Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ0IN7P)

• DOT Name: N-terminal kinase-like protein (SCYL1)
• Synonyms: Coated vesicle-associated kinase of 90 kDa; SCY1-like protein 1; Telomerase regulation-associated protein; Telomerase transcriptional element-interacting factor; Teratoma-associated tyrosine kinase
• Gene Name: SCYL1
• Related Disease:
  Advanced cancer
  Common variable immunodeficiency
  Acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome
  Acute liver failure
  Acute lymphocytic leukaemia
  Cerebellar ataxia
  Cholestasis
  Classic Hodgkin lymphoma
  Clear cell renal carcinoma
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Leukemia
  Lupus
  Myeloid leukaemia
  Non-hodgkin lymphoma
  Peripheral neuropathy
  Renal cell carcinoma
  Squamous cell carcinoma
  Systemic lupus erythematosus
  Triple negative breast cancer
  Vascular purpura
  Adult glioblastoma
  Carcinoma
  Cervical carcinoma
  Gastric cancer
  Glioblastoma multiforme
  Nasopharyngeal carcinoma
  Stomach cancer
  Asthma
  Crohn disease
  Glioma
  Neurodegenerative disease
  Non-small-cell lung cancer
  Ulcerative colitis
• UniProt ID: SCYL1_HUMAN
• Pfam ID: PF00069
• Sequence:
  MWFFARDPVRDFPFELIPEPPEGGLPGPWALHRGRKKATGSPVSIFVYDVKPGAEEQTQV
  AKAAFKRFKTLRHPNILAYIDGLETEKCLHVVTEAVTPLGIYLKARVEAGGLKELEISWG
  LHQIVKALSFLVNDCSLIHNNVCMAAVFVDRAGEWKLGGLDYMYSAQGNGGGPPRKGIPE
  LEQYDPPELADSSGRVVREKWSADMWRLGCLIWEVFNGPLPRAAALRNPGKIPKTLVPHY
  CELVGANPKVRPNPARFLQNCRAPGGFMSNRFVETNLFLEEIQIKEPAEKQKFFQELSKS
  LDAFPEDFCRHKVLPQLLTAFEFGNAGAVVLTPLFKVGKFLSAEEYQQKIIPVVVKMFSS
  TDRAMRIRLLQQMEQFIQYLDEPTVNTQIFPHVVHGFLDTNPAIREQTVKSMLLLAPKLN
  EANLNVELMKHFARLQAKDEQGPIRCNTTVCLGKIGSYLSASTRHRVLTSAFSRATRDPF
  APSRVAGVLGFAATHNLYSMNDCAQKILPVLCGLTVDPEKSVRDQAFKAIRSFLSKLESV
  SEDPTQLEEVEKDVHAASSPGMGGAAASWAGWAVTGVSSLTSKLIRSHPTTAPTETNIPQ
  RPTPEGVPAPAPTPVPATPTTSGHWETQEEDKDTAEDSSTADRWDDEDWGSLEQEAESVL
  AQQDDWSTGGQVSRASQVSNSDHKSSKSPESDWSSWEAEGSWEQGWQEPSSQEPPPDGTR
  LASEYNWGGPESSDKGDPFATLSARPSTQPRPDSWGEDNWEGLETDSRQVKAELARKKRE
  ERRREMEAKRAERKVAKGPMKLGARKLD
• Function: Regulates COPI-mediated retrograde protein traffic at the interface between the Golgi apparatus and the endoplasmic reticulum. Involved in the maintenance of the Golgi apparatus morphology. Has no detectable kinase activity in vitro ; Isoform 6 acts as a transcriptional activator. It binds to three different types of GC-rich DNA binding sites (box-A, -B and -C) in the beta-polymerase promoter region. It also binds to the TERT promoter region.
• Tissue Specificity: Ubiquitous.

