Details of Drug Off-Target (DOT)

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

• DOT Name: Myelin protein zero-like protein 1 (MPZL1)
• Synonyms: Protein zero-related
• Gene Name: MPZL1
• Related Disease:
  Carcinoma
  Gallbladder carcinoma
  Alzheimer disease
  Demyelinating polyneuropathy
  Epithelial ovarian cancer
  Hepatocellular carcinoma
  HER2/NEU overexpressing breast cancer
  Noonan syndrome
  Ovarian cancer
  Ovarian neoplasm
  Schizophrenia
  Neoplasm
  Undifferentiated carcinoma
• UniProt ID: MPZL1_HUMAN
• PDB ID: 6IGO; 6IGT; 6IGW
• Pfam ID: PF07686
• Sequence:
  MAASAGAGAVIAAPDSRRWLWSVLAAALGLLTAGVSALEVYTPKEIFVANGTQGKLTCKF
  KSTSTTGGLTSVSWSFQPEGADTTVSFFHYSQGQVYLGNYPPFKDRISWAGDLDKKDASI
  NIENMQFIHNGTYICDVKNPPDIVVQPGHIRLYVVEKENLPVFPVWVVVGIVTAVVLGLT
  LLISMILAVLYRRKNSKRDYTGCSTSESLSPVKQAPRKSPSDTEGLVKSLPSGSHQGPVI
  YAQLDHSGGHHSDKINKSESVVYADIRKN
• Function: Cell surface receptor, which is involved in signal transduction processes. Recruits PTPN11/SHP-2 to the cell membrane and is a putative substrate of PTPN11/SHP-2. Is a major receptor for concanavalin-A (ConA) and is involved in cellular signaling induced by ConA, which probably includes Src family tyrosine-protein kinases. Isoform 3 seems to have a dominant negative role; it blocks tyrosine phosphorylation of MPZL1 induced by ConA. Isoform 1, but not isoform 2 and isoform 3, may be involved in regulation of integrin-mediated cell motility.
• Tissue Specificity: Widely expressed with highest levels in heart, placenta, kidney and pancreas. Isoform 3 is relatively abundant in hematopoietic tissues and fetal liver. Isoform 1 and isoform 3 are expressed in CD14- PB monocytes and pre-B cell progenitors. Isoform 3 appears to be the major isoform in CD34- promyelocytic and promonocytic cells. During differentiation in monocytic cells, the expression level of isoform 3 decreases and that of isoform 1 increases. Isoform 1 is prominent in stromal cells and, to a lesser extent, in umbilical vein endothelial cells and erythroid progenitors. Isoform 2 is expressed in a erythroid progenitor cell line.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma	DISH9F1N	Definitive	Biomarker	[1]
Gallbladder carcinoma	DISD6ACL	Definitive	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Demyelinating polyneuropathy	DIS7IO4W	Strong	Biomarker	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
HER2/NEU overexpressing breast cancer	DISYKID5	Strong	Biomarker	[6]
Noonan syndrome	DIS7Q7DN	Strong	Biomarker	[7]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[5]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[5]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[8]
Neoplasm	DISZKGEW	moderate	Altered Expression	[2]
Undifferentiated carcinoma	DISIAZST	Disputed	Biomarker	[1]

22 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 Myelin protein zero-like protein 1 (MPZL1).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Myelin protein zero-like protein 1 (MPZL1).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Myelin protein zero-like protein 1 (MPZL1).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Myelin protein zero-like protein 1 (MPZL1).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Myelin protein zero-like protein 1 (MPZL1).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Myelin protein zero-like protein 1 (MPZL1).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Myelin protein zero-like protein 1 (MPZL1).	[15]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Myelin protein zero-like protein 1 (MPZL1).	[17]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Myelin protein zero-like protein 1 (MPZL1).	[18]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Myelin protein zero-like protein 1 (MPZL1).	[14]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of Myelin protein zero-like protein 1 (MPZL1).	[14]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Myelin protein zero-like protein 1 (MPZL1).	[19]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea decreases the expression of Myelin protein zero-like protein 1 (MPZL1).	[14]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of Myelin protein zero-like protein 1 (MPZL1).	[14]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Myelin protein zero-like protein 1 (MPZL1).	[20]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Myelin protein zero-like protein 1 (MPZL1).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Myelin protein zero-like protein 1 (MPZL1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Myelin protein zero-like protein 1 (MPZL1).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Myelin protein zero-like protein 1 (MPZL1).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Myelin protein zero-like protein 1 (MPZL1).	[26]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Myelin protein zero-like protein 1 (MPZL1).	[27]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Myelin protein zero-like protein 1 (MPZL1).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Myelin protein zero-like protein 1 (MPZL1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Myelin protein zero-like protein 1 (MPZL1).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Myelin protein zero-like protein 1 (MPZL1).	[16]

References

• [1] Global gene expression profiling of chemically induced rat mammary gland carcinomas and adenomas.Toxicol Pathol. 2005;33(7):768-75. doi: 10.1080/01926230500437027.
• [2] MPZL1 is highly expressed in advanced gallbladder carcinoma and promotes the aggressive behavior of human gallbladder carcinoma GBCSD cells.Mol Med Rep. 2019 Sep;20(3):2725-2733. doi: 10.3892/mmr.2019.10506. Epub 2019 Jul 18.
• [3] Genome-wide association and linkage study in the Amish detects a novel candidate late-onset Alzheimer disease gene.Ann Hum Genet. 2012 Sep;76(5):342-51. doi: 10.1111/j.1469-1809.2012.00721.x.
• [4] Infantile-Onset Myelin Protein Zero-Related Demyelinating Neuropathy Presenting as an Upper Extremity Monoplegia.Semin Pediatr Neurol. 2018 Jul;26:52-55. doi: 10.1016/j.spen.2017.03.005. Epub 2017 Apr 1.
• [5] MPZL1 promotes tumor cell proliferation and migration via activation of Src kinase in ovarian cancer.Oncol Rep. 2019 Aug;42(2):679-687. doi: 10.3892/or.2019.7199. Epub 2019 Jun 12.
• [6] MPZL1 forms a signalling complex with GRB2 adaptor and PTPN11 phosphatase in HER2-positive breast cancer cells.Sci Rep. 2017 Sep 14;7(1):11514. doi: 10.1038/s41598-017-11876-9.
• [7] Noonan syndrome-associated SHP-2/Ptpn11 mutants enhance SIRPalpha and PZR tyrosyl phosphorylation and promote adhesion-mediated ERK activation.J Biol Chem. 2008 May 30;283(22):15328-38. doi: 10.1074/jbc.M801382200. Epub 2008 Mar 31.
• [8] MPZL1/PZR, a novel candidate predisposing schizophrenia in Han Chinese.Mol Psychiatry. 2006 Aug;11(8):748-51. doi: 10.1038/sj.mp.4001841. Epub 2006 May 9.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [15] 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.
• [16] 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.
• [17] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [18] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [19] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [20] 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.
• [21] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [22] 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.
• [23] 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.
• [24] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [25] 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.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [27] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [28] An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat. Toxicol In Vitro. 2022 Jun;81:105333. doi: 10.1016/j.tiv.2022.105333. Epub 2022 Feb 16.