Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIMDDI3)

• DOT Name: Prosaposin receptor GPR37 (GPR37)
• Synonyms: Endothelin B receptor-like protein 1; ETBR-LP-1; G-protein coupled receptor 37; Parkin-associated endothelin receptor-like receptor; PAELR
• Gene Name: GPR37
• Related Disease:
  Small lymphocytic lymphoma
  Autism
  Autosomal recessive juvenile Parkinson disease 2
  Gastric cancer
  Hepatocellular carcinoma
  Malignant mesothelioma
  Multiple sclerosis
  Parkinson disease
  Progressive myoclonus epilepsy
  Stomach cancer
  Cutaneous melanoma
  Autism spectrum disorder
  Pervasive developmental disorder
  Stroke
• UniProt ID: GPR37_HUMAN
• Pfam ID: PF00001
• Sequence:
  MRAPGALLARMSRLLLLLLLKVSASSALGVAPASRNETCLGESCAPTVIQRRGRDAWGPG
  NSARDVLRARAPREEQGAAFLAGPSWDLPAAPGRDPAAGRGAEASAAGPPGPPTRPPGPW
  RWKGARGQEPSETLGRGNPTALQLFLQISEEEEKGPRGAGISGRSQEQSVKTVPGASDLF
  YWPRRAGKLQGSHHKPLSKTANGLAGHEGWTIALPGRALAQNGSLGEGIHEPGGPRRGNS
  TNRRVRLKNPFYPLTQESYGAYAVMCLSVVIFGTGIIGNLAVMCIVCHNYYMRSISNSLL
  ANLAFWDFLIIFFCLPLVIFHELTKKWLLEDFSCKIVPYIEVASLGVTTFTLCALCIDRF
  RAATNVQMYYEMIENCSSTTAKLAVIWVGALLLALPEVVLRQLSKEDLGFSGRAPAERCI
  IKISPDLPDTIYVLALTYDSARLWWYFGCYFCLPTLFTITCSLVTARKIRKAEKACTRGN
  KRQIQLESQMNCTVVALTILYGFCIIPENICNIVTAYMATGVSQQTMDLLNIISQFLLFF
  KSCVTPVLLFCLCKPFSRAFMECCCCCCEECIQKSSTVTSDDNDNEYTTELELSPFSTIR
  REMSTFASVGTHC
• Function: G-protein-coupled receptor that plays a role in several physiological pathways such as resolution of inflammatory pain and oligodendrocyte differentiation. Acts as a receptor for several ligands including prosaposin, osteocalcin or neuroprotectin D1. Ligand binding induces endocytosis, followed by an ERK phosphorylation cascade. Acts as a receptor for osteocalcin (OCN) to regulate oligodendrocyte differentiation and central nervous system myelination. Mechanistically, plays a negative role in oligodendrocyte differentiation and myelination during development via activation of the ERK1/2 signaling pathway. Therefore, regulates the stability of myelin or resistance of myelin itself to demyelination. Upon activation by neuroprotectin D1 (NPD1), promotes the activation of phagocytosis in macrophages as well as the shift in cytokine release toward an anti-inflammatory profile, and thus helps to reverse inflammatory pain. In addition, the increased macrophage phagocytosis mediates protection against sepsis upon pathogen infection. Additionally, extracellular vesicles derived from efferocyte express prosaposin, which binds to macrophage GPR37 to increase expression of the efferocytosis receptor TIM4 via an ERK-AP1-dependent signaling axis, leading to increased macrophage efferocytosis efficiency and accelerated resolution of inflammation. May also act as a maturation factor of LRP6, protecting LRP6 from the endoplasmic reticulum (ER)-associated protein degradation (ERAD) and thereby promoting the Wnt/beta-catenin signaling pathway.
• Tissue Specificity: Expressed in brain and spinal cord, and at lower levels in testis, placenta and liver, but no detectable expression observed in any other tissue. When overexpressed in cells, tends to become insoluble and unfolded. Accumulation of the unfolded protein may lead to dopaminergic neuronal death in juvenile Parkinson disease (PDJ).
• KEGG Pathway:
  Parkinson disease (hsa05012)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Small lymphocytic lymphoma	DIS30POX	Definitive	Genetic Variation	[1]
Autism	DISV4V1Z	Strong	Genetic Variation	[2]
Autosomal recessive juvenile Parkinson disease 2	DISNSTD1	Strong	Biomarker	[3]
Gastric cancer	DISXGOUK	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Malignant mesothelioma	DISTHJGH	Strong	Biomarker	[6]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[7]
Parkinson disease	DISQVHKL	Strong	Biomarker	[8]
Progressive myoclonus epilepsy	DISAMCNS	Strong	Genetic Variation	[9]
Stomach cancer	DISKIJSX	Strong	Biomarker	[4]
Cutaneous melanoma	DIS3MMH9	moderate	Genetic Variation	[10]
Autism spectrum disorder	DISXK8NV	Limited	Genetic Variation	[2]
Pervasive developmental disorder	DIS51975	Limited	Genetic Variation	[2]
Stroke	DISX6UHX	Limited	Biomarker	[11]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Prosaposin receptor GPR37 (GPR37) affects the response to substance of Etoposide.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Prosaposin receptor GPR37 (GPR37).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Prosaposin receptor GPR37 (GPR37).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Prosaposin receptor GPR37 (GPR37).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Prosaposin receptor GPR37 (GPR37).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Prosaposin receptor GPR37 (GPR37).	[15]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Prosaposin receptor GPR37 (GPR37).	[16]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Prosaposin receptor GPR37 (GPR37).	[17]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Prosaposin receptor GPR37 (GPR37).	[18]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Prosaposin receptor GPR37 (GPR37).	[19]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Prosaposin receptor GPR37 (GPR37).	[20]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Prosaposin receptor GPR37 (GPR37).	[21]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Prosaposin receptor GPR37 (GPR37).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Prosaposin receptor GPR37 (GPR37).	[24]

