Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV6U1ZN)

• DOT Name: Protein Aster-A (GRAMD1A)
• Synonyms: GRAM domain-containing protein 1A
• Gene Name: GRAMD1A
• Related Disease:
  Hepatocellular carcinoma
  Neoplasm
• UniProt ID: ASTRA_HUMAN
• Pfam ID: PF02893 ; PF16016
• Sequence:
  MFDTTPHSGRSTPSSSPSLRKRLQLLPPSRPPPEPEPGTMVEKGSDSSSEKGGVPGTPST
  QSLGSRNFIRNSKKMQSWYSMLSPTYKQRNEDFRKLFSKLPEAERLIVDYSCALQREILL
  QGRLYLSENWICFYSNIFRWETTISIQLKEVTCLKKEKTAKLIPNAIQICTESEKHFFTS
  FGARDRCFLLIFRLWQNALLEKTLSPRELWHLVHQCYGSELGLTSEDEDYVSPLQLNGLG
  TPKEVGDVIALSDITSSGAADRSQEPSPVGSRRGHVTPNLSRASSDADHGAEEDKEEQVD
  SQPDASSSQTVTPVAEPPSTEPTQPDGPTTLGPLDLLPSEELLTDTSNSSSSTGEEADLA
  ALLPDLSGRLLINSVFHVGAERLQQMLFSDSPFLQGFLQQCKFTDVTLSPWSGDSKCHQR
  RVLTYTIPISNPLGPKSASVVETQTLFRRGPQAGGCVVDSEVLTQGIPYQDYFYTAHRYC
  ILGLARNKARLRVSSEIRYRKQPWSLVKSLIEKNSWSGIEDYFHHLERELAKAEKLSLEE
  GGKDARGLLSGLRRRKRPLSWRAHGDGPQHPDPDPCARAGIHTSGSLSSRFSEPSVDQGP
  GAGIPSALVLISIVICVSLIILIALNVLLFYRLWSLERTAHTFESWHSLALAKGKFPQTA
  TEWAEILALQKQFHSVEVHKWRQILRASVELLDEMKFSLEKLHQGITVSDPPFDTQPRPD
  DSFS
• Function: Cholesterol transporter that mediates non-vesicular transport of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER). Contains unique domains for binding cholesterol and the PM, thereby serving as a molecular bridge for the transfer of cholesterol from the PM to the ER. Plays a crucial role in cholesterol homeostasis and has the unique ability to localize to the PM based on the level of membrane cholesterol. In lipid-poor conditions localizes to the ER membrane and in response to excess cholesterol in the PM is recruited to the endoplasmic reticulum-plasma membrane contact sites (EPCS) which is mediated by the GRAM domain. At the EPCS, the sterol-binding VASt/ASTER domain binds to the cholesterol in the PM and facilitates its transfer from the PM to ER. May play a role in tumor progression. Plays a role in autophagy regulation and is required for biogenesis of the autophagosome. This function in autophagy requires its cholesterol-transfer activity.
• Tissue Specificity: Expressed in liver.

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]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]

6 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 Protein Aster-A (GRAMD1A).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein Aster-A (GRAMD1A).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein Aster-A (GRAMD1A).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protein Aster-A (GRAMD1A).	[6]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protein Aster-A (GRAMD1A).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein Aster-A (GRAMD1A).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein Aster-A (GRAMD1A).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Protein Aster-A (GRAMD1A).	[7]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Protein Aster-A (GRAMD1A).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Protein Aster-A (GRAMD1A).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Protein Aster-A (GRAMD1A).	[11]

References

• [1] GRAM domain-containing protein 1A (GRAMD1A) promotes the expansion of hepatocellular carcinoma stem cell and hepatocellular carcinoma growth through STAT5.Sci Rep. 2016 Sep 2;6:31963. doi: 10.1038/srep31963.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] 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.
• [7] 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.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [9] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [10] 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.
• [11] 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.