Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWLV3X1)

• DOT Name: Partitioning defective 6 homolog alpha (PARD6A)
• Synonyms: PAR-6; PAR-6 alpha; PAR-6A; PAR6C; Tax interaction protein 40; TIP-40
• Gene Name: PARD6A
• Related Disease:
  Non-small-cell lung cancer
  Rheumatoid arthritis
  Choriocarcinoma
  Lung cancer
• UniProt ID: PAR6A_HUMAN
• PDB ID: 1WMH
• Pfam ID: PF00564 ; PF00595
• Sequence:
  MARPQRTPARSPDSIVEVKSKFDAEFRRFALPRASVSGFQEFSRLLRAVHQIPGLDVLLG
  YTDAHGDLLPLTNDDSLHRALASGPPPLRLLVQKRAEADSSGLAFASNSLQRRKKGLLLR
  PVAPLRTRPPLLISLPQDFRQVSSVIDVDLLPETHRRVRLHKHGSDRPLGFYIRDGMSVR
  VAPQGLERVPGIFISRLVRGGLAESTGLLAVSDEILEVNGIEVAGKTLDQVTDMMVANSH
  NLIVTVKPANQRNNVVRGASGRLTGPPSAGPGPAEPDSDDDSSDLVIENRQPPSSNGLSQ
  GPPCWDLHPGCRHPGTRSSLPSLDDQEQASSGWGSRIRGDGSGFSL
• Function: Adapter protein involved in asymmetrical cell division and cell polarization processes. Probably involved in the formation of epithelial tight junctions. Association with PARD3 may prevent the interaction of PARD3 with F11R/JAM1, thereby preventing tight junction assembly. The PARD6-PARD3 complex links GTP-bound Rho small GTPases to atypical protein kinase C proteins. Regulates centrosome organization and function. Essential for the centrosomal recruitment of key proteins that control centrosomal microtubule organization.
• Tissue Specificity: Expressed in pancreas, skeletal muscle, brain and heart. Weakly expressed in kidney and placenta.
• KEGG Pathway:
  Rap1 sig.ling pathway (hsa04015)
  Endocytosis (hsa04144)
  Axon guidance (hsa04360)
  Hippo sig.ling pathway (hsa04390)
  Tight junction (hsa04530)
  Human papillomavirus infection (hsa05165)
• Reactome Pathway:
  Tight junction interactions (R-HSA-420029)
  Asymmetric localization of PCP proteins (R-HSA-4608870)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RHOU GTPase cycle (R-HSA-9013420)
  RHOV GTPase cycle (R-HSA-9013424)
  TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) (R-HSA-2173791)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[1]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[2]
Choriocarcinoma	DISDBVNL	moderate	Altered Expression	[3]
Lung cancer	DISCM4YA	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Partitioning defective 6 homolog alpha (PARD6A).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Partitioning defective 6 homolog alpha (PARD6A).	[6]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Partitioning defective 6 homolog alpha (PARD6A).	[7]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Partitioning defective 6 homolog alpha (PARD6A).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Partitioning defective 6 homolog alpha (PARD6A).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Partitioning defective 6 homolog alpha (PARD6A).	[10]

References

• [1] Oncogenic activity of Ect2 is regulated through protein kinase C iota-mediated phosphorylation.J Biol Chem. 2011 Mar 11;286(10):8149-8157. doi: 10.1074/jbc.M110.196113. Epub 2010 Dec 28.
• [2] Atypical protein kinase C iota expression and aurothiomalate sensitivity in human lung cancer cells.Cancer Res. 2008 Jul 15;68(14):5888-95. doi: 10.1158/0008-5472.CAN-08-0438.
• [3] Where polarity meets fusion: role of Par6 in trophoblast differentiation during placental development and preeclampsia.Endocrinology. 2013 Mar;154(3):1296-309. doi: 10.1210/en.2012-1823. Epub 2013 Jan 22.
• [4] Roles of partitioning-defective protein 6 (Par6) and its complexes in the proliferation, migration and invasion of cancer cells.Clin Exp Pharmacol Physiol. 2017 Sep;44(9):909-913. doi: 10.1111/1440-1681.12794.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [8] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.