Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ2EQJ1)

• DOT Name: ARF GTPase-activating protein GIT2 (GIT2)
• Synonyms: ARF GAP GIT2; Cool-interacting tyrosine-phosphorylated protein 2; CAT-2; CAT2; G protein-coupled receptor kinase-interactor 2; GRK-interacting protein 2
• Gene Name: GIT2
• Related Disease:
  Rheumatoid arthritis
  Breast neoplasm
  Cardiovascular disease
  Cataract
  Chorioamnionitis
  Colitis
  Lung neoplasm
  Lung cancer
  Lung carcinoma
  Pulmonary tuberculosis
  Type-1/2 diabetes
• UniProt ID: GIT2_HUMAN
• Pfam ID: PF12796 ; PF01412 ; PF12205 ; PF16559 ; PF08518
• Sequence:
  MSKRLRSSEVCADCSGPDPSWASVNRGTFLCDECCSVHRSLGRHISQVRHLKHTPWPPTL
  LQMVETLYNNGANSIWEHSLLDPASIMSGRRKANPQDKVHPNKAEFIRAKYQMLAFVHRL
  PCRDDDSVTAKDLSKQLHSSVRTGNLETCLRLLSLGAQANFFHPEKGNTPLHVASKAGQI
  LQAELLAVYGADPGTQDSSGKTPVDYARQGGHHELAERLVEIQYELTDRLAFYLCGRKPD
  HKNGQHFIIPQMADSSLDLSELAKAAKKKLQSLSNHLFEELAMDVYDEVDRRETDAVWLA
  TQNHSALVTETTVVPFLPVNPEYSSTRNQGRQKLARFNAHEFATLVIDILSDAKRRQQGS
  SLSGSKDNVELILKTINNQHSVESQDNDQPDYDSVASDEDTDLETTASKTNRQKSLDSDL
  SDGPVTVQEFMEVKNALVASEAKIQQLMKVNNNLSDELRIMQKKLQTLQSENSNLRKQAT
  TNVYQVQTGSEYTDTSNHSSLKRRPSARGSRPMSMYETGSGQKPYLPMGEASRPEESRMR
  LQPFPAHIGRSALVTSSSSLPSFPSTLSWSRDESARRASRLEKQNSTPESDYDNTPNDME
  PDGMGSSRKGRQRSMVWPGDGLVPDTAEPHVAPSPTLPSTEDVIRKTEQITKNIQELLRA
  AQENKHDSYIPCSERIHVAVTEMAALFPKKPKSDMVRTSLRLLTSSAYRLQSECKKTLPG
  DPGSPTDVQLVTQQVIQCAYDIAKAAKQLVTITTKENNN
• Function: GTPase-activating protein for ADP ribosylation factor family members, including ARF1.
• KEGG Pathway:
  Endocytosis (hsa04144)
  Yersinia infection (hsa05135)
• Reactome Pathway:
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOQ GTPase cycle (R-HSA-9013406)
  RHOJ GTPase cycle (R-HSA-9013409)
  RHOU GTPase cycle (R-HSA-9013420)
  RAC3 GTPase cycle (R-HSA-9013423)
  RHOV GTPase cycle (R-HSA-9013424)
  CDC42 GTPase cycle (R-HSA-9013148)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Rheumatoid arthritis	DISTSB4J	Definitive	Genetic Variation	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[3]
Cataract	DISUD7SL	Strong	Genetic Variation	[4]
Chorioamnionitis	DISL1D9U	Strong	Altered Expression	[5]
Colitis	DISAF7DD	Strong	Biomarker	[6]
Lung neoplasm	DISVARNB	Strong	Genetic Variation	[7]
Lung cancer	DISCM4YA	Limited	Biomarker	[8]
Lung carcinoma	DISTR26C	Limited	Biomarker	[8]
Pulmonary tuberculosis	DIS6FLUM	Limited	Biomarker	[9]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[10]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Camptothecin	DM6CHNJ	Phase 3	ARF GTPase-activating protein GIT2 (GIT2) decreases the response to substance of Camptothecin.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of ARF GTPase-activating protein GIT2 (GIT2).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of ARF GTPase-activating protein GIT2 (GIT2).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ARF GTPase-activating protein GIT2 (GIT2).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of ARF GTPase-activating protein GIT2 (GIT2).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of ARF GTPase-activating protein GIT2 (GIT2).	[15]
Marinol	DM70IK5	Approved	Marinol increases the expression of ARF GTPase-activating protein GIT2 (GIT2).	[16]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of ARF GTPase-activating protein GIT2 (GIT2).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of ARF GTPase-activating protein GIT2 (GIT2).	[17]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of ARF GTPase-activating protein GIT2 (GIT2).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of ARF GTPase-activating protein GIT2 (GIT2).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of ARF GTPase-activating protein GIT2 (GIT2).	[22]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of ARF GTPase-activating protein GIT2 (GIT2).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of ARF GTPase-activating protein GIT2 (GIT2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of ARF GTPase-activating protein GIT2 (GIT2).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of ARF GTPase-activating protein GIT2 (GIT2).	[18]

