Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ1Z0OU)

• DOT Name: Proline-rich protein 5-like (PRR5L)
• Synonyms: Protein observed with Rictor-2; Protor-2
• Gene Name: PRR5L
• Related Disease:
  Atopic dermatitis
  Breast cancer
  Breast carcinoma
  Asthma
  Non-insulin dependent diabetes
• UniProt ID: PRR5L_HUMAN
• Pfam ID: PF08539
• Sequence:
  MTRGFAPILPVEFHKMGSFRRPRPRFMSSPVLSDLPRFQAARQALQLSSSSAWNSVQTAV
  INVFKGGGLQSNELYALNENIRRLLKSELGSFITDYFQNQLLAKGLFFVEEKIKLCEGEN
  RIEVLAEVWDHFFTETLPTLQAIFYPVQGQELTIRQISLLGFRDLVLLKVKLGDLLLLAQ
  SKLPSSIVQMLLILQSVHEPTGPSESYLQLEELVKQVVSPFLGISGDRSFSGPTYTLARR
  HSRVRPKVTVLNYASPITAVSRPLNEMVLTPLTEQEGEAYLEKCGSVRRHTVANAHSDIQ
  LLAMATMMHSGLGEEASSENKCLLLPPSFPPPHRQCSSEPNITDNPDGLEEGARGSQEGS
  ELNCASLS
• Function: Associates with the mTORC2 complex that regulates cellular processes including survival and organization of the cytoskeleton. Regulates the activity of the mTORC2 complex in a substrate-specific manner preventing for instance the specific phosphorylation of PKCs and thereby controlling cell migration. Plays a role in the stimulation of ZFP36-mediated mRNA decay of several ZFP36-associated mRNAs, such as TNF-alpha and GM-CSF, in response to stress. Required for ZFP36 localization to cytoplasmic stress granule (SG) and P-body (PB) in response to stress.
• KEGG Pathway: mTOR sig.ling pathway (hsa04150)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atopic dermatitis	DISTCP41	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Asthma	DISW9QNS	Limited	Genetic Variation	[3]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Proline-rich protein 5-like (PRR5L).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Proline-rich protein 5-like (PRR5L).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Proline-rich protein 5-like (PRR5L).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Proline-rich protein 5-like (PRR5L).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Proline-rich protein 5-like (PRR5L).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Proline-rich protein 5-like (PRR5L).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Proline-rich protein 5-like (PRR5L).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Proline-rich protein 5-like (PRR5L).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Proline-rich protein 5-like (PRR5L).	[7]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Proline-rich protein 5-like (PRR5L).	[14]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Proline-rich protein 5-like (PRR5L).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Proline-rich protein 5-like (PRR5L).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Proline-rich protein 5-like (PRR5L).	[19]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Proline-rich protein 5-like (PRR5L).	[21]

4 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 Proline-rich protein 5-like (PRR5L).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Proline-rich protein 5-like (PRR5L).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Proline-rich protein 5-like (PRR5L).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Proline-rich protein 5-like (PRR5L).	[20]

References

• [1] Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.Nat Genet. 2015 Dec;47(12):1449-1456. doi: 10.1038/ng.3424. Epub 2015 Oct 19.
• [2] Genetic variants in the mTOR pathway and interaction with body size and weight gain on breast cancer risk in African-American and European American women.Cancer Causes Control. 2016 Aug;27(8):965-76. doi: 10.1007/s10552-016-0774-x. Epub 2016 Jun 17.
• [3] Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.Am J Hum Genet. 2019 Apr 4;104(4):665-684. doi: 10.1016/j.ajhg.2019.02.022. Epub 2019 Mar 28.
• [4] Epigenetic associations of type 2 diabetes and BMI in an Arab population.Clin Epigenetics. 2016 Jan 28;8:13. doi: 10.1186/s13148-016-0177-6. eCollection 2016.
• [5] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [6] 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.
• [7] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [8] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [9] 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.
• [10] 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.
• [11] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [12] 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.
• [13] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [14] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [15] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [16] 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.
• [17] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [18] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [19] 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.
• [20] 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.
• [21] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.