Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW0SOID)

• DOT Name: Serine/threonine-protein kinase N2 (PKN2)
• Synonyms: EC 2.7.11.13; PKN gamma; Protein kinase C-like 2; Protein-kinase C-related kinase 2
• Gene Name: PKN2
• UniProt ID: PKN2_HUMAN
• PDB ID: 4CRS; 4RRV; 6CCY; 6GBE
• EC Number: 2.7.11.13
• Pfam ID: PF02185 ; PF00069 ; PF00433
• Sequence:
  MASNPERGEILLTELQGDSRSLPFSENVSAVQKLDFSDTMVQQKLDDIKDRIKREIRKEL
  KIKEGAENLRKVTTDKKSLAYVDNILKKSNKKLEELHHKLQELNAHIVVSDPEDITDCPR
  TPDTPNNDPRCSTSNNRLKALQKQLDIELKVKQGAENMIQMYSNGSSKDRKLHGTAQQLL
  QDSKTKIEVIRMQILQAVQTNELAFDNAKPVISPLELRMEELRHHFRIEFAVAEGAKNVM
  KLLGSGKVTDRKALSEAQARFNESSQKLDLLKYSLEQRLNEVPKNHPKSRIIIEELSLVA
  ASPTLSPRQSMISTQNQYSTLSKPAALTGTLEVRLMGCQDILENVPGRSKATSVALPGWS
  PSETRSSFMSRTSKSKSGSSRNLLKTDDLSNDVCAVLKLDNTVVGQTSWKPISNQSWDQK
  FTLELDRSRELEISVYWRDWRSLCAVKFLRLEDFLDNQRHGMCLYLEPQGTLFAEVTFFN
  PVIERRPKLQRQKKIFSKQQGKTFLRAPQMNINIATWGRLVRRAIPTVNHSGTFSPQAPV
  PTTVPVVDVRIPQLAPPASDSTVTKLDFDLEPEPPPAPPRASSLGEIDESSELRVLDIPG
  QDSETVFDIQNDRNSILPKSQSEYKPDTPQSGLEYSGIQELEDRRSQQRFQFNLQDFRCC
  AVLGRGHFGKVLLAEYKNTNEMFAIKALKKGDIVARDEVDSLMCEKRIFETVNSVRHPFL
  VNLFACFQTKEHVCFVMEYAAGGDLMMHIHTDVFSEPRAVFYAACVVLGLQYLHEHKIVY
  RDLKLDNLLLDTEGFVKIADFGLCKEGMGYGDRTSTFCGTPEFLAPEVLTETSYTRAVDW
  WGLGVLIYEMLVGESPFPGDDEEEVFDSIVNDEVRYPRFLSTEAISIMRRLLRRNPERRL
  GASEKDAEDVKKHPFFRLIDWSALMDKKVKPPFIPTIRGREDVSNFDDEFTSEAPILTPP
  REPRILSEEEQEMFRDFDYIADWC
• Function: PKC-related serine/threonine-protein kinase and Rho/Rac effector protein that participates in specific signal transduction responses in the cell. Plays a role in the regulation of cell cycle progression, actin cytoskeleton assembly, cell migration, cell adhesion, tumor cell invasion and transcription activation signaling processes. Phosphorylates CTTN in hyaluronan-induced astrocytes and hence decreases CTTN ability to associate with filamentous actin. Phosphorylates HDAC5, therefore lead to impair HDAC5 import. Direct RhoA target required for the regulation of the maturation of primordial junctions into apical junction formation in bronchial epithelial cells. Required for G2/M phases of the cell cycle progression and abscission during cytokinesis in a ECT2-dependent manner. Stimulates FYN kinase activity that is required for establishment of skin cell-cell adhesion during keratinocytes differentiation. Regulates epithelial bladder cells speed and direction of movement during cell migration and tumor cell invasion. Inhibits Akt pro-survival-induced kinase activity. Mediates Rho protein-induced transcriptional activation via the c-fos serum response factor (SRF). Involved in the negative regulation of ciliogenesis ; (Microbial infection) Phosphorylates HCV NS5B leading to stimulation of HCV RNA replication.
• Tissue Specificity: Ubiquitous. Expressed in numerous tumor cell lines, especially in bladder tumor cells.
• KEGG Pathway:
  PI3K-Akt sig.ling pathway (hsa04151)
  NOD-like receptor sig.ling pathway (hsa04621)
  Yersinia infection (hsa05135)
• Reactome Pathway:
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  RHOC GTPase cycle (R-HSA-9013106)
  RAC1 GTPase cycle (R-HSA-9013149)
  RHO GTPases activate PKNs (R-HSA-5625740)

Molecular Interaction Atlas (MIA) of This DOT

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 Serine/threonine-protein kinase N2 (PKN2).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Serine/threonine-protein kinase N2 (PKN2).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine/threonine-protein kinase N2 (PKN2).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein kinase N2 (PKN2).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Serine/threonine-protein kinase N2 (PKN2).	[6]
Marinol	DM70IK5	Approved	Marinol increases the expression of Serine/threonine-protein kinase N2 (PKN2).	[7]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Serine/threonine-protein kinase N2 (PKN2).	[8]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Serine/threonine-protein kinase N2 (PKN2).	[9]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Serine/threonine-protein kinase N2 (PKN2).	[10]
Ximelegatran	DMU8ANS	Approved	Ximelegatran decreases the activity of Serine/threonine-protein kinase N2 (PKN2).	[11]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Serine/threonine-protein kinase N2 (PKN2).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Serine/threonine-protein kinase N2 (PKN2).	[8]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Serine/threonine-protein kinase N2 (PKN2).	[13]
Fasudil	DMTCNOM	Investigative	Fasudil decreases the activity of Serine/threonine-protein kinase N2 (PKN2).	[11]

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 Serine/threonine-protein kinase N2 (PKN2).	[5]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Serine/threonine-protein kinase N2 (PKN2).	[5]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Serine/threonine-protein kinase N2 (PKN2).	[5]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] 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.
• [5] 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.
• [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] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [8] 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.
• [9] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [10] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [11] Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105.
• [12] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [13] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.