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Common variable immunodeficiency	DISHE7JQ	Definitive	Biomarker	[2]
Acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome	DISHUX1K	Strong	Autosomal recessive	[3]
Acute liver failure	DIS5EZKX	Strong	Genetic Variation	[4]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[5]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[6]
Cholestasis	DISDJJWE	Strong	Genetic Variation	[7]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[8]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[9]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[11]
Leukemia	DISNAKFL	Strong	Altered Expression	[12]
Lupus	DISOKJWA	Strong	Biomarker	[13]
Myeloid leukaemia	DISMN944	Strong	Altered Expression	[14]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Altered Expression	[15]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[4]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[9]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[10]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[13]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[16]
Vascular purpura	DIS6ZZMF	Strong	Biomarker	[17]
Adult glioblastoma	DISVP4LU	moderate	Biomarker	[18]
Carcinoma	DISH9F1N	moderate	Altered Expression	[19]
Cervical carcinoma	DIST4S00	moderate	Biomarker	[20]
Gastric cancer	DISXGOUK	moderate	Biomarker	[19]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[18]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Altered Expression	[21]
Stomach cancer	DISKIJSX	moderate	Biomarker	[19]
Asthma	DISW9QNS	Limited	Altered Expression	[22]
Crohn disease	DIS2C5Q8	Limited	Biomarker	[23]
Glioma	DIS5RPEH	Limited	Altered Expression	[24]
Neurodegenerative disease	DISM20FF	Limited	CausalMutation	[4]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[25]
Ulcerative colitis	DIS8K27O	Limited	Biomarker	[23]

2 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 N-terminal kinase-like protein (SCYL1).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of N-terminal kinase-like protein (SCYL1).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of N-terminal kinase-like protein (SCYL1).	[27]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of N-terminal kinase-like protein (SCYL1).	[28]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of N-terminal kinase-like protein (SCYL1).	[29]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of N-terminal kinase-like protein (SCYL1).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of N-terminal kinase-like protein (SCYL1).	[33]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of N-terminal kinase-like protein (SCYL1).	[31]

