Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2E7A6W)

• DOT Name: KN motif and ankyrin repeat domain-containing protein 1 (KANK1)
• Synonyms: Ankyrin repeat domain-containing protein 15; Kidney ankyrin repeat-containing protein
• Gene Name: KANK1
• Related Disease:
  Alcohol dependence
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Congenital fibrosis of extraocular muscles
  Gastric cancer
  Kidney cancer
  Malignant peripheral nerve sheath tumor
  Neoplasm
  Nervous system disease
  Neurofibroma
  Polycythemia vera
  Renal carcinoma
  Renal cell carcinoma
  Stomach cancer
  Thrombocytosis disease
  Uterine fibroids
  Acute myelogenous leukaemia
  Advanced cancer
  Nasopharyngeal carcinoma
  Nicotine dependence
  Spastic quadriplegic cerebral palsy
  Intellectual disability
  Basal cell carcinoma
  Basal cell neoplasm
  Cerebral palsy, spastic quadriplegic, 2
  Cholestasis
  Invasive breast carcinoma
  Neoplasm of esophagus
  Nephrotic syndrome
  Neurodevelopmental disorder
• UniProt ID: KANK1_HUMAN
• PDB ID: 5YBJ; 5YBU; 8IW0
• Pfam ID: PF12796 ; PF12075
• Sequence:
  MAHTTKVNGSASGKAGDILSGDQDKEQKDPYFVETPYGYQLDLDFLKYVDDIQKGNTIKR
  LNIQKRRKPSVPCPEPRTTSGQQGIWTSTESLSSSNSDDNKQCPNFLIARSQVTSTPISK
  PPPPLETSLPFLTIPENRQLPPPSPQLPKHNLHVTKTLMETRRRLEQERATMQMTPGEFR
  RPRLASFGGMGTTSSLPSFVGSGNHNPAKHQLQNGYQGNGDYGSYAPAAPTTSSMGSSIR
  HSPLSSGISTPVTNVSPMHLQHIREQMAIALKRLKELEEQVRTIPVLQVKISVLQEEKRQ
  LVSQLKNQRAASQINVCGVRKRSYSAGNASQLEQLSRARRSGGELYIDYEEEEMETVEQS
  TQRIKEFRQLTADMQALEQKIQDSSCEASSELRENGECRSVAVGAEENMNDIVVYHRGSR
  SCKDAAVGTLVEMRNCGVSVTEAMLGVMTEADKEIELQQQTIESLKEKIYRLEVQLRETT
  HDREMTKLKQELQAAGSRKKVDKATMAQPLVFSKVVEAVVQTRDQMVGSHMDLVDTCVGT
  SVETNSVGISCQPECKNKVVGPELPMNWWIVKERVEMHDRCAGRSVEMCDKSVSVEVSVC
  ETGSNTEESVNDLTLLKTNLNLKEVRSIGCGDCSVDVTVCSPKECASRGVNTEAVSQVEA
  AVMAVPRTADQDTSTDLEQVHQFTNTETATLIESCTNTCLSTLDKQTSTQTVETRTVAVG
  EGRVKDINSSTKTRSIGVGTLLSGHSGFDRPSAVKTKESGVGQININDNYLVGLKMRTIA
  CGPPQLTVGLTASRRSVGVGDDPVGESLENPQPQAPLGMMTGLDHYIERIQKLLAEQQTL
  LAENYSELAEAFGEPHSQMGSLNSQLISTLSSINSVMKSASTEELRNPDFQKTSLGKITG
  NYLGYTCKCGGLQSGSPLSSQTSQPEQEVGTSEGKPISSLDAFPTQEGTLSPVNLTDDQI
  AAGLYACTNNESTLKSIMKKKDGNKDSNGAKKNLQFVGINGGYETTSSDDSSSDESSSSE
  SDDECDVIEYPLEEEEEEEDEDTRGMAEGHHAVNIEGLKSARVEDEMQVQECEPEKVEIR
  ERYELSEKMLSACNLLKNTINDPKALTSKDMRFCLNTLQHEWFRVSSQKSAIPAMVGDYI
  AAFEAISPDVLRYVINLADGNGNTALHYSVSHSNFEIVKLLLDADVCNVDHQNKAGYTPI
  MLAALAAVEAEKDMRIVEELFGCGDVNAKASQAGQTALMLAVSHGRIDMVKGLLACGADV
  NIQDDEGSTALMCASEHGHVEIVKLLLAQPGCNGHLEDNDGSTALSIALEAGHKDIAVLL
  YAHVNFAKAQSPGTPRLGRKTSPGPTHRGSFD
• Function: Involved in the control of cytoskeleton formation by regulating actin polymerization. Inhibits actin fiber formation and cell migration. Inhibits RhoA activity; the function involves phosphorylation through PI3K/Akt signaling and may depend on the competitive interaction with 14-3-3 adapter proteins to sequester them from active complexes. Inhibits the formation of lamellipodia but not of filopodia; the function may depend on the competitive interaction with BAIAP2 to block its association with activated RAC1. Inhibits fibronectin-mediated cell spreading; the function is partially mediated by BAIAP2. Inhibits neurite outgrowth. Involved in the establishment and persistence of cell polarity during directed cell movement in wound healing. In the nucleus, is involved in beta-catenin-dependent activation of transcription. Potential tumor suppressor for renal cell carcinoma. Regulates Rac signaling pathways.
• Tissue Specificity: Widely expressed. Isoform 1 is predominantly expressed in heart and kidney. Isoform 2 probably is widely expressed at basic levels.
• Reactome Pathway:
  Signaling by membrane-tethered fusions of PDGFRA or PDGFRB (R-HSA-9673768)
  Estrogen-dependent gene expression (R-HSA-9018519)

