Details of Drug Off-Target (DOT)

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

• DOT Name: Citron Rho-interacting kinase (CIT)
• Synonyms: CRIK; EC 2.7.11.1; Serine/threonine-protein kinase 21
• Gene Name: CIT
• Related Disease:
  Microcephaly 11, primary, autosomal recessive
  Microcephaly 17, primary, autosomal recessive
  Autosomal recessive primary microcephaly
• UniProt ID: CTRO_HUMAN
• EC Number: 2.7.11.1
• Pfam ID: PF00780 ; PF00169 ; PF00069 ; PF00433
• Sequence:
  MLKFKYGARNPLDAGAAEPIASRASRLNLFFQGKPPFMTQQQMSPLSREGILDALFVLFE
  ECSQPALMKIKHVSNFVRKYSDTIAELQELQPSAKDFEVRSLVGCGHFAEVQVVREKATG
  DIYAMKVMKKKALLAQEQVSFFEEERNILSRSTSPWIPQLQYAFQDKNHLYLVMEYQPGG
  DLLSLLNRYEDQLDENLIQFYLAELILAVHSVHLMGYVHRDIKPENILVDRTGHIKLVDF
  GSAAKMNSNKMVNAKLPIGTPDYMAPEVLTVMNGDGKGTYGLDCDWWSVGVIAYEMIYGR
  SPFAEGTSARTFNNIMNFQRFLKFPDDPKVSSDFLDLIQSLLCGQKERLKFEGLCCHPFF
  SKIDWNNIRNSPPPFVPTLKSDDDTSNFDEPEKNSWVSSSPCQLSPSGFSGEELPFVGFS
  YSKALGILGRSESVVSGLDSPAKTSSMEKKLLIKSKELQDSQDKCHKMEQEMTRLHRRVS
  EVEAVLSQKEVELKASETQRSLLEQDLATYITECSSLKRSLEQARMEVSQEDDKALQLLH
  DIREQSRKLQEIKEQEYQAQVEEMRLMMNQLEEDLVSARRRSDLYESELRESRLAAEEFK
  RKATECQHKLLKAKDQGKPEVGEYAKLEKINAEQQLKIQELQEKLEKAVKASTEATELLQ
  NIRQAKERAERELEKLQNREDSSEGIRKKLVEAEELEEKHREAQVSAQHLEVHLKQKEQH
  YEEKIKVLDNQIKKDLADKETLENMMQRHEEEAHEKGKILSEQKAMINAMDSKIRSLEQR
  IVELSEANKLAANSSLFTQRNMKAQEEMISELRQQKFYLETQAGKLEAQNRKLEEQLEKI
  SHQDHSDKNRLLELETRLREVSLEHEEQKLELKRQLTELQLSLQERESQLTALQAARAAL
  ESQLRQAKTELEETTAEAEEEIQALTAHRDEIQRKFDALRNSCTVITDLEEQLNQLTEDN
  AELNNQNFYLSKQLDEASGANDEIVQLRSEVDHLRREITEREMQLTSQKQTMEALKTTCT
  MLEEQVMDLEALNDELLEKERQWEAWRSVLGDEKSQFECRVRELQRMLDTEKQSRARADQ
  RITESRQVVELAVKEHKAEILALQQALKEQKLKAESLSDKLNDLEKKHAMLEMNARSLQQ
  KLETERELKQRLLEEQAKLQQQMDLQKNHIFRLTQGLQEALDRADLLKTERSDLEYQLEN
  IQVLYSHEKVKMEGTISQQTKLIDFLQAKMDQPAKKKKGLFSRRKEDPALPTQVPLQYNE
  LKLALEKEKARCAELEEALQKTRIELRSAREEAAHRKATDHPHPSTPATARQQIAMSAIV
  RSPEHQPSAMSLLAPPSSRRKESSTPEEFSRRLKERMHHNIPHRFNVGLNMRATKCAVCL
  DTVHFGRQASKCLECQVMCHPKCSTCLPATCGLPAEYATHFTEAFCRDKMNSPGLQTKEP
  SSSLHLEGWMKVPRNNKRGQQGWDRKYIVLEGSKVLIYDNEAREAGQRPVEEFELCLPDG
  DVSIHGAVGASELANTAKADVPYILKMESHPHTTCWPGRTLYLLAPSFPDKQRWVTALES
  VVAGGRVSREKAEADAKLLGNSLLKLEGDDRLDMNCTLPFSDQVVLVGTEEGLYALNVLK
  NSLTHVPGIGAVFQIYIIKDLEKLLMIAGEERALCLVDVKKVKQSLAQSHLPAQPDISPN
  IFEAVKGCHLFGAGKIENGLCICAAMPSKVVILRYNENLSKYCIRKEIETSEPCSCIHFT
  NYSILIGTNKFYEIDMKQYTLEEFLDKNDHSLAPAVFAASSNSFPVSIVQVNSAGQREEY
  LLCFHEFGVFVDSYGRRSRTDDLKWSRLPLAFAYREPYLFVTHFNSLEVIEIQARSSAGT
  PARAYLDIPNPRYLGPAISSGAIYLASSYQDKLRVICCKGNLVKESGTEHHRGPSTSRSS
  PNKRGPPTYNEHITKRVASSPAPPEGPSHPREPSTPHRYREGRTELRRDKSPGRPLEREK
  SPGRMLSTRRERSPGRLFEDSSRGRLPAGAVRTPLSQVNKVWDQSSV
• Function: Plays a role in cytokinesis. Required for KIF14 localization to the central spindle and midbody. Putative RHO/RAC effector that binds to the GTP-bound forms of RHO and RAC1. It probably binds p21 with a tighter specificity in vivo. Displays serine/threonine protein kinase activity. Plays an important role in the regulation of cytokinesis and the development of the central nervous system. Phosphorylates MYL9/MLC2.
• 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 CIT (R-HSA-5625900)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Microcephaly 11, primary, autosomal recessive	DIS07CMQ	Strong	Autosomal recessive	[1]
