Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3SSYYC)

• DOT Name: Girdin (CCDC88A)
• Synonyms: Akt phosphorylation enhancer; APE; Coiled-coil domain-containing protein 88A; G alpha-interacting vesicle-associated protein; GIV; Girders of actin filament; Hook-related protein 1; HkRP1
• Gene Name: CCDC88A
• Related Disease:
  Advanced cancer
  Breast cancer
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Enterovirus infection
  Gastroenteritis
  Graves disease
  Hepatitis E virus infection
  Hepatocellular carcinoma
  Infantile epileptic-dyskinetic encephalopathy
  Lung cancer
  Lung carcinoma
  Metabolic disorder
  Non-small-cell lung cancer
  PEHO-like syndrome
  Rhabdomyosarcoma
  Vascular disease
  Vitiligo
  Amyotrophic lateral sclerosis
  Astrocytoma
  Breast carcinoma
  Isolated congenital microcephaly
  Metastatic malignant neoplasm
  Stroke
  Hepatitis A virus infection
  Intellectual disability
  Adenocarcinoma
  Carcinoma
  PEHO syndrome
  Rectal carcinoma
• UniProt ID: GRDN_HUMAN
• PDB ID: 6MHF
• Pfam ID: PF19047
• Sequence:
  MENEIFTPLLEQFMTSPLVTWVKTFGPLAAGNGTNLDEYVALVDGVFLNQVMLQINPKLE
  SQRVNKKVNNDASLRMHNLSILVRQIKFYYQETLQQLIMMSLPNVLIIGKNPFSEQGTEE
  VKKLLLLLLGCAVQCQKKEEFIERIQGLDFDTKAAVAAHIQEVTHNQENVFDLQWMEVTD
  MSQEDIEPLLKNMALHLKRLIDERDEHSETIIELSEERDGLHFLPHASSSAQSPCGSPGM
  KRTESRQHLSVELADAKAKIRRLRQELEEKTEQLLDCKQELEQMEIELKRLQQENMNLLS
  DARSARMYRDELDALREKAVRVDKLESEVSRYKERLHDIEFYKARVEELKEDNQVLLETK
  TMLEDQLEGTRARSDKLHELEKENLQLKAKLHDMEMERDMDRKKIEELMEENMTLEMAQK
  QSMDESLHLGWELEQISRTSELSEAPQKSLGHEVNELTSSRLLKLEMENQSLTKTVEELR
  TTVDSVEGNASKILKMEKENQRLSKKVEILENEIVQEKQSLQNCQNLSKDLMKEKAQLEK
  TIETLRENSERQIKILEQENEHLNQTVSSLRQRSQISAEARVKDIEKENKILHESIKETS
  SKLSKIEFEKRQIKKELEHYKEKGERAEELENELHHLEKENELLQKKITNLKITCEKIEA
  LEQENSELERENRKLKKTLDSFKNLTFQLESLEKENSQLDEENLELRRNVESLKCASMKM
  AQLQLENKELESEKEQLKKGLELLKASFKKTERLEVSYQGLDIENQRLQKTLENSNKKIQ
  QLESELQDLEMENQTLQKNLEELKISSKRLEQLEKENKSLEQETSQLEKDKKQLEKENKR
  LRQQAEIKDTTLEENNVKIGNLEKENKTLSKEIGIYKESCVRLKELEKENKELVKRATID
  IKTLVTLREDLVSEKLKTQQMNNDLEKLTHELEKIGLNKERLLHDEQSTDDSRYKLLESK
  LESTLKKSLEIKEEKIAALEARLEESTNYNQQLRQELKTVKKNYEALKQRQDEERMVQSS
  PPISGEDNKWERESQETTRELLKVKDRLIEVERNNATLQAEKQALKTQLKQLETQNNNLQ
  AQILALQRQTVSLQEQNTTLQTQNAKLQVENSTLNSQSTSLMNQNAQLLIQQSSLENENE
  SVIKEREDLKSLYDSLIKDHEKLELLHERQASEYESLISKHGTLKSAHKNLEVEHRDLED
  RYNQLLKQKGQLEDLEKMLKVEQEKMLLENKNHETVAAEYKKLCGENDRLNHTYSQLLKE
  TEVLQTDHKNLKSLLNNSKLEQTRLEAEFSKLKEQYQQLDITSTKLNNQCELLSQLKGNL
