Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXZ2W65)

• DOT Name: ADP-ribosylation factor-binding protein GGA3 (GGA3)
• Synonyms: Golgi-localized, gamma ear-containing, ARF-binding protein 3
• Gene Name: GGA3
• Related Disease:
  Hepatocellular carcinoma
  Non-insulin dependent diabetes
• UniProt ID: GGA3_HUMAN
• PDB ID: 1JPL; 1JUQ; 1LF8; 1P4U; 1WR6; 1YD8
• Pfam ID: PF02883 ; PF03127 ; PF18308 ; PF00790
• Sequence:
  MAEAEGESLESWLNKATNPSNRQEDWEYIIGFCDQINKELEGPQIAVRLLAHKIQSPQEW
  EALQALTVLEACMKNCGRRFHNEVGKFRFLNELIKVVSPKYLGDRVSEKVKTKVIELLYS
  WTMALPEEAKIKDAYHMLKRQGIVQSDPPIPVDRTLIPSPPPRPKNPVFDDEEKSKLLAK
  LLKSKNPDDLQEANKLIKSMVKEDEARIQKVTKRLHTLEEVNNNVRLLSEMLLHYSQEDS
  SDGDRELMKELFDQCENKRRTLFKLASETEDNDNSLGDILQASDNLSRVINSYKTIIEGQ
  VINGEVATLTLPDSEGNSQCSNQGTLIDLAELDTTNSLSSVLAPAPTPPSSGIPILPPPP
  QASGPPRSRSSSQAEATLGPSSTSNALSWLDEELLCLGLADPAPNVPPKESAGNSQWHLL
  QREQSDLDFFSPRPGTAACGASDAPLLQPSAPSSSSSQAPLPPPFPAPVVPASVPAPSAG
  SSLFSTGVAPALAPKVEPAVPGHHGLALGNSALHHLDALDQLLEEAKVTSGLVKPTTSPL
  IPTTTPARPLLPFSTGPGSPLFQPLSFQSQGSPPKGPELSLASIHVPLESIKPSSALPVT
  AYDKNGFRILFHFAKECPPGRPDVLVVVVSMLNTAPLPVKSIVLQAAVPKSMKVKLQPPS
  GTELSPFSPIQPPAAITQVMLLANPLKEKVRLRYKLTFALGEQLSTEVGEVDQFPPVEQW
  GNL
• 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. nvolved in BACE1 transport and sorting as well as regulation of BACE1 protein levels. Regulates retrograde transport of BACE1 from endosomes to the trans-Golgi network via interaction through the VHS motif and dependent of BACE1 phosphorylation. Modulates BACE1 protein levels independently of the interaction between VHS domain and DXXLL motif through recognition of ubiquitination. Key player in a novel DXXLL-mediated endosomal sorting machinery to the recycling pathway that targets NTRK1 to the plasma membrane.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway: Lysosome (hsa04142)
• Reactome Pathway:
  MET receptor recycling (R-HSA-8875656)
  Amyloid fiber formation (R-HSA-977225)
  TBC/RABGAPs (R-HSA-8854214)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[2]

3 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 ADP-ribosylation factor-binding protein GGA3 (GGA3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of ADP-ribosylation factor-binding protein GGA3 (GGA3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ADP-ribosylation factor-binding protein GGA3 (GGA3).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of ADP-ribosylation factor-binding protein GGA3 (GGA3).	[6]

References

• [1] The Therapeutic Targeting of HGF/c-Met Signaling in Hepatocellular Carcinoma: Alternative Approaches.Cancers (Basel). 2017 May 26;9(6):58. doi: 10.3390/cancers9060058.
• [2] Two novel susceptibility loci for type 2 diabetes mellitus identified by longitudinal exome-wide association studies in a Japanese population.Genomics. 2019 Jan;111(1):34-42. doi: 10.1016/j.ygeno.2017.12.010. Epub 2017 Dec 19.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] 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.
• [6] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.