Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6RPMRM)

• DOT Name: G-protein-signaling modulator 2 (GPSM2)
• Synonyms: Mosaic protein LGN
• Gene Name: GPSM2
• Related Disease:
  Chudley-McCullough syndrome
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Familial adenomatous polyposis
  Hepatocellular carcinoma
  Neoplasm
  Renal cell carcinoma
  Hepatitis B virus infection
  Hearing loss, autosomal recessive
  Nervous system disease
  Type-1/2 diabetes
  Sensorineural hearing loss disorder
• UniProt ID: GPSM2_HUMAN
• PDB ID: 3SF4; 4WND; 4WNE; 4WNF; 4WNG; 5A6C; 6HC2
• Pfam ID: PF02188 ; PF13374 ; PF13424 ; PF13176 ; PF13181
• Sequence:
  MEENLISMREDHSFHVRYRMEASCLELALEGERLCKSGDCRAGVSFFEAAVQVGTEDLKT
  LSAIYSQLGNAYFYLHDYAKALEYHHHDLTLARTIGDQLGEAKASGNLGNTLKVLGNFDE
  AIVCCQRHLDISRELNDKVGEARALYNLGNVYHAKGKSFGCPGPQDVGEFPEEVRDALQA
  AVDFYEENLSLVTALGDRAAQGRAFGNLGNTHYLLGNFRDAVIAHEQRLLIAKEFGDKAA
  ERRAYSNLGNAYIFLGEFETASEYYKKTLLLARQLKDRAVEAQSCYSLGNTYTLLQDYEK
  AIDYHLKHLAIAQELNDRIGEGRACWSLGNAYTALGNHDQAMHFAEKHLEISREVGDKSG
  ELTARLNLSDLQMVLGLSYSTNNSIMSENTEIDSSLNGVRPKLGRRHSMENMELMKLTPE
  KVQNWNSEILAKQKPLIAKPSAKLLFVNRLKGKKYKTNSSTKVLQDASNSIDHRIPNSQR
  KISADTIGDEGFFDLLSRFQSNRMDDQRCCLQEKNCHTASTTTSSTPPKMMLKTSSVPVV
  SPNTDEFLDLLASSQSRRLDDQRASFSNLPGLRLTQNSQSVLSHLMTNDNKEADEDFFDI
  LVKCQGSRLDDQRCAPPPATTKGPTVPDEDFFSLILRSQGKRMDEQRVLLQRDQNRDTDF
  GLKDFLQNNALLEFKNSGKKSADH
• Function: Plays an important role in mitotic spindle pole organization via its interaction with NUMA1. Required for cortical dynein-dynactin complex recruitment during metaphase. Plays a role in metaphase spindle orientation. Also plays an important role in asymmetric cell divisions. Has guanine nucleotide dissociation inhibitor (GDI) activity towards G(i) alpha proteins, such as GNAI1 and GNAI3, and thereby regulates their activity.
• Tissue Specificity: Ubiquitously expressed.
• Reactome Pathway: G alpha (i) signalling events (R-HSA-418594)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chudley-McCullough syndrome	DISJHGAP	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[4]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[4]
Hepatitis B virus infection	DISLQ2XY	moderate	Altered Expression	[6]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[7]
Nervous system disease	DISJ7GGT	Disputed	Genetic Variation	[8]
Type-1/2 diabetes	DISIUHAP	Disputed	Biomarker	[9]
Sensorineural hearing loss disorder	DISJV45Z	Limited	Genetic Variation	[8]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	G-protein-signaling modulator 2 (GPSM2) affects the response to substance of Doxorubicin.	[31]
Etoposide	DMNH3PG	Approved	G-protein-signaling modulator 2 (GPSM2) affects the response to substance of Etoposide.	[31]
Mitomycin	DMH0ZJE	Approved	G-protein-signaling modulator 2 (GPSM2) affects the response to substance of Mitomycin.	[31]
Topotecan	DMP6G8T	Approved	G-protein-signaling modulator 2 (GPSM2) affects the response to substance of Topotecan.	[31]
Vinblastine	DM5TVS3	Approved	G-protein-signaling modulator 2 (GPSM2) affects the response to substance of Vinblastine.	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of G-protein-signaling modulator 2 (GPSM2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of G-protein-signaling modulator 2 (GPSM2).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of G-protein-signaling modulator 2 (GPSM2).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of G-protein-signaling modulator 2 (GPSM2).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of G-protein-signaling modulator 2 (GPSM2).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of G-protein-signaling modulator 2 (GPSM2).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of G-protein-signaling modulator 2 (GPSM2).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of G-protein-signaling modulator 2 (GPSM2).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of G-protein-signaling modulator 2 (GPSM2).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of G-protein-signaling modulator 2 (GPSM2).	[18]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of G-protein-signaling modulator 2 (GPSM2).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of G-protein-signaling modulator 2 (GPSM2).	[20]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of G-protein-signaling modulator 2 (GPSM2).	[19]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of G-protein-signaling modulator 2 (GPSM2).	[21]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of G-protein-signaling modulator 2 (GPSM2).	[22]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of G-protein-signaling modulator 2 (GPSM2).	[23]
Promegestone	DMK4S8I	Approved	Promegestone increases the expression of G-protein-signaling modulator 2 (GPSM2).	[24]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of G-protein-signaling modulator 2 (GPSM2).	[25]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of G-protein-signaling modulator 2 (GPSM2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of G-protein-signaling modulator 2 (GPSM2).	[27]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of G-protein-signaling modulator 2 (GPSM2).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of G-protein-signaling modulator 2 (GPSM2).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of G-protein-signaling modulator 2 (GPSM2).	[30]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of G-protein-signaling modulator 2 (GPSM2).	[15]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of G-protein-signaling modulator 2 (GPSM2).	[18]