  EEENRHLLDQIQTLMLQNRTLLEQNMESKDLFHVEQRQYIDKLNELRRQKEKLEEKIMDQ
  YKFYDPSPPRRRGNWITLKMRKLIKSKKDINRERQKSLTLTPTRSDSSEGFLQLPHQDSQ
  DSSSVGSNSLEDGQTLGTKKSSMVALKRLPFLRNRPKDKDKMKACYRRSMSMNDLVQSMV
  LAGQWTGSTENLEVPDDISTGKRRKELGAMAFSTTAINFSTVNSSAGFRSKQLVNNKDTT
  SFEDISPQGVSDDSSTGSRVHASRPASLDSGRTSTSNSNNNASLHEVKAGAVNNQSRPQS
  HSSGEFSLLHDHEAWSSSGSSPIQYLKRQTRSSPVLQHKISETLESRHHKIKTGSPGSEV
  VTLQQFLEESNKLTSVQIKSSSQENLLDEVMKSLSVSSDFLGKDKPVSCGLARSVSGKTP
  GDFYDRRTTKPEFLRPGPRKTEDTYFISSAGKPTPGTQGKIKLVKESSLSRQSKDSNPYA
  TLPRASSVISTAEGTTRRTSIHDFLTKDSRLPISVDSPPAAADSNTTAASNVDKVQESRN
  SKSRSREQQSS
• Function: Bifunctional modulator of guanine nucleotide-binding proteins (G proteins). Acts as a non-receptor guanine nucleotide exchange factor which binds to and activates guanine nucleotide-binding protein G(i) alpha subunits. Also acts as a guanine nucleotide dissociation inhibitor for guanine nucleotide-binding protein G(s) subunit alpha GNAS. Essential for cell migration. Interacts in complex with G(i) alpha subunits with the EGFR receptor, retaining EGFR at the cell membrane following ligand stimulation and promoting EGFR signaling which triggers cell migration. Binding to Gi-alpha subunits displaces the beta and gamma subunits from the heterotrimeric G-protein complex which enhances phosphoinositide 3-kinase (PI3K)-dependent phosphorylation and kinase activity of AKT1/PKB. Phosphorylation of AKT1/PKB induces the phosphorylation of downstream effectors GSK3 and FOXO1/FKHR, and regulates DNA replication and cell proliferation. Binds in its tyrosine-phosphorylated form to the phosphatidylinositol 3-kinase (PI3K) regulatory subunit PIK3R1 which enables recruitment of PIK3R1 to the EGFR receptor, enhancing PI3K activity and cell migration. Plays a role as a key modulator of the AKT-mTOR signaling pathway, controlling the tempo of the process of newborn neuron integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Inhibition of G(s) subunit alpha GNAS leads to reduced cellular levels of cAMP and suppression of cell proliferation. Essential for the integrity of the actin cytoskeleton. Required for formation of actin stress fibers and lamellipodia. May be involved in membrane sorting in the early endosome. Plays a role in ciliogenesis and cilium morphology and positioning and this may partly be through regulation of the localization of scaffolding protein CROCC/Rootletin.
• Tissue Specificity: Expressed ubiquitously.