References

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• [2] Haploinsufficiency of the NF-B1 Subunit p50 in Common Variable Immunodeficiency. Am J Hum Genet. 2015 Sep 3;97(3):389-403. doi: 10.1016/j.ajhg.2015.07.008. Epub 2015 Aug 13.
• [3] An early onset progressive motor neuron disorder in Scyl1-deficient mice is associated with mislocalization of TDP-43. J Neurosci. 2012 Nov 21;32(47):16560-73. doi: 10.1523/JNEUROSCI.1787-12.2012.
• [4] SCYL1 variants cause a syndrome with low -glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN).Genet Med. 2018 Oct;20(10):1255-1265. doi: 10.1038/gim.2017.260. Epub 2018 Feb 8.
• [5] Related subunits of NF-kappa B map to two distinct loci associated with translocations in leukemia, NFKB1 and NFKB2.Genomics. 1992 Jun;13(2):287-92. doi: 10.1016/0888-7543(92)90244-m.
• [6] Variant in SCYL1 gene causes aberrant splicing in a family with cerebellar ataxia, recurrent episodes of liver failure, and growth retardation.Eur J Hum Genet. 2019 Feb;27(2):263-268. doi: 10.1038/s41431-018-0268-2. Epub 2018 Sep 26.
• [7] Generation of an induced pluripotent stem cell (iPSC) line, DHMCi005-A, from a patient with CALFAN syndrome due to mutations in SCYL1.Stem Cell Res. 2019 May;37:101428. doi: 10.1016/j.scr.2019.101428. Epub 2019 Mar 22.
• [8] Flow cytometric measurements of proliferation-associated nuclear antigen p105 and DNA content in non-Hodgkin's lymphomas.Arch Pathol Lab Med. 1989 Aug;113(8):907-11.
• [9] Flow cytometric quantitation of the proliferation-associated nuclear antigen p105 and DNA content in patients with renal cell carcinoma.Cancer. 1996 Aug 15;78(4):819-26. doi: 10.1002/(SICI)1097-0142(19960815)78:4<819::AID-CNCR19>3.0.CO;2-Y.
• [10] Flow cytometric quantification of the proliferation-associated nuclear antigen p105 and DNA content in advanced head & neck cancers: results of RTOG 91-08.Int J Radiat Oncol Biol Phys. 1994 Jul 1;29(4):661-71. doi: 10.1016/0360-3016(94)90552-5.
• [11] Overexpression of N-terminal kinase like gene promotes tumorigenicity of hepatocellular carcinoma by regulating cell cycle progression and cell motility.Oncotarget. 2015 Jan 30;6(3):1618-30. doi: 10.18632/oncotarget.2730.
• [12] Altered expression of the human retinoblastoma gene in monocytic leukaemias.Br J Haematol. 1993 Mar;83(3):428-32. doi: 10.1111/j.1365-2141.1993.tb04667.x.
• [13] Characterization of novel antigens recognized by serum autoantibodies from anti-CD1 TCR-transgenic lupus mice.Eur J Immunol. 2004 Jun;34(6):1654-62. doi: 10.1002/eji.200324201.
• [14] The role of decreased retinoblastoma protein expression in acute myelomonocytic and monoblastic leukemias.Leuk Lymphoma. 1995 Mar;17(1-2):135-7. doi: 10.3109/10428199509051713.
• [15] Altered expression of the retinoblastoma gene product in human high grade non-Hodgkin's lymphomas.Leukemia. 1994 Jan;8(1):97-101.
• [16] SCYL1 does not regulate REST expression and turnover.PLoS One. 2017 Jun 1;12(6):e0178680. doi: 10.1371/journal.pone.0178680. eCollection 2017.
• [17] Hereditary ataxias and paraparesias: clinical and genetic update. Curr Opin Neurol. 2018 Aug;31(4):462-471. doi: 10.1097/WCO.0000000000000585.
• [18] NFKB1: a suppressor of inflammation, ageing and cancer.FEBS J. 2016 May;283(10):1812-22. doi: 10.1111/febs.13627. Epub 2016 Jan 13.
• [19] Status of c-erbB-2 in gastric adenocarcinoma: a comparative study of immunohistochemistry, fluorescence in situ hybridization and enzyme-linked immuno-sorbent assay.Int J Cancer. 2002 Apr 20;98(6):833-7. doi: 10.1002/ijc.10257.
• [20] Identification of a promoter in position 56 within the long control region of human papillomavirus type 18.Arch Virol. 2001;146(11):2069-84. doi: 10.1007/s007050170021.
• [21] Genome-wide expression profiling reveals EBV-associated inhibition of MHC class I expression in nasopharyngeal carcinoma.Cancer Res. 2006 Aug 15;66(16):7999-8006. doi: 10.1158/0008-5472.CAN-05-4399.
• [22] Peripheral blood mononuclear cell NF-kappaB p105 mRNA decreases during asthmatic attacks.Biomed Pharmacother. 2008 Mar;62(3):147-52. doi: 10.1016/j.biopha.2007.08.004. Epub 2007 Sep 5.
• [23] Proteasome-mediated degradation of IkappaBalpha and processing of p105 in Crohn disease and ulcerative colitis.J Clin Invest. 2006 Dec;116(12):3195-203. doi: 10.1172/JCI28804. Epub 2006 Nov 22.
• [24] Multiparameter flow cytometric analysis of neoplasms of the central nervous system: correlation of nuclear antigen p105 and DNA content with clinical behavior.Neurosurgery. 1990 Jul;27(1):83-96.
• [25] The circulating urokinase plasminogen activator (uPA) and its soluble receptor (suPAR) are not up-regulated by the circulating P105 fraction of the HER-2/neu proto-oncogene: in vivo evidence from patients with advanced non-small cell lung cancer (NSCLC).Anticancer Res. 2002 Jul-Aug;22(4):2073-6.
• [26] 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.
• [27] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [28] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [29] 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.
• [30] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [31] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [32] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [33] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.