Microcephaly 17, primary, autosomal recessive	DISDKOW7	Strong	Autosomal recessive	[2]
Autosomal recessive primary microcephaly	DIS29IE3	Supportive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Citron Rho-interacting kinase (CIT).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Citron Rho-interacting kinase (CIT).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Citron Rho-interacting kinase (CIT).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Citron Rho-interacting kinase (CIT).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Citron Rho-interacting kinase (CIT).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Citron Rho-interacting kinase (CIT).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Citron Rho-interacting kinase (CIT).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Citron Rho-interacting kinase (CIT).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Citron Rho-interacting kinase (CIT).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Citron Rho-interacting kinase (CIT).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Citron Rho-interacting kinase (CIT).	[10]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Citron Rho-interacting kinase (CIT).	[11]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Citron Rho-interacting kinase (CIT).	[12]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Citron Rho-interacting kinase (CIT).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Citron Rho-interacting kinase (CIT).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein affects the expression of Citron Rho-interacting kinase (CIT).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Citron Rho-interacting kinase (CIT).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Citron Rho-interacting kinase (CIT).	[17]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Citron Rho-interacting kinase (CIT).	[20]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Citron Rho-interacting kinase (CIT).	[21]

References

• [1] Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly. Am J Hum Genet. 2016 Aug 4;99(2):501-10. doi: 10.1016/j.ajhg.2016.07.004. Epub 2016 Jul 21.
• [2] Mutations in Citron Kinase Cause Recessive Microlissencephaly with Multinucleated Neurons. Am J Hum Genet. 2016 Aug 4;99(2):511-20. doi: 10.1016/j.ajhg.2016.07.003. Epub 2016 Jul 21.
• [3] 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.
• [4] 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.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [7] 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.
• [8] 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.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [11] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [12] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [13] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [14] 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.
• [15] The molecular basis of genistein-induced mitotic arrest and exit of self-renewal in embryonal carcinoma and primary cancer cell lines. BMC Med Genomics. 2008 Oct 10;1:49.
• [16] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] 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.
• [20] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [21] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.