• Reactome Pathway:
  RND1 GTPase cycle (R-HSA-9696273)
  RND3 GTPase cycle (R-HSA-9696264)

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Altered Expression	[3]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Enterovirus infection	DISH2UDP	Strong	Biomarker	[5]
Gastroenteritis	DISXQCG5	Strong	Biomarker	[6]
Graves disease	DISU4KOQ	Strong	Genetic Variation	[7]
Hepatitis E virus infection	DIS0TXIR	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[8]
Infantile epileptic-dyskinetic encephalopathy	DISD2ZNC	Strong	Biomarker	[9]
Lung cancer	DISCM4YA	Strong	Biomarker	[10]
Lung carcinoma	DISTR26C	Strong	Biomarker	[10]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[12]
PEHO-like syndrome	DIS1SRCH	Strong	Autosomal recessive	[9]
Rhabdomyosarcoma	DISNR7MS	Strong	Altered Expression	[13]
Vascular disease	DISVS67S	Strong	Biomarker	[14]
Vitiligo	DISR05SL	Strong	Biomarker	[15]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Altered Expression	[16]
Astrocytoma	DISL3V18	moderate	Biomarker	[17]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[18]
Isolated congenital microcephaly	DISUXHZ6	moderate	Biomarker	[19]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[18]
Stroke	DISX6UHX	moderate	Genetic Variation	[20]
Hepatitis A virus infection	DISUMFQV	Disputed	Genetic Variation	[5]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[21]
Adenocarcinoma	DIS3IHTY	Limited	Genetic Variation	[22]
Carcinoma	DISH9F1N	Limited	Genetic Variation	[22]
PEHO syndrome	DISPO5IP	Limited	Genetic Variation	[19]
Rectal carcinoma	DIS8FRR7	Limited	Genetic Variation	[23]

3 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 Girdin (CCDC88A).	[24]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Girdin (CCDC88A).	[39]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Girdin (CCDC88A).	[41]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Girdin (CCDC88A).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Girdin (CCDC88A).	[26]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Girdin (CCDC88A).	[27]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Girdin (CCDC88A).	[28]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Girdin (CCDC88A).	[29]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Girdin (CCDC88A).	[30]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Girdin (CCDC88A).	[31]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Girdin (CCDC88A).	[32]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Girdin (CCDC88A).	[33]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Girdin (CCDC88A).	[34]
Marinol	DM70IK5	Approved	Marinol increases the expression of Girdin (CCDC88A).	[35]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Girdin (CCDC88A).	[36]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Girdin (CCDC88A).	[37]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Girdin (CCDC88A).	[38]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Girdin (CCDC88A).	[40]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Girdin (CCDC88A).	[42]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Girdin (CCDC88A).	[43]

References

• [1] The G-interacting vesicle-associated protein interacts with and promotes cell surface localization of GRP78 during endoplasmic reticulum stress.FEBS Lett. 2020 Mar;594(6):1088-1100. doi: 10.1002/1873-3468.13685. Epub 2019 Nov 30.
• [2] Prognostic impact of total and tyrosine phosphorylated GIV/Girdin in breast cancers.FASEB J. 2016 Nov;30(11):3702-3713. doi: 10.1096/fj.201600500. Epub 2016 Jul 20.
• [3] Expression of GIV/Girdin, a metastasis-related protein, predicts patient survival in colon cancer.FASEB J. 2011 Feb;25(2):590-9. doi: 10.1096/fj.10-167304. Epub 2010 Oct 25.
• [4] Stem cell gene Girdin: a potential early liver metastasis predictor of colorectal cancer.Mol Biol Rep. 2012 Sep;39(9):8717-22. doi: 10.1007/s11033-012-1731-8. Epub 2012 Jun 20.
• [5] Molecular characterization of human enteric viruses in food, water samples, and surface swabs in Sicily.Int J Infect Dis. 2019 Mar;80:66-72. doi: 10.1016/j.ijid.2018.12.011. Epub 2019 Jan 9.
• [6] Molecular characterization of calicivirus strains detected in outbreaks of gastroenteritis in Argentina.J Med Virol. 2007 Nov;79(11):1703-9. doi: 10.1002/jmv.20989.
• [7] Polymorphisms of DNA base-excision repair genes APE/Ref-1 and XRCC1 are not associated with the risk for Graves' disease.Cell Biochem Funct. 2009 Oct;27(7):462-7. doi: 10.1002/cbf.1595.
• [8] Silencing the Girdin gene enhances radio-sensitivity of hepatocellular carcinoma via suppression of glycolytic metabolism.J Exp Clin Cancer Res. 2017 Aug 15;36(1):110. doi: 10.1186/s13046-017-0580-7.
• [9] CCDC88A mutations cause PEHO-like syndrome in humans and mouse. Brain. 2016 Apr;139(Pt 4):1036-44. doi: 10.1093/brain/aww014. Epub 2016 Feb 25.
• [10] Girdin protein: A potential metastasis predictor associated with prognosis in lung cancer.Exp Ther Med. 2018 Mar;15(3):2837-2843. doi: 10.3892/etm.2018.5773. Epub 2018 Jan 19.
