Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHO92S5)

• DOT Name: ARF GTPase-activating protein GIT1 (GIT1)
• Synonyms: ARF GAP GIT1; Cool-associated and tyrosine-phosphorylated protein 1; CAT-1; CAT1; G protein-coupled receptor kinase-interactor 1; GRK-interacting protein 1; p95-APP1
• Gene Name: GIT1
• Related Disease:
  Cone-rod dystrophy 2
  Advanced cancer
  Attention deficit hyperactivity disorder
  Benign prostatic hyperplasia
  Breast cancer
  Breast carcinoma
  Chronic bronchitis
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Congestive heart failure
  Gastric cancer
  Huntington disease
  Intellectual disability
  Medullary thyroid gland carcinoma
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
  Stomach cancer
  Hepatocellular carcinoma
  Melanoma
  Neurodevelopmental disorder
  Bone osteosarcoma
  Osteosarcoma
  Parkinson disease
  Pulmonary tuberculosis
• UniProt ID: GIT1_HUMAN
• Pfam ID: PF12796 ; PF01412 ; PF12205 ; PF16559 ; PF08518
• Sequence:
  MSRKGPRAEVCADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVKHLRHSAWPPTL
  LQMVHTLASNGANSIWEHSLLDPAQVQSGRRKANPQDKVHPIKSEFIRAKYQMLAFVHKL
  PCRDDDGVTAKDLSKQLHSSVRTGNLETCLRLLSLGAQANFFHPEKGTTPLHVAAKAGQT
  LQAELLVVYGADPGSPDVNGRTPIDYARQAGHHELAERLVECQYELTDRLAFYLCGRKPD
  HKNGHYIIPQMADSLDLSELAKAAKKKLQALSNRLFEELAMDVYDEVDRRENDAVWLATQ
  NHSTLVTERSAVPFLPVNPEYSATRNQGRQKLARFNAREFATLIIDILSEAKRRQQGKSL
  SSPTDNLELSLRSQSDLDDQHDYDSVASDEDTDQEPLRSTGATRSNRARSMDSSDLSDGA
  VTLQEYLELKKALATSEAKVQQLMKVNSSLSDELRRLQREIHKLQAENLQLRQPPGPVPT
  PPLPSERAEHTPMAPGGSTHRRDRQAFSMYEPGSALKPFGGPPGDELTTRLQPFHSTELE
  DDAIYSVHVPAGLYRIRKGVSASAVPFTPSSPLLSCSQEGSRHTSKLSRHGSGADSDYEN
  TQSGDPLLGLEGKRFLELGKEEDFHPELESLDGDLDPGLPSTEDVILKTEQVTKNIQELL
  RAAQEFKHDSFVPCSEKIHLAVTEMASLFPKRPALEPVRSSLRLLNASAYRLQSECRKTV
  PPEPGAPVDFQLLTQQVIQCAYDIAKAAKQLVTITTREKKQ
• Function: GTPase-activating protein for ADP ribosylation factor family members, including ARF1. Multidomain scaffold protein that interacts with numerous proteins and therefore participates in many cellular functions, including receptor internalization, focal adhesion remodeling, and signaling by both G protein-coupled receptors and tyrosine kinase receptors. Through PAK1 activation, positively regulates microtubule nucleation during interphase. Plays a role in the regulation of cytokinesis; for this function, may act in a pathway also involving ENTR1 and PTPN13. May promote cell motility both by regulating focal complex dynamics and by local activation of RAC1. May act as scaffold for MAPK1/3 signal transduction in focal adhesions. Recruits MAPK1/3/ERK1/2 to focal adhesions after EGF stimulation via a Src-dependent pathway, hence stimulating cell migration. Plays a role in brain development and function. Involved in the regulation of spine density and synaptic plasticity that is required for processes involved in learning. Plays an important role in dendritic spine morphogenesis and synapse formation. In hippocampal neurons, recruits guanine nucleotide exchange factors (GEFs), such as ARHGEF7/beta-PIX, to the synaptic membrane. These in turn locally activate RAC1, which is an