic arthritis ( ) Lung cancer ( ) Lung neoplasm ( ) Malignant rhabdoid tumour ( ) Metastatic malignant neoplasm ( ) Narcolepsy ( ) Non-small-cell lung cancer ( ) Prostate carcinoma ( ) Rhabdomyosarcoma ( ) Stomach cancer ( ) Wilms tumor ( ) High blood pressure ( ) Immunodeficiency ( ) Lymphoproliferative syndrome ( ) Melanoma ( ) Prostate cancer ( ) Severe combined immunodeficiency ( ) Stormorken syndrome ( ) Chorea-acanthocytosis ( ) Myopathy ( ) Plasma cell myeloma ( ) Thrombocytopenia ( )
UniProt ID	STIM1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	2K60; 2MAJ; 2MAK; 3TEQ; 4O9B; 6YEL
Pfam ID	PF07647 ; PF16533
Sequence	MDVCVRLALWLLWGLLLHQGQSLSHSHSEKATGTSSGANSEESTAAEFCRIDKPLCHSED EKLSFEAVRNIHKLMDDDANGDVDVEESDEFLREDLNYHDPTVKHSTFHGEDKLISVEDL WKAWKSSEVYNWTVDEVVQWLITYVELPQYEETFRKLQLSGHAMPRLAVTNTTMTGTVLK MTDRSHRQKLQLKALDTVLFGPPLLTRHNHLKDFMLVVSIVIGVGGCWFAYIQNRYSKEH MKKMMKDLEGLHRAEQSLHDLQERLHKAQEEHRTVEVEKVHLEKKLRDEINLAKQEAQRL KELREGTENERSRQKYAEEELEQVREALRKAEKELESHSSWYAPEALQKWLQLTHEVEVQ YYNIKKQNAEKQLLVAKEGAEKIKKKRNTLFGTFHVAHSSSLDDVDHKILTAKQALSEVT AALRERLHRWQQIEILCGFQIVNNPGIHSLVAALNIDPSWMGSTRPNPAHFIMTDDVDDM DEEIVSPLSMQSPSLQSSVRQRLTEPQHGLGSQRDLTHSDSESSLHMSDRQRVAPKPPQM SRAADEALNAMTSNGSHRLIEGVHPGSLVEKLPDSPALAKKALLALNHGLDKAHSLMELS PSAPPGGSPHLDSSRSHSPSSPDPDTPSPVGDSRALQASRNTRIPHLAGKKAVAEEDNGS IGEETDSSPGRKKFPLKIFKKPLKK
Function	Plays a role in mediating store-operated Ca(2+) entry (SOCE), a Ca(2+) influx following depletion of intracellular Ca(2+) stores. Acts as a Ca(2+) sensor in the endoplasmic reticulum via its EF-hand domain. Upon Ca(2+) depletion, translocates from the endoplasmic reticulum to the plasma membrane where it activates the Ca(2+) release-activated Ca(2+) (CRAC) channel subunit ORAI1. Involved in enamel formation. Activated following interaction with STIMATE, leading to promote STIM1 conformational switch.
Tissue Specificity	Ubiquitously expressed in various human primary cells and tumor cell lines.
