Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT34MT8)

• DOT Name: Kinesin-1 heavy chain (KIF5B)
• Synonyms: Conventional kinesin heavy chain; Ubiquitous kinesin heavy chain; UKHC
• Gene Name: KIF5B
• Related Disease:
  Glioma
  Lung cancer
  Neuroblastoma
  Adult glioblastoma
  Advanced cancer
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Fibrosarcoma
  Glioblastoma multiforme
  Hereditary spastic paraplegia 10
  Histiocytosis
  Lung carcinoma
  Lung neoplasm
  Lung squamous cell carcinoma
  Medullary thyroid gland carcinoma
  Metastatic malignant neoplasm
  Neoplasm
  Non-small-cell lung cancer
  Osteosarcoma
  Pure hereditary spastic paraplegia
  Squamous cell carcinoma
  Thyroid gland papillary carcinoma
  Vascular purpura
  Adenocarcinoma
  Melanoma
  Amyotrophic lateral sclerosis
  Hereditary spastic paraplegia
  Lung adenocarcinoma
  Type-1/2 diabetes
• UniProt ID: KINH_HUMAN
• PDB ID: 1BG2; 1MKJ; 2P4N; 3J8X; 3J8Y; 4HNA; 4LNU; 5LT0; 5LT1; 5LT2; 5LT3; 5LT4; 6OJQ; 7RIK; 8IXA; 8IXB; 8IXD; 8IXE; 8IXF; 8IXG
• Pfam ID: PF00225
• Sequence:
  MADLAECNIKVMCRFRPLNESEVNRGDKYIAKFQGEDTVVIASKPYAFDRVFQSSTSQEQ
  VYNDCAKKIVKDVLEGYNGTIFAYGQTSSGKTHTMEGKLHDPEGMGIIPRIVQDIFNYIY
  SMDENLEFHIKVSYFEIYLDKIRDLLDVSKTNLSVHEDKNRVPYVKGCTERFVCSPDEVM
  DTIDEGKSNRHVAVTNMNEHSSRSHSIFLINVKQENTQTEQKLSGKLYLVDLAGSEKVSK
  TGAEGAVLDEAKNINKSLSALGNVISALAEGSTYVPYRDSKMTRILQDSLGGNCRTTIVI
  CCSPSSYNESETKSTLLFGQRAKTIKNTVCVNVELTAEQWKKKYEKEKEKNKILRNTIQW
  LENELNRWRNGETVPIDEQFDKEKANLEAFTVDKDITLTNDKPATAIGVIGNFTDAERRK
  CEEEIAKLYKQLDDKDEEINQQSQLVEKLKTQMLDQEELLASTRRDQDNMQAELNRLQAE
  NDASKEEVKEVLQALEELAVNYDQKSQEVEDKTKEYELLSDELNQKSATLASIDAELQKL
  KEMTNHQKKRAAEMMASLLKDLAEIGIAVGNNDVKQPEGTGMIDEEFTVARLYISKMKSE
  VKTMVKRCKQLESTQTESNKKMEENEKELAACQLRISQHEAKIKSLTEYLQNVEQKKRQL
  EESVDALSEELVQLRAQEKVHEMEKEHLNKVQTANEVKQAVEQQIQSHRETHQKQISSLR
  DEVEAKAKLITDLQDQNQKMMLEQERLRVEHEKLKATDQEKSRKLHELTVMQDRREQARQ
  DLKGLEETVAKELQTLHNLRKLFVQDLATRVKKSAEIDSDDTGGSAAQKQKISFLENNLE
  QLTKVHKQLVRDNADLRCELPKLEKRLRATAERVKALESALKEAKENASRDRKRYQQEVD
  RIKEAVRSKNMARRGHSAQIAKPIRPGQHPAASPTHPSAIRGGGAFVQNSQPVAVRGGGG
  KQV
• Function: Microtubule-dependent motor required for normal distribution of mitochondria and lysosomes. Can induce formation of neurite-like membrane protrusions in non-neuronal cells in a ZFYVE27-dependent manner. Regulates centrosome and nuclear positioning during mitotic entry. During the G2 phase of the cell cycle in a BICD2-dependent manner, antagonizes dynein function and drives the separation of nuclei and centrosomes. Required for anterograde axonal transportation of MAPK8IP3/JIP3 which is essential for MAPK8IP3/JIP3 function in axon elongation. Through binding with PLEKHM2 and ARL8B, directs lysosome movement toward microtubule plus ends (Probable). Involved in NK cell-mediated cytotoxicity. Drives the polarization of cytolytic granules and microtubule-organizing centers (MTOCs) toward the immune synapse between effector NK lymphocytes and target cells.
• KEGG Pathway:
  Endocytosis (hsa04144)
  Dopaminergic sy.pse (hsa04728)
  Motor proteins (hsa04814)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Salmonella infection (hsa05132)
  Non-small cell lung cancer (hsa05223)
• Reactome Pathway:
  Insulin processing (R-HSA-264876)
  RHO GTPases activate KTN1 (R-HSA-5625970)
  COPI-dependent Golgi-to-ER retrograde traffic (R-HSA-6811434)
  Signaling by ALK fusions and activated point mutants (R-HSA-9725370)
  Nuclear events stimulated by ALK signaling in cancer (R-HSA-9725371)
  Kinesins (R-HSA-983189)
  MHC class II antigen presentation (R-HSA-2132295)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioma	DIS5RPEH	Definitive	Biomarker	[1]
Lung cancer	DISCM4YA	Definitive	Altered Expression	[2]
Neuroblastoma	DISVZBI4	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[4]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[6]
Carcinoma	DISH9F1N	Strong	Biomarker	[7]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[8]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[8]
Fibrosarcoma	DISWX7MU	Strong	Biomarker	[9]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Hereditary spastic paraplegia 10	DISYFO3L	Strong	Genetic Variation	[10]
Histiocytosis	DISIYLND	Strong	Genetic Variation	[11]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[2]
Lung neoplasm	DISVARNB	Strong	Biomarker	[12]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[13]
Medullary thyroid gland carcinoma	DISHBL3K	Strong	Genetic Variation	[14]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[15]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[16]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[5]
Pure hereditary spastic paraplegia	DIS8X71E	Strong	Biomarker	[17]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[18]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Biomarker	[16]
Vascular purpura	DIS6ZZMF	Strong	Genetic Variation	[19]
Adenocarcinoma	DIS3IHTY	moderate	Genetic Variation	[20]
Melanoma	DIS1RRCY	moderate	Biomarker	[21]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[22]
Hereditary spastic paraplegia	DISGZQV1	Limited	Genetic Variation	[23]
Lung adenocarcinoma	DISD51WR	Limited	Biomarker	[20]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[24]