essential step for spine morphogenesis and synapse formation. May contribute to the organization of presynaptic active zones through oligomerization and formation of a Piccolo/PCLO-based protein network, which includes ARHGEF7/beta-PIX and FAK1. In neurons, through its interaction with liprin-alpha family members, may be required for AMPA receptor (GRIA2/3) proper targeting to the cell membrane. In complex with GABA(A) receptors and ARHGEF7, plays a crucial role in regulating GABA(A) receptor synaptic stability, maintaining GPHN/gephyrin scaffolds and hence GABAergic inhibitory synaptic transmission, by locally coordinating RAC1 and PAK1 downstream effector activity, leading to F-actin stabilization. May also be important for RAC1 downstream signaling pathway through PAK3 and regulation of neuronal inhibitory transmission at presynaptic input. Required for successful bone regeneration during fracture healing. The function in intramembranous ossification may, at least partly, exerted by macrophages in which GIT1 is a key negative regulator of redox homeostasis, IL1B production, and glycolysis, acting through the ERK1/2/NRF2/NFE2L2 axis. May play a role in angiogenesis during fracture healing. In this process, may regulate activation of the canonical NF-kappa-B signal in bone mesenchymal stem cells by enhancing the interaction between NEMO and 'Lys-63'-ubiquitinated RIPK1/RIP1, eventually leading to enhanced production of VEGFA and others angiogenic factors. Essential for VEGF signaling through the activation of phospholipase C-gamma and ERK1/2, hence may control endothelial cell proliferation and angiogenesis.
• KEGG Pathway:
  Endocytosis (hsa04144)
  Regulation of actin cytoskeleton (hsa04810)
  Epithelial cell sig.ling in Helicobacter pylori infection (hsa05120)
• Reactome Pathway:
  CDC42 GTPase cycle (R-HSA-9013148)
  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)
  Activation of RAC1 downstream of NMDARs (R-HSA-9619229)
  Ephrin signaling (R-HSA-3928664)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cone-rod dystrophy 2	DISX2RWY	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[3]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Chronic bronchitis	DISS8O8V	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[7]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[8]
Gastric cancer	DISXGOUK	Strong	Biomarker	[9]
Huntington disease	DISQPLA4	Strong	Biomarker	[10]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[3]
Medullary thyroid gland carcinoma	DISHBL3K	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[13]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[13]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[14]
Stomach cancer	DISKIJSX	Strong	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[15]
Melanoma	DIS1RRCY	moderate	Biomarker	[16]
Neurodevelopmental disorder	DIS372XH	moderate	Biomarker	[17]
Bone osteosarcoma	DIST1004	Limited	Altered Expression	[12]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[12]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[18]
Pulmonary tuberculosis	DIS6FLUM	Limited	Biomarker	[19]

