Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5S9KYM)

• DOT Name: Golgin subfamily A member 2 (GOLGA2)
• Synonyms: 130 kDa cis-Golgi matrix protein; GM130; GM130 autoantigen; Golgin-95
• Gene Name: GOLGA2
• Related Disease:
  Alzheimer disease
  Cerebellar ataxia
  Developmental delay with hypotonia, myopathy, and brain abnormalities
  Familial long QT syndrome
  Gastric cancer
  IgA nephropathy
  Isolated congenital microcephaly
  Long QT syndrome 2
  Lung cancer
  Lung carcinoma
  Male infertility
  Neoplasm
  Neuromuscular disease
  Prostate cancer
  Prostate carcinoma
  Stomach cancer
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
• UniProt ID: GOGA2_HUMAN
• PDB ID: 4REY; 6IW8; 6IWA; 6K06
• Pfam ID: PF19046 ; PF15070
• Sequence:
  MWPQPRLPPRPAMSEETRQSKLAAAKKKLREYQQRNSPGVPTGAKKKKKIKNGSNPETTT
  SGGCHSPEDTPKDNAATLQPSDDTVLPGGVPSPGASLTSMAASQNHDADNVPNLMDETKT
  FSSTESLRQLSQQLNGLVCESATCVNGEGPASSANLKDLESRYQQLAVALDSSYVTNKQL
  NITIEKLKQQNQEITDQLEEEKKECHQKQGALREQLQVHIQTIGILVSEKAELQTALAHT
  QHAARQKEGESEDLASRLQYSRRRVGELERALSAVSTQQKKADRYNKELTKERDALRLEL
  YKNTQSNEDLKQEKSELEEKLRVLVTEKAGMQLNLEELQKKLEMTELLLQQFSSRCEAPD
  ANQQLQQAMEERAQLEAHLGQVMESVRQLQMERDKYAENLKGESAMWRQRMQQMSEQVHT
  LREEKECSMSRVQELETSLAELRNQMAEPPPPEPPAGPSEVEQQLQAEAEHLRKELEGLA
  GQLQAQVQDNEGLSRLNREQEERLLELERAAELWGEQAEARRQILETMQNDRTTISRALS
  QNRELKEQLAELQSGFVKLTNENMEITSALQSEQHVKRELGKKLGELQEKLSELKETVEL
  KSQEAQSLQQQRDQYLGHLQQYVAAYQQLTSEKEVLHNQLLLQTQLVDQLQQQEAQGKAV
  AEMARQELQETQERLEAATQQNQQLRAQLSLMAHPGEGDGLDREEEEDEEEEEEEAVAVP
  QPMPSIPEDLESREAMVAFFNSAVASAEEEQARLRGQLKEQRVRCRRLAHLLASAQKEPE
  AAAPAPGTGGDSVCGETHRALQGAMEKLQSRFMELMQEKADLKERVEELEHRCIQLSGET
  DTIGEYIALYQSQRAVLKERHREKEEYISRLAQDKEEMKVKLLELQELVLRLVGDRNEWH
  GRFLAAAQNPADEPTSGAPAPQELGAANQQGDLCEVSLAGSVEPAQGEAREGSPRDNPTA
  QQIMQLLREMQNPRERPGLGSNPCIPFFYRADENDEVKITVI
• Function: Peripheral membrane component of the cis-Golgi stack that acts as a membrane skeleton that maintains the structure of the Golgi apparatus, and as a vesicle thether that facilitates vesicle fusion to the Golgi membrane (Probable). Required for normal protein transport from the endoplasmic reticulum to the Golgi apparatus and the cell membrane. Together with p115/USO1 and STX5, involved in vesicle tethering and fusion at the cis-Golgi membrane to maintain the stacked and inter-connected structure of the Golgi apparatus. Plays a central role in mitotic Golgi disassembly: phosphorylation at Ser-37 by CDK1 at the onset of mitosis inhibits the interaction with p115/USO1, preventing tethering of COPI vesicles and thereby inhibiting transport through the Golgi apparatus during mitosis. Also plays a key role in spindle pole assembly and centrosome organization. Promotes the mitotic spindle pole assembly by activating the spindle assembly factor TPX2 to nucleate microtubules around the Golgi and capture them to couple mitotic membranes to the spindle: upon phosphorylation at the onset of mitosis, GOLGA2 interacts with importin-alpha via the nuclear localization signal region, leading to recruit importin-alpha to the Golgi membranes and liberate the spindle assembly factor TPX2 from importin-alpha. TPX2 then activates AURKA kinase and stimulates local microtubule nucleation. Upon filament assembly, nascent microtubules are further captured by GOLGA2, thus linking Golgi membranes to the spindle. Regulates the meiotic spindle pole assembly, probably via the same mechanism. Also regulates the centrosome organization. Also required for the Golgi ribbon formation and glycosylation of membrane and secretory proteins.
• Reactome Pathway:
  COPII-mediated vesicle transport (R-HSA-204005)
  COPI-mediated anterograde transport (R-HSA-6807878)
  Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models (R-HSA-8862803)
  Golgi Cisternae Pericentriolar Stack Reorganization (R-HSA-162658)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[2]
Developmental delay with hypotonia, myopathy, and brain abnormalities	DISNQAS6	Strong	Autosomal recessive	[3]
Familial long QT syndrome	DISRNNCY	Strong	Genetic Variation	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[5]
IgA nephropathy	DISZ8MTK	Strong	Altered Expression	[6]
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[3]
Long QT syndrome 2	DISQQFTJ	Strong	Genetic Variation	[4]
Lung cancer	DISCM4YA	Strong	Altered Expression	[7]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[7]
Male infertility	DISY3YZZ	Strong	Posttranslational Modification	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Neuromuscular disease	DISQTIJZ	Strong	Biomarker	[9]
Prostate cancer	DISF190Y	Strong	Biomarker	[10]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[10]
Stomach cancer	DISKIJSX	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[11]
Breast cancer	DIS7DPX1	moderate	Biomarker	[11]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[11]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[12]