8 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 Kinesin-1 heavy chain (KIF5B).	[25]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Kinesin-1 heavy chain (KIF5B).	[26]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Kinesin-1 heavy chain (KIF5B).	[27]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Kinesin-1 heavy chain (KIF5B).	[28]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Kinesin-1 heavy chain (KIF5B).	[29]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Kinesin-1 heavy chain (KIF5B).	[30]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Kinesin-1 heavy chain (KIF5B).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Kinesin-1 heavy chain (KIF5B).	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Kinesin-1 heavy chain (KIF5B).	[32]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Kinesin-1 heavy chain (KIF5B).	[33]

References

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• [2] Correction to: KIF5B-RET fusion kinase promotes cell growth by multilevel activation of STAT3 in lung cancer.Mol Cancer. 2019 Nov 19;18(1):164. doi: 10.1186/s12943-019-1093-0.
• [3] Differential display of messenger ribonucleic acid: a useful technique for analyzing differential gene expression in human brain tumors.Neurosurgery. 1995 Sep;37(3):464-9; discussion 469-70. doi: 10.1227/00006123-199509000-00014.
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• [8] Macrophage ER promoted invasion of endometrial cancer cell by mTOR/KIF5B-mediated epithelial to mesenchymal transition.Immunol Cell Biol. 2019 Jul;97(6):563-576. doi: 10.1111/imcb.12245. Epub 2019 Mar 14.
• [9] Altered expression of ubiquitous kinesin heavy chain results in resistance to etoposide and hypersensitivity to colchicine: mapping of the domain associated with drug response.Cancer Res. 1998 Aug 1;58(15):3423-8.
• [10] A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10).Am J Hum Genet. 2002 Nov;71(5):1189-94. doi: 10.1086/344210. Epub 2002 Sep 24.
• [11] Atypical juvenile histiocytosis with novel KIF5B-ALK gene fusion mimicking subglottic hemangioma.Int J Pediatr Otorhinolaryngol. 2019 Nov;126:109585. doi: 10.1016/j.ijporl.2019.07.010. Epub 2019 Jul 13.
• [12] Preclinical Modeling of KIF5B-RET Fusion Lung Adenocarcinoma.Mol Cancer Ther. 2016 Oct;15(10):2521-2529. doi: 10.1158/1535-7163.MCT-16-0258. Epub 2016 Aug 5.
• [13] IFN-gamma-induced change in microtubule organization and alpha-tubulin expression during growth inhibition of lung squamous carcinoma cells.J Interferon Cytokine Res. 2000 Nov;20(11):983-90. doi: 10.1089/10799900050198426.
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• [17] Evidence of kinesin heavy chain (KIF5A) involvement in pure hereditary spastic paraplegia.Neurology. 2004 Sep 28;63(6):1108-10. doi: 10.1212/01.wnl.0000138731.60693.d2.
• [18] Expression of Kif5b protein is significantly associated with the progression, recurrence and prognosis of oral squamous cell carcinoma.Eur Rev Med Pharmacol Sci. 2018 Jul;22(14):4542-4550. doi: 10.26355/eurrev_201807_15509.
• [19] Three routes to suppression of the neurodegenerative phenotypes caused by kinesin heavy chain mutations.Genetics. 2012 Sep;192(1):173-83. doi: 10.1534/genetics.112.140798. Epub 2012 Jun 19.
• [20] Oncogenic Function of a KIF5B-MET Fusion Variant in Non-Small Cell Lung Cancer.Neoplasia. 2018 Aug;20(8):838-847. doi: 10.1016/j.neo.2018.06.007. Epub 2018 Jul 13.
• [21] MicroRNA-203 regulates melanosome transport and tyrosinase expression in melanoma cells by targeting kinesin superfamily protein 5b.J Invest Dermatol. 2014 Feb;134(2):461-469. doi: 10.1038/jid.2013.310. Epub 2013 Jul 22.
• [22] Dexpramipexole as an oral steroid-sparing agent in hypereosinophilic syndromes.Blood. 2018 Aug 2;132(5):501-509. doi: 10.1182/blood-2018-02-835330. Epub 2018 May 8.
• [23] SPG10 is a rare cause of spastic paraplegia in European families.J Neurol Neurosurg Psychiatry. 2008 May;79(5):584-7. doi: 10.1136/jnnp.2007.137596. Epub 2008 Feb 1.
• [24] Diabetes alters KIF1A and KIF5B motor proteins in the hippocampus.PLoS One. 2013 Jun 12;8(6):e65515. doi: 10.1371/journal.pone.0065515. Print 2013.
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• [26] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [27] 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.
• [28] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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.
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• [31] 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.
• [32] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [33] 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.
• [34] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.