Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV2AXQM)

• DOT Name: Rhotekin-2 (RTKN2)
• Synonyms: Pleckstrin homology domain-containing family K member 1; PH domain-containing family K member 1
• Gene Name: RTKN2
• Related Disease:
  Advanced cancer
  Bladder cancer
  Breast carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Hepatocellular carcinoma
  Neoplasm
  Ovarian cancer
  Schizophrenia
  Urinary bladder cancer
  Urinary bladder neoplasm
  Bone osteosarcoma
  Idiopathic interstitial pneumonia
  Osteosarcoma
  Rheumatoid arthritis
  Systemic lupus erythematosus
• UniProt ID: RTKN2_HUMAN
• Pfam ID: PF08174 ; PF00169
• Sequence:
  MEGPSLRGPALRLAGLPTQQDCNIQEKIDLEIRMREGIWKLLSLSTQKDQVLHAVKNLMV
  CNARLMAYTSELQKLEEQIANQTGRCDVKFESKERTACKGKIAISDIRIPLMWKDSDHFS
  NKERSRRYAIFCLFKMGANVFDTDVVNVDKTITDICFENVTIFNEAGPDFQIKVEVYSCC
  TEESSITNTPKKLAKKLKTSISKATGKKISSVLQEEDDEMCLLLSSAVFGVKYNLLAHTT
  LTLESAEDSFKTHNLSINGNEESSFWLPLYGNMCCRLVAQPACMAEDAFAGFLNQQQMVE
  GLISWRRLYCVLRGGKLYCFYSPEEIEAKVEPALVVPINKETRIRAMDKDAKKRIHNFSV
  INPVPGQAITQIFAVDNREDLQKWMEAFWQHFFDLSQWKHCCEELMKIEIMSPRKPPLFL
  TKEATSVYHDMSIDSPMKLESLTDIIQKKIEETNGQFLIGQHEESLPPPWATLFDGNHQM
  VIQKKVLYPASEPLHDEKGKKRQAPLPPSDKLPFSLKSQSNTDQLVKDNWGKTSVSQTSS
  LDTKLSTLMHHLQKPMAAPRKLLPARRNRLSDGEHTDTKTNFEAKPVPAPRQKSIKDILD
  PRSWLQAQV
• Function: May play an important role in lymphopoiesis.
• Tissue Specificity: Expressed in lymphocytes, CD4 positive T-cells and bone marrow-derived cells. Also expressed in lung, colon, thymus and brain.

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[6]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[7]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[1]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[1]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[8]
Idiopathic interstitial pneumonia	DISH7LPY	Limited	Altered Expression	[9]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[8]
Rheumatoid arthritis	DISTSB4J	Limited	Genetic Variation	[10]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Rhotekin-2 (RTKN2).	[12]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Rhotekin-2 (RTKN2).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Rhotekin-2 (RTKN2).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Rhotekin-2 (RTKN2).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Rhotekin-2 (RTKN2).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Rhotekin-2 (RTKN2).	[16]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Rhotekin-2 (RTKN2).	[16]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Rhotekin-2 (RTKN2).	[17]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of Rhotekin-2 (RTKN2).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Rhotekin-2 (RTKN2).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Rhotekin-2 (RTKN2).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Rhotekin-2 (RTKN2).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Rhotekin-2 (RTKN2).	[23]

References

• [1] Silencing of RTKN2 by siRNA suppresses proliferation, and induces G1 arrest and apoptosis in human bladder cancer cells.Mol Med Rep. 2016 Jun;13(6):4872-8. doi: 10.3892/mmr.2016.5127. Epub 2016 Apr 14.
• [2] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [3] Knockdown of Rhotekin 2 expression suppresses proliferation and induces apoptosis in colon cancer cells.Oncol Lett. 2017 Dec;14(6):8028-8034. doi: 10.3892/ol.2017.7182. Epub 2017 Oct 13.
• [4] Genome-wide association study identifies a new SMAD7 risk variant associated with colorectal cancer risk in East Asians.Int J Cancer. 2014 Aug 15;135(4):948-55. doi: 10.1002/ijc.28733. Epub 2014 Jan 29.
• [5] Knockdown of Rhotekin2 expression suppresses proliferation and invasion and induces apoptosis in hepatocellular carcinoma cells.Mol Med Rep. 2016 Jun;13(6):4865-71. doi: 10.3892/mmr.2016.5113. Epub 2016 Apr 13.
• [6] MicroRNA-181 Functions as an Antioncogene and Mediates NF-B Pathway by Targeting RTKN2 in Ovarian Cancers.Reprod Sci. 2019 Aug;26(8):1071-1081. doi: 10.1177/1933719118805865. Epub 2018 Oct 11.
• [7] Genome-wide association study of schizophrenia in Ashkenazi Jews.Am J Med Genet B Neuropsychiatr Genet. 2015 Dec;168(8):649-59. doi: 10.1002/ajmg.b.32349. Epub 2015 Jul 21.
• [8] Rhotekin 2 silencing inhibits proliferation and induces apoptosis in human osteosarcoma cells.Biosci Rep. 2018 Nov 20;38(6):BSR20181384. doi: 10.1042/BSR20181384. Print 2018 Dec 21.
• [9] Relationship between gene expression and lung function in Idiopathic Interstitial Pneumonias.BMC Genomics. 2015 Oct 26;16:869. doi: 10.1186/s12864-015-2102-3.
• [10] Functional variants in NFKBIE and RTKN2 involved in activation of the NF-B pathway are associated with rheumatoid arthritis in Japanese.PLoS Genet. 2012 Sep;8(9):e1002949. doi: 10.1371/journal.pgen.1002949. Epub 2012 Sep 13.
• [11] Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus.Nat Genet. 2015 Dec;47(12):1457-1464. doi: 10.1038/ng.3434. Epub 2015 Oct 26.
• [12] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [13] 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.
• [14] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [17] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [18] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [19] 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.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [22] 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.
• [23] 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.