References

• [1] 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.
• [2] Genes linked to energy metabolism and immunoregulatory mechanisms are associated with subcutaneous adipose tissue distribution in HIV-infected men.Pharmacogenet Genomics. 2011 Dec;21(12):798-807. doi: 10.1097/FPC.0b013e32834b68f9.
• [3] Critical roles of LGN/GPSM2 phosphorylation by PBK/TOPK in cell division of breast cancer cells.Genes Chromosomes Cancer. 2010 Oct;49(10):861-72. doi: 10.1002/gcc.20795.
• [4] Identification of key genes and pathways in renal cell carcinoma through expression profiling data.Kidney Blood Press Res. 2015;40(3):288-97. doi: 10.1159/000368504. Epub 2015 May 27.
• [5] Familial amyloid polyneuropathy associated with transthyretin Gly42 mutation: a quantitative light and electron microscopic study of the peripheral nervous system.Acta Neuropathol. 1995;90(5):516-25. doi: 10.1007/BF00294814.
• [6] High expression of G-protein signaling modulator 2 in hepatocellular carcinoma facilitates tumor growth and metastasis by activating the PI3K/AKT signaling pathway.Tumour Biol. 2017 Mar;39(3):1010428317695971. doi: 10.1177/1010428317695971.
• [7] Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [8] Defective Gpsm2/G(i3) signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome.Nat Commun. 2017 Apr 7;8:14907. doi: 10.1038/ncomms14907.
• [9] Endogenous ornithine decarboxylase/polyamine system mediated the antagonist role of insulin/PEG-CMCS preconditioning against heart ischemia/reperfusion injury in diabetes mellitus.Int J Nanomedicine. 2018 Apr 23;13:2507-2520. doi: 10.2147/IJN.S160848. eCollection 2018.
• [10] 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.
• [11] 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.
• [12] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [16] 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.
• [17] 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.
• [18] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [19] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [20] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [21] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [22] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [23] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [24] Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition. Proc Natl Acad Sci U S A. 2004 May 4;101(18):7199-204.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] 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.
• [27] 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.
• [28] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [29] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [30] 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.
• [31] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.