• [11] Circulating exosomes may identify biomarkers for cows at risk for metabolic dysfunction.Sci Rep. 2019 Sep 25;9(1):13879. doi: 10.1038/s41598-019-50244-7.
• [12] Interleukin-17 promotes angiogenesis by stimulating VEGF production of cancer cells via the STAT3/GIV signaling pathway in non-small-cell lung cancer.Sci Rep. 2015 Nov 3;5:16053. doi: 10.1038/srep16053.
• [13] Histology-specific expression of a DNA repair protein in pediatric rhabdomyosarcomas.J Pediatr Hematol Oncol. 2001 May;23(4):234-9. doi: 10.1097/00043426-200105000-00011.
• [14] Angiotensin II facilitates neointimal formation by increasing vascular smooth muscle cell migration: Involvement of APE/Ref-1-mediated overexpression of sphingosine-1-phosphate receptor 1.Toxicol Appl Pharmacol. 2018 May 15;347:45-53. doi: 10.1016/j.taap.2018.03.032. Epub 2018 Mar 30.
• [15] Involvement of Different Genes Expressions during Immunological and Inflammatory Responses in Vitiligo.Crit Rev Eukaryot Gene Expr. 2017;27(3):277-287. doi: 10.1615/CritRevEukaryotGeneExpr.2017019558.
• [16] DNA base-excision repair enzyme apurinic/apyrimidinic endonuclease/redox factor-1 is increased and competent in the brain and spinal cord of individuals with amyotrophic lateral sclerosis.Neuromolecular Med. 2002;2(1):47-60. doi: 10.1007/s12017-002-0038-7.
• [17] Region-Specific Dok2 Overexpression Associates with Poor Prognosis in Human Astrocytoma.Mol Neurobiol. 2018 Jan;55(1):402-408. doi: 10.1007/s12035-016-0324-2. Epub 2016 Dec 14.
• [18] STAT3 protein up-regulates G-interacting vesicle-associated protein (GIV)/Girdin expression, and GIV enhances STAT3 activation in a positive feedback loop during wound healing and tumor invasion/metastasis.J Biol Chem. 2012 Dec 7;287(50):41667-83. doi: 10.1074/jbc.M112.390781. Epub 2012 Oct 12.
• [19] A novel homozygous nonsense mutation in CCDC88A gene cause PEHO-like syndrome in consanguineous Saudi family.Neurol Sci. 2019 Feb;40(2):299-303. doi: 10.1007/s10072-018-3626-5. Epub 2018 Nov 3.
• [20] A prospective study of polymorphisms of DNA repair genes XRCC1, XPD23 and APE/ref-1 and risk of stroke in Linxian, China.J Epidemiol Community Health. 2007 Aug;61(8):737-41. doi: 10.1136/jech.2006.048934.
• [21] Implementing the adapted physical education E-learning program into physical education teacher education program.Res Dev Disabil. 2017 Oct;69:18-29. doi: 10.1016/j.ridd.2017.07.001. Epub 2017 Aug 8.
• [22] Bladder cancer and polymorphisms of DNA repair genes (XRCC1, XRCC3, XPD, XPG, APE1, hOGG1).Anticancer Res. 2009 Apr;29(4):1389-93.
• [23] Association between operative technique and intrusive thoughts on health-related Quality of Life 3years after APE/ELAPE for rectal cancer: results from a national Swedish cohort with comparison with normative Swedish data.Cancer Med. 2018 Jun;7(6):2727-2735. doi: 10.1002/cam4.1402. Epub 2018 Apr 17.
• [24] 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.
• [25] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [26] Identification of potential biomarkers of hepatitis B-induced acute liver failure using hepatic cells derived from human skin precursors. Toxicol In Vitro. 2015 Sep;29(6):1231-9. doi: 10.1016/j.tiv.2014.10.012. Epub 2014 Oct 24.
• [27] 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.
• [28] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [29] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [30] 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.
• [31] 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.
• [32] 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.
• [33] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [34] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [35] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [36] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [37] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [38] 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.
• [39] 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.
• [40] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [41] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [42] 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.
• [43] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.