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 Golgin subfamily A member 2 (GOLGA2).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Golgin subfamily A member 2 (GOLGA2).	[26]

14 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 Golgin subfamily A member 2 (GOLGA2).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Golgin subfamily A member 2 (GOLGA2).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Golgin subfamily A member 2 (GOLGA2).	[16]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Golgin subfamily A member 2 (GOLGA2).	[17]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Golgin subfamily A member 2 (GOLGA2).	[18]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Golgin subfamily A member 2 (GOLGA2).	[19]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Golgin subfamily A member 2 (GOLGA2).	[20]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Golgin subfamily A member 2 (GOLGA2).	[21]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Golgin subfamily A member 2 (GOLGA2).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Golgin subfamily A member 2 (GOLGA2).	[25]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Golgin subfamily A member 2 (GOLGA2).	[27]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Golgin subfamily A member 2 (GOLGA2).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Golgin subfamily A member 2 (GOLGA2).	[29]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Golgin subfamily A member 2 (GOLGA2).	[30]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Chloroquine	DMSI5CB	Phase 3 Trial	Chloroquine affects the localization of Golgin subfamily A member 2 (GOLGA2).	[22]
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Golgin subfamily A member 2 (GOLGA2).	[23]

References

• [1] Novel genetic tools reveal Cdk5's major role in Golgi fragmentation in Alzheimer's disease.Mol Biol Cell. 2008 Jul;19(7):3052-69. doi: 10.1091/mbc.e07-11-1106. Epub 2008 May 14.
• [2] Loss of the golgin GM130 causes Golgi disruption, Purkinje neuron loss, and ataxia in mice.Proc Natl Acad Sci U S A. 2017 Jan 10;114(2):346-351. doi: 10.1073/pnas.1608576114. Epub 2016 Dec 27.
• [3] GOLGA2, encoding a master regulator of golgi apparatus, is mutated in a patient with a neuromuscular disorder. Hum Genet. 2016 Feb;135(2):245-251. doi: 10.1007/s00439-015-1632-8. Epub 2016 Jan 7.
• [4] Interaction with GM130 during HERG ion channel trafficking. Disruption by type 2 congenital long QT syndrome mutations. Human Ether--go-go-Related Gene.J Biol Chem. 2002 Dec 6;277(49):47779-85. doi: 10.1074/jbc.M206638200. Epub 2002 Sep 20.
• [5] GM130 regulates epithelial-to-mesenchymal transition and invasion of gastric cancer cells via snail.Int J Clin Exp Pathol. 2015 Sep 1;8(9):10784-91. eCollection 2015.
• [6] Loss of the Golgi Matrix Protein 130 Cause Aberrant IgA1 Glycosylation in IgA Nephropathy.Am J Nephrol. 2019;49(4):307-316. doi: 10.1159/000499110. Epub 2019 Mar 27.
• [7] GOLGA2/GM130, cis-Golgi matrix protein, is a novel target of anticancer gene therapy.Mol Ther. 2012 Nov;20(11):2052-63. doi: 10.1038/mt.2012.125. Epub 2012 Jun 26.
• [8] Globozoospermia and lack of acrosome formation in GM130-deficient mice.Cell Death Dis. 2017 Jan 5;8(1):e2532. doi: 10.1038/cddis.2016.414.
• [9] Golga5 is dispensable for mouse embryonic development and postnatal survival.Genesis. 2017 Jul;55(7):10.1002/dvg.23039. doi: 10.1002/dvg.23039. Epub 2017 Jun 2.
• [10] DGAT1 Inhibitor Suppresses Prostate Tumor Growth and Migration by Regulating Intracellular Lipids and Non-Centrosomal MTOC Protein GM130.Sci Rep. 2019 Feb 28;9(1):3035. doi: 10.1038/s41598-019-39537-z.
• [11] Loss of GM130 in breast cancer cells and its effects on cell migration, invasion and polarity.Cell Cycle. 2015;14(8):1139-47. doi: 10.1080/15384101.2015.1007771.
• [12] Identification and Verification of Two Novel Differentially Expressed Proteins from Non-neoplastic Mucosa and Colorectal Carcinoma Via iTRAQ Combined with Liquid Chromatography-Mass Spectrometry.Pathol Oncol Res. 2020 Apr;26(2):967-976. doi: 10.1007/s12253-019-00651-y. Epub 2019 Mar 29.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [17] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [18] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [19] 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.
• [20] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [21] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [22] Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy. 2018;14(8):1435-1455. doi: 10.1080/15548627.2018.1474314. Epub 2018 Jul 20.
• [23] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [24] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [25] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [26] 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.
• [27] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [28] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [29] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [30] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.