KEGG Pathway	Calcium sig.ling pathway (hsa04020 ) Platelet activation (hsa04611 )
Reactome Pathway	Ion homeostasis (R-HSA-5578775 ) Antigen activates B Cell Receptor (BCR) leading to generation of second messengers (R-HSA-983695 ) Elevation of cytosolic Ca2+ levels (R-HSA-139853 )

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Amelogenesis imperfecta	DISGYR9E	Definitive	Genetic Variation	[2]
Ectodermal dysplasia	DISLRS4M	Definitive	Biomarker	[3]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Myopathy, tubular aggregate, 1	DISLKMBA	Definitive	Autosomal dominant	[4]
Tubular aggregate myopathy	DISC11WH	Definitive	Autosomal dominant	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[7]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[8]
B-cell neoplasm	DISVY326	Strong	Biomarker	[9]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[10]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[10]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[11]
Cardiac failure	DISDC067	Strong	Biomarker	[12]
Cervical cancer	DISFSHPF	Strong	Biomarker	[13]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[13]
Childhood kidney Wilms tumor	DIS0NMK3	Strong	Altered Expression	[14]
Coagulation defect	DIS9X3H6	Strong	Genetic Variation	[15]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[16]
Combined immunodeficiency due to STIM1 deficiency	DISULHPI	Strong	Autosomal recessive	[17]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[12]
Gastric cancer	DISXGOUK	Strong	Biomarker	[18]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[13]
Immune system disorder	DISAEGPH	Strong	Biomarker	[19]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[20]
Lung cancer	DISCM4YA	Strong	Biomarker	[21]
Lung neoplasm	DISVARNB	Strong	Biomarker	[21]
Malignant rhabdoid tumour	DIS46HZU	Strong	Biomarker	[22]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[23]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[24]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[25]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[26]
Rhabdomyosarcoma	DISNR7MS	Strong	Altered Expression	[27]
Stomach cancer	DISKIJSX	Strong	Biomarker	[18]
Wilms tumor	DISB6T16	Strong	Altered Expression	[14]
High blood pressure	DISY2OHH	moderate	Biomarker	[28]
Immunodeficiency	DIS093I0	moderate	Genetic Variation	[29]
Lymphoproliferative syndrome	DISMVL8O	moderate	Biomarker	[30]
Melanoma	DIS1RRCY	moderate	Biomarker	[31]
Prostate cancer	DISF190Y	moderate	Biomarker	[26]
Severe combined immunodeficiency	DIS6MF4Q	moderate	Altered Expression	[32]
Stormorken syndrome	DIS9US3H	Supportive	Autosomal dominant	[19]
Chorea-acanthocytosis	DISW1V6N	Limited	Altered Expression	[33]
Myopathy	DISOWG27	Limited	Genetic Variation	[34]
Plasma cell myeloma	DIS0DFZ0	Limited	Altered Expression	[35]
Thrombocytopenia	DISU61YW	Limited	Genetic Variation	[36]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Stromal interaction molecule 1 (STIM1).	[37]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Stromal interaction molecule 1 (STIM1).	[38]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Stromal interaction molecule 1 (STIM1).	[39]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Stromal interaction molecule 1 (STIM1).	[40]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Stromal interaction molecule 1 (STIM1).	[41]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Stromal interaction molecule 1 (STIM1).	[41]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Stromal interaction molecule 1 (STIM1).	[43]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Stromal interaction molecule 1 (STIM1).	[44]
USNIC ACID	DMGOURX	Investigative	USNIC ACID increases the expression of Stromal interaction molecule 1 (STIM1).	[46]
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⏷ Show the Full List of 9 Drug(s)

2 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 increases the methylation of Stromal interaction molecule 1 (STIM1).	[42]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Stromal interaction molecule 1 (STIM1).	[45]
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References

1	Suppression of STIM1 inhibits human glioblastoma cell proliferation and induces G0/G1 phase arrest.J Exp Clin Cancer Res. 2013 Apr 11;32(1):20. doi: 10.1186/1756-9966-32-20.
2	CRAC channels in dental enamel cells.Cell Calcium. 2018 Nov;75:14-20. doi: 10.1016/j.ceca.2018.07.012. Epub 2018 Aug 9.
3	Stim1 Regulates Enamel Mineralization and Ameloblast Modulation.J Dent Res. 2017 Nov;96(12):1422-1429. doi: 10.1177/0022034517719872. Epub 2017 Jul 21.
4	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.
5	Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
6	The distinct role of STIM1 and STIM2 in the regulation of store-operated Ca(2+) entry and cellular function.J Cell Physiol. 2019 Jun;234(6):8727-8739. doi: 10.1002/jcp.27532. Epub 2018 Oct 14.