9 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 ARF GTPase-activating protein GIT1 (GIT1).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of ARF GTPase-activating protein GIT1 (GIT1).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ARF GTPase-activating protein GIT1 (GIT1).	[22]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of ARF GTPase-activating protein GIT1 (GIT1).	[23]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ARF GTPase-activating protein GIT1 (GIT1).	[24]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of ARF GTPase-activating protein GIT1 (GIT1).	[25]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of ARF GTPase-activating protein GIT1 (GIT1).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ARF GTPase-activating protein GIT1 (GIT1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ARF GTPase-activating protein GIT1 (GIT1).	[29]

2 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 affects the phosphorylation of ARF GTPase-activating protein GIT1 (GIT1).	[28]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of ARF GTPase-activating protein GIT1 (GIT1).	[28]

References

• [1] GPCR kinase 2-interacting protein-1 protects against ischemia-reperfusion injury of the spinal cord by modulating ASK1/JNK/p38 signaling.FASEB J. 2018 Jun 18:fj201800548. doi: 10.1096/fj.201800548. Online ahead of print.
• [2] The adaptor protein and Arf GTPase-activating protein Cat-1/Git-1 is required for cellular transformation.J Biol Chem. 2012 Sep 7;287(37):31462-70. doi: 10.1074/jbc.M112.353615. Epub 2012 Jul 17.
• [3] GIT1 regulates synaptic structural plasticity underlying learning.PLoS One. 2018 Mar 19;13(3):e0194350. doi: 10.1371/journal.pone.0194350. eCollection 2018.
• [4] CaT1 expression correlates with tumor grade in prostate cancer. Biochem Biophys Res Commun. 2001 Apr 6;282(3):729-34.
• [5] Targeting of GIT1 by miR-149* in breast cancer suppresses cell proliferation and metastasis in vitro and tumor growth in vivo.Onco Targets Ther. 2017 Dec 11;10:5873-5882. doi: 10.2147/OTT.S144280. eCollection 2017.
• [6] Alternative definitions of chronic bronchitis and their correlation with CT parameters.Int J Chron Obstruct Pulmon Dis. 2018 Jun 13;13:1893-1899. doi: 10.2147/COPD.S164055. eCollection 2018.
• [7] Overexpression of arginine transporter CAT-1 is associated with accumulation of L-arginine and cell growth in human colorectal cancer tissue.PLoS One. 2013 Sep 6;8(9):e73866. doi: 10.1371/journal.pone.0073866. eCollection 2013.
• [8] Reduced myocardial and systemic L-arginine uptake in heart failure.Circ Res. 2002 Dec 13;91(12):1198-203. doi: 10.1161/01.res.0000047506.52381.90.
• [9] lncRNA CCAT1 contributes to the growth and invasion of gastric cancer via targeting miR-219-1.J Cell Biochem. 2019 Dec;120(12):19457-19468. doi: 10.1002/jcb.29239. Epub 2019 Sep 3.
• [10] A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease.Mol Cell. 2004 Sep 24;15(6):853-65. doi: 10.1016/j.molcel.2004.09.016.
• [11] miR-149-5p inhibits cell proliferation and invasion through targeting GIT1 in medullary thyroid carcinoma.Oncol Lett. 2019 Jan;17(1):372-378. doi: 10.3892/ol.2018.9628. Epub 2018 Oct 26.
• [12] Inhibiting GIT1 reduces the growth, invasion, and angiogenesis of osteosarcoma.Cancer Manag Res. 2018 Nov 29;10:6445-6455. doi: 10.2147/CMAR.S181066. eCollection 2018.
• [13] Alternative RNA splicing of the GIT1 gene is associated with neuroendocrine prostate cancer.Cancer Sci. 2019 Jan;110(1):245-255. doi: 10.1111/cas.13869. Epub 2018 Dec 12.
• [14] Functional analysis of rare variants found in schizophrenia implicates a critical role for GIT1-PAK3 signaling in neuroplasticity.Mol Psychiatry. 2017 Mar;22(3):417-429. doi: 10.1038/mp.2016.98. Epub 2016 Jul 26.
• [15] Hepatitis B virus X protein-induced upregulation of CAT-1 stimulates proliferation and inhibits apoptosis in hepatocellular carcinoma cells.Oncotarget. 2017 May 5;8(37):60962-60974. doi: 10.18632/oncotarget.17631. eCollection 2017 Sep 22.
• [16] G-protein-coupled receptor-2-interacting protein-1 is required for endothelial cell directional migration and tumor angiogenesis via cortactin-dependent lamellipodia formation.Arterioscler Thromb Vasc Biol. 2014 Feb;34(2):419-26. doi: 10.1161/ATVBAHA.113.302689. Epub 2013 Nov 21.
• [17] Indexing Effects of Copy Number Variation on Genes Involved in Developmental Delay.Sci Rep. 2016 Jul 1;6:28663. doi: 10.1038/srep28663.
• [18] Global microRNA expression profiling of Caenorhabditis elegans Parkinson's disease models.J Mol Neurosci. 2010 May;41(1):210-8. doi: 10.1007/s12031-009-9325-1. Epub 2010 Jan 21.
• [19] Determination of drug susceptibility patterns and genotypes of Mycobacterium tuberculosis isolates from Kanpur district, North India.Infect Genet Evol. 2011 Mar;11(2):469-75. doi: 10.1016/j.meegid.2010.12.010. Epub 2011 Jan 13.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [24] 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.
• [25] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [26] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] 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.
• [29] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.