Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUCGL9L)

• DOT Name: Protein PALS1 (PALS1)
• Synonyms: MAGUK p55 subfamily member 5; Membrane protein, palmitoylated 5; Protein associated with Lin-7 1
• Gene Name: PALS1
• UniProt ID: PALS1_HUMAN
• PDB ID: 1Y76; 3UIT; 4UU5; 4UU6; 4WSI; 7M4R; 7NTJ; 7NTK; 7QCS
• Pfam ID: PF00625 ; PF02828 ; PF09060 ; PF00595 ; PF07653
• Sequence:
  MTTSHMNGHVTEESDSEVKNVDLASPEEHQKHREMAVDCPGDLGTRMMPIRRSAQLERIR
  QQQEDMRRRREEEGKKQELDLNSSMRLKKLAQIPPKTGIDNPMFDTEEGIVLESPHYAVK
  ILEIEDLFSSLKHIQHTLVDSQSQEDISLLLQLVQNKDFQNAFKIHNAITVHMNKASPPF
  PLISNAQDLAQEVQTVLKPVHHKEGQELTALLNTPHIQALLLAHDKVAEQEMQLEPITDE
  RVYESIGQYGGETVKIVRIEKARDIPLGATVRNEMDSVIISRIVKGGAAEKSGLLHEGDE
  VLEINGIEIRGKDVNEVFDLLSDMHGTLTFVLIPSQQIKPPPAKETVIHVKAHFDYDPSD
  DPYVPCRELGLSFQKGDILHVISQEDPNWWQAYREGDEDNQPLAGLVPGKSFQQQREAMK
  QTIEEDKEPEKSGKLWCAKKNKKKRKKVLYNANKNDDYDNEEILTYEEMSLYHQPANRKR
  PIILIGPQNCGQNELRQRLMNKEKDRFASAVPHTTRSRRDQEVAGRDYHFVSRQAFEADI
  AAGKFIEHGEFEKNLYGTSIDSVRQVINSGKICLLSLRTQSLKTLRNSDLKPYIIFIAPP
  SQERLRALLAKEGKNPKPEELREIIEKTREMEQNNGHYFDTAIVNSDLDKAYQELLRLIN
  KLDTEPQWVPSTWLR
• Function: Plays a role in tight junction biogenesis and in the establishment of cell polarity in epithelial cells. Also involved in adherens junction biogenesis by ensuring correct localization of the exocyst complex protein EXOC4/SEC8 which allows trafficking of adherens junction structural component CDH1 to the cell surface. Plays a role through its interaction with CDH5 in vascular lumen formation and endothelial membrane polarity. Required during embryonic and postnatal retinal development. Required for the maintenance of cerebellar progenitor cells in an undifferentiated proliferative state, preventing premature differentiation, and is required for cerebellar histogenesis, fissure formation, cerebellar layer organization and cortical development. Plays a role in neuronal progenitor cell survival, potentially via promotion of mTOR signaling. Plays a role in the radial and longitudinal extension of the myelin sheath in Schwann cells. May modulate SC6A1/GAT1-mediated GABA uptake by stabilizing the transporter. Plays a role in the T-cell receptor-mediated activation of NF-kappa-B. Required for localization of EZR to the apical membrane of parietal cells and may play a role in the dynamic remodeling of the apical cytoskeleton. Required for the normal polarized localization of the vesicular marker STX4. Required for the correct trafficking of the myelin proteins PMP22 and MAG. Involved in promoting phosphorylation and cytoplasmic retention of transcriptional coactivators YAP1 and WWTR1/TAZ which leads to suppression of TGFB1-dependent transcription of target genes such as CCN2/CTGF, SERPINE1/PAI1, SNAI1/SNAIL1 and SMAD7; (Microbial infection) Acts as an interaction partner for human coronaviruses SARS-CoV and, probably, SARS-CoV-2 envelope protein E which results in delayed formation of tight junctions and disregulation of cell polarity.
• Tissue Specificity: Expressed at the outer limiting membrane in the retina (at protein level) . Expressed in T lymphocytes (at protein level) . Expressed in the kidney (at protein level) .
• KEGG Pathway:
  Hippo sig.ling pathway (hsa04390)
  Tight junction (hsa04530)
  Human papillomavirus infection (hsa05165)
• Reactome Pathway:
  SARS-CoV-1 targets PDZ proteins in cell-cell junction (R-HSA-9692912)
  SARS-CoV-2 targets PDZ proteins in cell-cell junction (R-HSA-9705677)
  Tight junction interactions (R-HSA-420029)

Molecular Interaction Atlas (MIA) of This DOT

10 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 Protein PALS1 (PALS1).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein PALS1 (PALS1).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein PALS1 (PALS1).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein PALS1 (PALS1).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein PALS1 (PALS1).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Protein PALS1 (PALS1).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein PALS1 (PALS1).	[8]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Protein PALS1 (PALS1).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein PALS1 (PALS1).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein PALS1 (PALS1).	[11]

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 Protein PALS1 (PALS1).	[4]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Protein PALS1 (PALS1).	[12]

References

• [1] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] 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.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] 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.
• [7] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [8] 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.
• [9] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [10] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [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] 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.