7	STIM1 deficiency is linked to Alzheimer's disease and triggers cell death in SH-SY5Y cells by upregulation of L-type voltage-operated Ca(2+) entry.J Mol Med (Berl). 2018 Oct;96(10):1061-1079. doi: 10.1007/s00109-018-1677-y. Epub 2018 Aug 7.
8	Structural and Mechanistic Insights of CRAC Channel as a Drug Target in Autoimmune Disorder.Curr Drug Targets. 2020;21(1):55-75. doi: 10.2174/1389450120666190926150258.
9	Calcium Independent Effect of Orai1 and STIM1 in Non-Hodgkin B Cell Lymphoma Dissemination.Cancers (Basel). 2018 Oct 26;10(11):402. doi: 10.3390/cancers10110402.
10	miRNA-dependent regulation of STIM1 expression in breast cancer.Sci Rep. 2019 Sep 10;9(1):13076. doi: 10.1038/s41598-019-49629-5.
11	sp(2) -Iminosugar -glucosidase inhibitor 1-C-octyl-2-oxa-3-oxocastanospermine specifically affected breast cancer cell migration through Stim1, 1-integrin, and FAK signaling pathways.J Cell Physiol. 2017 Dec;232(12):3631-3640. doi: 10.1002/jcp.25832. Epub 2017 Apr 25.
12	Enhanced store-operated Ca(2+) influx and ORAI1 expression in ventricular fibroblasts from human failing heart.Biol Open. 2017 Mar 15;6(3):326-332. doi: 10.1242/bio.022632.
13	Suppression of stromal interaction molecule 1 inhibits SMMC7721 hepatocellular carcinoma cell proliferation by inducing cell cycle arrest.Biotechnol Appl Biochem. 2015 Jan-Feb;62(1):107-11. doi: 10.1002/bab.1245. Epub 2014 Dec 15.
14	WT1/EGR1-mediated control of STIM1 expression and function in cancer cells.Front Biosci (Landmark Ed). 2011 Jun 1;16(7):2402-15. doi: 10.2741/3862.
15	Complex phenotypes associated with STIM1 mutations in both coiled coil and EF-hand domains.Neuromuscul Disord. 2017 Sep;27(9):861-872. doi: 10.1016/j.nmd.2017.05.002. Epub 2017 May 4.
16	Silencing Heat Shock Protein 27 Inhibits the Progression and Metastasis of Colorectal Cancer (CRC) by Maintaining the Stability of Stromal Interaction Molecule 1 (STIM1) Proteins.Cells. 2018 Dec 10;7(12):262. doi: 10.3390/cells7120262.
17	STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity. N Engl J Med. 2009 May 7;360(19):1971-80. doi: 10.1056/NEJMoa0900082.
18	Overexpression of stromal interaction molecule 1 may promote epithelialmesenchymal transition and indicate poor prognosis in gastric cancer.Mol Med Rep. 2017 Jul;16(1):151-158. doi: 10.3892/mmr.2017.6607. Epub 2017 May 18.
19	Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis. Proc Natl Acad Sci U S A. 2014 Mar 18;111(11):4197-202. doi: 10.1073/pnas.1312520111. Epub 2014 Mar 3.
20	Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets.Arthritis Rheum. 2009 Jul;60(7):2113-23. doi: 10.1002/art.24534.
21	Elevated expression of STIM1 is involved in lung tumorigenesis.Oncotarget. 2016 Dec 27;7(52):86584-86593. doi: 10.18632/oncotarget.13359.
22	Exon structure and promoter identification of STIM1 (alias GOK), a human gene causing growth arrest of the human tumor cell lines G401 and RD.Cytogenet Cell Genet. 1999;86(3-4):214-8. doi: 10.1159/000015341.
23	STIM1 silencing inhibits the migration and invasion of A549 cells.Mol Med Rep. 2017 Sep;16(3):3283-3289. doi: 10.3892/mmr.2017.7010. Epub 2017 Jul 15.
