Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT43HO27)

• DOT Name: ADP-ribosylation factor-binding protein GGA2 (GGA2)
• Synonyms: Gamma-adaptin-related protein 2; Golgi-localized, gamma ear-containing, ARF-binding protein 2; VHS domain and ear domain of gamma-adaptin; Vear
• Gene Name: GGA2
• Related Disease:
  Lung adenocarcinoma
  Neoplasm
  Polydactyly
  Colorectal carcinoma
  Hepatocellular carcinoma
• UniProt ID: GGA2_HUMAN
• PDB ID: 1MHQ
• Pfam ID: PF02883 ; PF03127 ; PF18308 ; PF00790
• Sequence:
  MAATAVAAAVAGTESAQGPPGPAASLELWLNKATDPSMSEQDWSAIQNFCEQVNTDPNGP
  THAPWLLAHKIQSPQEKEALYALTVLEMCMNHCGEKFHSEVAKFRFLNELIKVLSPKYLG
  SWATGKVKGRVIEILFSWTVWFPEDIKIRDAYQMLKKQGIIKQDPKLPVDKILPPPSPWP
  KSSIFDADEEKSKLLTRLLKSNHPEDLQAANRLIKNLVKEEQEKSEKVSKRVSAVEEVRS
  HVKVLQEMLSMYRRPGQAPPDQEALQVVYERCEKLRPTLFRLASDTTDDDDALAEILQAN
  DLLTQGVLLYKQVMEGRVTFGNRVTSSLGDIPVSRVFQNPAGCMKTCPLIDLEVDNGPAQ
  MGTVVPSLLHQDLAALGISDAPVTGMVSGQNCCEEKRNPSSSTLPGGGVQNPSADRNLLD
  LLSAQPAPCPLNYVSQKSVPKEVPPGTKSSPGWSWEAGPLAPSPSSQNTPLAQVFVPLES
  VKPSSLPPLIVYDRNGFRILLHFSQTGAPGHPEVQVLLLTMMSTAPQPVWDIMFQVAVPK
  SMRVKLQPASSSKLPAFSPLMPPAVISQMLLLDNPHKEPIRLRYKLTFNQGGQPFSEVGE
  VKDFPDLAVLGAA
• Function: Plays a role in protein sorting and trafficking between the trans-Golgi network (TGN) and endosomes. Mediates the ARF-dependent recruitment of clathrin to the TGN and binds ubiquitinated proteins and membrane cargo molecules with a cytosolic acidic cluster-dileucine (DXXLL) motif. Mediates export of the GPCR receptor ADRA2B to the cell surface. Regulates retrograde transport of phosphorylated form of BACE1 from endosomes to the trans-Golgi network.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway: Lysosome (hsa04142)
• Reactome Pathway:
  Amyloid fiber formation (R-HSA-977225)
  TBC/RABGAPs (R-HSA-8854214)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Polydactyly	DIS25BMZ	Strong	Genetic Variation	[2]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[3]

8 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 ADP-ribosylation factor-binding protein GGA2 (GGA2).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of ADP-ribosylation factor-binding protein GGA2 (GGA2).	[6]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the expression of ADP-ribosylation factor-binding protein GGA2 (GGA2).	[7]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of ADP-ribosylation factor-binding protein GGA2 (GGA2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of ADP-ribosylation factor-binding protein GGA2 (GGA2).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ADP-ribosylation factor-binding protein GGA2 (GGA2).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of ADP-ribosylation factor-binding protein GGA2 (GGA2).	[12]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of ADP-ribosylation factor-binding protein GGA2 (GGA2).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of ADP-ribosylation factor-binding protein GGA2 (GGA2).	[5]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of ADP-ribosylation factor-binding protein GGA2 (GGA2).	[10]

References

• [1] Integrative Genomic Analyses Identifies GGA2 as a Cooperative Driver of EGFR-Mediated Lung Tumorigenesis.J Thorac Oncol. 2019 Apr;14(4):656-671. doi: 10.1016/j.jtho.2018.12.004. Epub 2018 Dec 19.
• [2] Association of SNP rs80659072 in the ZRS with polydactyly in Beijing You chickens.PLoS One. 2017 Oct 9;12(10):e0185953. doi: 10.1371/journal.pone.0185953. eCollection 2017.
• [3] GGA2 interacts with EGFR cytoplasmic domain to stabilize the receptor expression and promote cell growth.Sci Rep. 2018 Jan 22;8(1):1368. doi: 10.1038/s41598-018-19542-4.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [6] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [7] ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. doi: 10.1158/1078-0432.CCR-11-2113. Epub 2012 Feb 20.
• [8] Gene expression preferentially regulated by tamoxifen in breast cancer cells and correlations with clinical outcome. Cancer Res. 2006 Jul 15;66(14):7334-40.
• [9] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.