Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7ZI7AG)

• DOT Name: Endoplasmic reticulum resident protein 44 (ERP44)
• Synonyms: ER protein 44; ERp44; Thioredoxin domain-containing protein 4
• Gene Name: ERP44
• Related Disease:
  Diabetic kidney disease
  Insulinoma
  Non-insulin dependent diabetes
  Prostate cancer
  Prostate neoplasm
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Neuroblastoma
• UniProt ID: ERP44_HUMAN
• PDB ID: 2R2J; 5GU6; 5GU7; 5HQP; 5XWM
• Pfam ID: PF00085 ; PF13848
• Sequence:
  MHPAVFLSLPDLRCSLLLLVTWVFTPVTTEITSLDTENIDEILNNADVALVNFYADWCRF
  SQMLHPIFEEASDVIKEEFPNENQVVFARVDCDQHSDIAQRYRISKYPTLKLFRNGMMMK
  REYRGQRSVKALADYIRQQKSDPIQEIRDLAEITTLDRSKRNIIGYFEQKDSDNYRVFER
  VANILHDDCAFLSAFGDVSKPERYSGDNIIYKPPGHSAPDMVYLGAMTNFDVTYNWIQDK
  CVPLVREITFENGEELTEEGLPFLILFHMKEDTESLEIFQNEVARQLISEKGTINFLHAD
  CDKFRHPLLHIQKTPADCPVIAIDSFRHMYVFGDFKDVLIPGKLKQFVFDLHSGKLHREF
  HHGPDPTDTAPGEQAQDVASSPPESSFQKLAPSEYRYTLLRDRDEL
• Function: Mediates thiol-dependent retention in the early secretory pathway, forming mixed disulfides with substrate proteins through its conserved CRFS motif. Inhibits the calcium channel activity of ITPR1. May have a role in the control of oxidative protein folding in the endoplasmic reticulum. Required to retain ERO1A and ERO1B in the endoplasmic reticulum.
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[1]
Insulinoma	DISIU1JS	Strong	Altered Expression	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Biomarker	[4]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[4]
Lung adenocarcinoma	DISD51WR	Limited	Biomarker	[5]
Lung cancer	DISCM4YA	Limited	Biomarker	[5]
Lung carcinoma	DISTR26C	Limited	Biomarker	[5]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[5]

1 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 Endoplasmic reticulum resident protein 44 (ERP44).	[6]

11 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 Endoplasmic reticulum resident protein 44 (ERP44).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Endoplasmic reticulum resident protein 44 (ERP44).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Endoplasmic reticulum resident protein 44 (ERP44).	[9]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Endoplasmic reticulum resident protein 44 (ERP44).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Endoplasmic reticulum resident protein 44 (ERP44).	[11]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Endoplasmic reticulum resident protein 44 (ERP44).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Endoplasmic reticulum resident protein 44 (ERP44).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Endoplasmic reticulum resident protein 44 (ERP44).	[14]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Endoplasmic reticulum resident protein 44 (ERP44).	[15]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Endoplasmic reticulum resident protein 44 (ERP44).	[16]
L-Serine	DM6WPIS	Investigative	L-Serine increases the expression of Endoplasmic reticulum resident protein 44 (ERP44).	[17]

References

• [1] ERp44 depletion exacerbates ER stress and aggravates diabetic nephropathy in db/db mice.Biochem Biophys Res Commun. 2018 Oct 12;504(4):921-926. doi: 10.1016/j.bbrc.2018.09.037. Epub 2018 Sep 14.
• [2] IRE1-XBP1 pathway regulates oxidative proinsulin folding in pancreatic cells.J Cell Biol. 2018 Apr 2;217(4):1287-1301. doi: 10.1083/jcb.201707143. Epub 2018 Mar 5.
• [3] The role of ERp44 in glucose and lipid metabolism.Arch Biochem Biophys. 2019 Aug 15;671:175-184. doi: 10.1016/j.abb.2019.06.011. Epub 2019 Jul 5.
• [4] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [5] ERP44 inhibits human lung cancer cell migration mainly via IP3R2.Aging (Albany NY). 2016 Jun;8(6):1276-86. doi: 10.18632/aging.100984.
• [6] 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.
• [7] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [8] 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.
• [9] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [10] 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.
• [11] 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.
• [12] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [13] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [15] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [16] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.
• [17] Mechanisms of L-Serine Neuroprotection in vitro Include ER Proteostasis Regulation. Neurotox Res. 2018 Jan;33(1):123-132. doi: 10.1007/s12640-017-9829-3. Epub 2017 Nov 2.