References

• [1] Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia.Nat Commun. 2017 Feb 6;8:14175. doi: 10.1038/ncomms14175.
• [2] CASPR2 forms a complex with GPR37 via MUPP1 but not with GPR37(R558Q), an autism spectrum disorder-related mutation.J Neurochem. 2015 Aug;134(4):783-93. doi: 10.1111/jnc.13168. Epub 2015 Jun 3.
• [3] Folding Underlies Bidirectional Role of GPR37/Pael-R in Parkinson Disease.Trends Pharmacol Sci. 2017 Aug;38(8):749-760. doi: 10.1016/j.tips.2017.05.006. Epub 2017 Jun 16.
• [4] REG4 promotes peritoneal metastasis of gastric cancer through GPR37.Oncotarget. 2016 May 10;7(19):27874-88. doi: 10.18632/oncotarget.8442.
• [5] A low level of GPR37 is associated with human hepatocellular carcinoma progression and poor patient survival.Pathol Res Pract. 2014 Dec;210(12):885-92. doi: 10.1016/j.prp.2014.07.011. Epub 2014 Aug 9.
• [6] MicroRNA and mRNA features of malignant pleural mesothelioma and benign asbestos-related pleural effusion.Biomed Res Int. 2015;2015:635748. doi: 10.1155/2015/635748. Epub 2015 Feb 1.
• [7] Mice lacking Gpr37 exhibit decreased expression of the myelin-associated glycoprotein MAG and increased susceptibility to demyelination.Neuroscience. 2017 Sep 1;358:49-57. doi: 10.1016/j.neuroscience.2017.06.006. Epub 2017 Jun 20.
• [8] GPR37 and GPR37L1 differently interact with dopamine 2 receptors in live cells.Neuropharmacology. 2019 Jul 1;152:51-57. doi: 10.1016/j.neuropharm.2018.11.009. Epub 2018 Nov 10.
• [9] GPR37L1 modulates seizure susceptibility: Evidence from mouse studies and analyses of a human GPR37L1 variant.Neurobiol Dis. 2017 Oct;106:181-190. doi: 10.1016/j.nbd.2017.07.006. Epub 2017 Jul 6.
• [10] Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma.Nat Genet. 2015 Sep;47(9):987-995. doi: 10.1038/ng.3373. Epub 2015 Aug 3.
• [11] Protective effects of GPR37 via regulation of inflammation and multiple cell death pathways after ischemic stroke in mice.FASEB J. 2019 Oct;33(10):10680-10691. doi: 10.1096/fj.201900070R. Epub 2019 Jul 3.
• [12] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [13] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [14] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [15] 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.
• [16] 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.
• [17] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [18] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [19] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [20] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [21] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [22] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [23] 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.
• [24] 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.
• [25] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.