24	Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
25	Knockdown of STIM1 expression inhibits non-small-cell lung cancer cell proliferation in vitro and in nude mouse xenografts.Bioengineered. 2019 Dec;10(1):425-436. doi: 10.1080/21655979.2019.1669518.
26	Suppression of STIM1 inhibits the migration and invasion of human prostate cancer cells and is associated with PI3K/Akt signaling inactivation.Oncol Rep. 2017 Nov;38(5):2629-2636. doi: 10.3892/or.2017.5961. Epub 2017 Sep 18.
27	Store-operated Ca(2+) entry in rhabdomyosarcoma cells.Biochem Biophys Res Commun. 2016 Aug 12;477(1):129-136. doi: 10.1016/j.bbrc.2016.06.032. Epub 2016 Jun 10.
28	TRPP2 associates with STIM1 to regulate cerebral vasoconstriction and enhance high salt intake-induced hypertensive cerebrovascular spasm.Hypertens Res. 2019 Dec;42(12):1894-1904. doi: 10.1038/s41440-019-0324-5. Epub 2019 Sep 20.
29	Missense mutation in immunodeficient patients shows the multifunctional roles of coiled-coil domain 3 (CC3) in STIM1 activation.Proc Natl Acad Sci U S A. 2015 May 12;112(19):6206-11. doi: 10.1073/pnas.1418852112. Epub 2015 Apr 27.
30	Stromal Interaction Molecule Deficiency in T Cells Promotes Spontaneous Follicular Helper T Cell Development and Causes Type 2 Immune Disorders.J Immunol. 2019 May 1;202(9):2616-2627. doi: 10.4049/jimmunol.1700610. Epub 2019 Mar 25.
31	STIM1- and Orai1-mediated Ca(2+) oscillation orchestrates invadopodium formation and melanoma invasion.J Cell Biol. 2014 Nov 24;207(4):535-48. doi: 10.1083/jcb.201407082. Epub 2014 Nov 17.
32	Combined immunodeficiency due to a homozygous mutation in ORAI1 that deletes the C-terminus that interacts with STIM 1.Clin Immunol. 2016 May;166-167:100-2. doi: 10.1016/j.clim.2016.03.012. Epub 2016 Apr 6.
33	Inhibition of Lithium Sensitive Orai1/ STIM1 Expression and Store Operated Ca2+ Entry in Chorea-Acanthocytosis Neurons by NF-B Inhibitor Wogonin.Cell Physiol Biochem. 2018;51(1):278-289. doi: 10.1159/000495229. Epub 2018 Nov 19.
34	Stormorken Syndrome: A Rare Cause of Myopathy With Tubular Aggregates and Dystrophic Features.J Child Neurol. 2019 May;34(6):321-324. doi: 10.1177/0883073819829389. Epub 2019 Feb 14.
35	Orai1 and Stim1 Mediate the Majority of Store-Operated Calcium Entry in Multiple Myeloma and Have Strong Implications for Adverse Prognosis.Cell Physiol Biochem. 2018;48(6):2273-2285. doi: 10.1159/000492645. Epub 2018 Aug 16.
36	York platelet syndrome is a CRAC channelopathy due to gain-of-function mutations in STIM1.Mol Genet Metab. 2015 Mar;114(3):474-82. doi: 10.1016/j.ymgme.2014.12.307. Epub 2014 Dec 24.
37	Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
38	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.
39	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.
40	Inhibition of store-operated Ca(2+) channels prevent ethanol-induced intracellular Ca(2+) increase and cell injury in a human hepatoma cell line. Toxicol Lett. 2012 Feb 5;208(3):254-61. doi: 10.1016/j.toxlet.2011.11.007. Epub 2011 Nov 17.
41	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.
42	Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
43	Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
44	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.
45	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.
46	Endoplasmic Reticulum Stress and Store-Operated Calcium Entry Contribute to Usnic Acid-Induced Toxicity in Hepatic Cells. Toxicol Sci. 2015 Jul;146(1):116-26. doi: 10.1093/toxsci/kfv075. Epub 2015 Apr 13.