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[3]
Congenital fibrosis of extraocular muscles	DISE84PU	Strong	Genetic Variation	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[5]
Kidney cancer	DISBIPKM	Strong	Altered Expression	[6]
Malignant peripheral nerve sheath tumor	DIS0JTN6	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Nervous system disease	DISJ7GGT	Strong	Genetic Variation	[8]
Neurofibroma	DISIJJMH	Strong	Biomarker	[7]
Polycythemia vera	DISB5FPO	Strong	Genetic Variation	[9]
Renal carcinoma	DISER9XT	Strong	Altered Expression	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[3]
Stomach cancer	DISKIJSX	Strong	Biomarker	[5]
Thrombocytosis disease	DISNG0P4	Strong	Biomarker	[10]
Uterine fibroids	DISBZRMJ	Strong	Genetic Variation	[11]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[12]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[13]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[3]
Nicotine dependence	DISZD9W7	moderate	Genetic Variation	[1]
Spastic quadriplegic cerebral palsy	DISBJRHC	Supportive	Autosomal recessive	[14]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[15]
Basal cell carcinoma	DIS7PYN3	Limited	Genetic Variation	[16]
Basal cell neoplasm	DIS37IXW	Limited	Genetic Variation	[16]
Cerebral palsy, spastic quadriplegic, 2	DISPIXK5	Limited	Autosomal dominant inheritance with maternal imprinting HP:0012275	[14]
Cholestasis	DISDJJWE	Limited	Biomarker	[17]
Invasive breast carcinoma	DISANYTW	Limited	Altered Expression	[2]
Neoplasm of esophagus	DISOLKAQ	Limited	Genetic Variation	[18]
Nephrotic syndrome	DISSPSC2	Limited	Genetic Variation	[19]
Neurodevelopmental disorder	DIS372XH	Limited	Genetic Variation	[20]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitomycin	DMH0ZJE	Approved	KN motif and ankyrin repeat domain-containing protein 1 (KANK1) affects the response to substance of Mitomycin.	[40]
Vinblastine	DM5TVS3	Approved	KN motif and ankyrin repeat domain-containing protein 1 (KANK1) affects the response to substance of Vinblastine.	[40]

4 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 KN motif and ankyrin repeat domain-containing protein 1 (KANK1).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of KN motif and ankyrin repeat domain-containing protein 1 (KANK1).	[33]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of KN motif and ankyrin repeat domain-containing protein 1 (KANK1).	[35]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of KN motif and ankyrin repeat domain-containing protein 1 (KANK1).	[35]

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 KN motif and ankyrin repeat domain-containing protein 1 (KANK1).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of KN motif and ankyrin repeat domain-containing protein 1 (KANK1).	[23]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of KN motif and ankyrin repeat domain-containing protein 1 (KANK1).	[24]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of KN motif and ankyrin repeat domain-containing protein 1 (KANK1).	[25]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of KN motif and ankyrin repeat domain-containing protein 1 (KANK1).	[26]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of KN motif and ankyrin repeat domain-containing protein 1 (KANK1).	[27]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of KN motif and ankyrin repeat domain-containing protein 1 (KANK1).	[28]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of KN motif and ankyrin repeat domain-containing protein 1 (KANK1).	[29]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of KN motif and ankyrin repeat domain-containing protein 1 (KANK1).	[30]
Menadione	DMSJDTY	Approved	Menadione affects the expression of KN motif and ankyrin repeat domain-containing protein 1 (KANK1).	[31]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of KN motif and ankyrin repeat domain-containing protein 1 (KANK1).	[32]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of KN motif and ankyrin repeat domain-containing protein 1 (KANK1).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of KN motif and ankyrin repeat domain-containing protein 1 (KANK1).	[36]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of KN motif and ankyrin repeat domain-containing protein 1 (KANK1).	[37]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of KN motif and ankyrin repeat domain-containing protein 1 (KANK1).	[38]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of KN motif and ankyrin repeat domain-containing protein 1 (KANK1).	[39]

References

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• [2] Prognostic significance of KN motif and ankyrin repeat domains 1 (KANK1) in invasive breast cancer.Breast Cancer Res Treat. 2020 Jan;179(2):349-357. doi: 10.1007/s10549-019-05466-8. Epub 2019 Nov 2.
• [3] Kank1 reexpression induced by 5-Aza-2'-deoxycytidine suppresses nasopharyngeal carcinoma cell proliferation and promotes apoptosis.Int J Clin Exp Pathol. 2015 Feb 1;8(2):1658-65. eCollection 2015.
• [4] A major mutation of KIF21A associated with congenital fibrosis of the extraocular muscles type 1 (CFEOM1) enhances translocation of Kank1 to the membrane.Biochem Biophys Res Commun. 2009 Sep 4;386(4):639-44. doi: 10.1016/j.bbrc.2009.06.109. Epub 2009 Jun 24.
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• [16] Combined analysis of keratinocyte cancers identifies novel genome-wide loci.Hum Mol Genet. 2019 Sep 15;28(18):3148-3160. doi: 10.1093/hmg/ddz121.
• [17] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [18] Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions.Nat Genet. 2012 Oct;44(10):1090-7. doi: 10.1038/ng.2411. Epub 2012 Sep 9.
• [19] Structural insights into ankyrin repeat-mediated recognition of the kinesin motor protein KIF21A by KANK1, a scaffold protein in focal adhesion.J Biol Chem. 2018 Feb 9;293(6):1944-1956. doi: 10.1074/jbc.M117.815779. Epub 2017 Dec 7.
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• [35] 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.
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• [39] Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol. 2012 Apr;86(4):571-89.
• [40] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.