Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2ZCDS7)

• DOT Name: Lysosomal cholesterol signaling protein (GPR155)
• Synonyms: LYCHOS; G-protein coupled receptor PGR22
• Gene Name: GPR155
• Related Disease:
  Autism
  Autism spectrum disorder
  Gastric cancer
  Hepatocellular carcinoma
  Stomach cancer
• UniProt ID: LYCHS_HUMAN
• Pfam ID: PF00610 ; PF03547
• Sequence:
  MNSNLPAENLTIAVNMTKTLPTAVTHGFNSTNDPPSMSITRLFPALLECFGIVLCGYIAG
  RANVITSTQAKGLGNFVSRFALPALLFKNMVVLNFSNVDWSFLYSILIAKASVFFIVCVL
  TLLVASPDSRFSKAGLFPIFATQSNDFALGYPIVEALYQTTYPEYLQYIYLVAPISLMML
  NPIGFIFCEIQKWKDTQNASQNKIKIVGLGLLRVLQNPIVFMVFIGIAFNFILDRKVPVY
  VENFLDGLGNSFSGSALFYLGLTMVGKIKRLKKSAFVVLILLITAKLLVLPLLCREMVEL
  LDKGDSVVNHTSLSNYAFLYGVFPVAPGVAIFATQFNMEVEIITSGMVISTFVSAPIMYV
  SAWLLTFPTMDPKPLAYAIQNVSFDISIVSLISLIWSLAILLLSKKYKQLPHMLTTNLLI
  AQSIVCAGMMIWNFVKEKNFVGQILVFVLLYSSLYSTYLWTGLLAISLFLLKKRERVQIP
  VGIIIISGWGIPALLVGVLLITGKHNGDSIDSAFFYGKEQMITTAVTLFCSILIAGISLM
  CMNQTAQAGSYEGFDQSQSHKVVEPGNTAFEESPAPVNEPELFTSSIPETSCCSCSMGNG
  ELHCPSIEPIANTSTSEPVIPSFEKNNHCVSRCNSQSCILAQEEEQYLQSGDQQLTRHVL
  LCLLLIIGLFANLSSCLWWLFNQEPGRLYVELQFFCAVFNFGQGFISFGIFGLDKHLIIL
  PFKRRLEFLWNNKDTAENRDSPVSEEIKMTCQQFIHYHRDLCIRNIVKERRCGAKTSAGT
  FCGCDLVSWLIEVGLASDRGEAVIYGDRLVQGGVIQHITNEYEFRDEYLFYRFLQKSPEQ
  SPPAINANTLQQERYKEIEHSSPPSHSPKT
• Function: Cholesterol-binding protein that acts as a regulator of mTORC1 signaling pathway. Acts as a sensor of cholesterol to signal cholesterol sufficiency to mTORC1: in presence of cholesterol, binds cholesterol, leading to disrupt interaction between the GATOR1 and KICSTOR complexes and promote mTORC1 signaling. Upon cholesterol starvation, GPR155/LYCHOS is unable to perturb the association between GATOR1 and KICSTOR, leading to mTORC1 signaling inhibition.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Strong	Biomarker	[1]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[1]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[3]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Lysosomal cholesterol signaling protein (GPR155).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Lysosomal cholesterol signaling protein (GPR155).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Lysosomal cholesterol signaling protein (GPR155).	[6]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Lysosomal cholesterol signaling protein (GPR155).	[8]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Lysosomal cholesterol signaling protein (GPR155).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Lysosomal cholesterol signaling protein (GPR155).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Lysosomal cholesterol signaling protein (GPR155).	[12]

2 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 Lysosomal cholesterol signaling protein (GPR155).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Lysosomal cholesterol signaling protein (GPR155).	[11]

References

• [1] Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways.Hum Mol Genet. 2007 Jul 15;16(14):1682-98. doi: 10.1093/hmg/ddm116. Epub 2007 May 21.
• [2] GPR155 Serves as a Predictive Biomarker for Hematogenous Metastasis in Patients with Gastric Cancer.Sci Rep. 2017 Feb 6;7:42089. doi: 10.1038/srep42089.
• [3] Downregulation of GPR155 as a prognostic factor after curative resection of hepatocellular carcinoma.BMC Cancer. 2017 Sep 1;17(1):610. doi: 10.1186/s12885-017-3629-2.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 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.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] 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.
• [12] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.