References

• [1] Genetic deletion of GIT2 prolongs functional recovery and suppresses chondrocyte differentiation in rats with rheumatoid arthritis.J Cell Biochem. 2018 Feb;119(2):1538-1547. doi: 10.1002/jcb.26313. Epub 2017 Sep 18.
• [2] The lncRNA H19 mediates breast cancer cell plasticity during EMT and MET plasticity by differentially sponging miR-200b/c and let-7b.Sci Signal. 2017 Jun 13;10(483):eaak9557. doi: 10.1126/scisignal.aak9557.
• [3] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [4] Cataract mutations and lens development.Prog Retin Eye Res. 1999 Mar;18(2):235-67. doi: 10.1016/s1350-9462(98)00018-4.
• [5] GIT2 deficiency attenuates inflammation-induced expression of pro-labor mediators in human amnion and myometrial cells?"Lim R.Biol Reprod. 2019 Jun 1;100(6):1617-1629. doi: 10.1093/biolre/ioz041.
• [6] The GTPase-activating protein GIT2 protects against colitis by negatively regulating Toll-like receptor signaling.Proc Natl Acad Sci U S A. 2014 Jun 17;111(24):8883-8. doi: 10.1073/pnas.1309218111. Epub 2014 May 30.
• [7] The Combination of MEK Inhibitor With Immunomodulatory Antibodies Targeting Programmed Death 1 and Programmed Death Ligand 1 Results in Prolonged Survival in Kras/p53-Driven Lung Cancer.J Thorac Oncol. 2019 Jun;14(6):1046-1060. doi: 10.1016/j.jtho.2019.02.004. Epub 2019 Feb 13.
• [8] EGF-stimulated activation of Rab35 regulates RUSC2-GIT2 complex formation to stabilize GIT2 during directional lung cancer cell migration.Cancer Lett. 2016 Aug 28;379(1):70-83. doi: 10.1016/j.canlet.2016.05.027. Epub 2016 May 26.
• [9] Efficacy and Safety of Mycobacterium indicus pranii as an adjunct therapy in Category II pulmonary tuberculosis in a randomized trial.Sci Rep. 2017 Jun 13;7(1):3354. doi: 10.1038/s41598-017-03514-1.
• [10] Relationship between catalase haplotype and arterial aging.Atherosclerosis. 2013 Mar;227(1):100-5. doi: 10.1016/j.atherosclerosis.2012.12.015. Epub 2013 Jan 8.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [13] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [14] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [15] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [16] 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.
• [17] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [18] 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.
• [19] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [20] 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.
• [21] 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.
• [22] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [24] ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014 Dec 1;74(23):6968-79.