Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0OE8SX)

• DOT Name: Protein Hook homolog 3 (HOOK3)
• Synonyms: h-hook3; hHK3
• Gene Name: HOOK3
• Related Disease:
  Neoplasm
  Alzheimer disease
  Polycystic ovarian syndrome
  Prostate cancer
  Prostate carcinoma
  Thyroid gland papillary carcinoma
• UniProt ID: HOOK3_HUMAN
• PDB ID: 5J8E; 6B9H
• Pfam ID: PF05622 ; PF19047
• Sequence:
  MFSVESLERAELCESLLTWIQTFNVDAPCQTVEDLTNGVVMAQVLQKIDPAYFDENWLNR
  IKTEVGDNWRLKISNLKKILKGILDYNHEILGQQINDFTLPDVNLIGEHSDAAELGRMLQ
  LILGCAVNCEQKQEYIQAIMMMEESVQHVVMTAIQELMSKESPVSAGNDAYVDLDRQLKK
  TTEELNEALSAKEEIAQRCHELDMQVAALQEEKSSLLAENQVLMERLNQSDSIEDPNSPA
  GRRHLQLQTQLEQLQEETFRLEAAKDDYRIRCEELEKEISELRQQNDELTTLADEAQSLK
  DEIDVLRHSSDKVSKLEGQVESYKKKLEDLGDLRRQVKLLEEKNTMYMQNTVSLEEELRK
  ANAARSQLETYKRQVVELQNRLSEESKKADKLDFEYKRLKEKVDSLQKEKDRLRTERDSL
  KETIEELRCVQAQEGQLTTQGLMPLGSQESSDSLAAEIVTPEIREKLIRLQHENKMLKLN
  QEGSDNEKIALLQSLLDDANLRKNELETENRLVNQRLLEVQSQVEELQKSLQDQGSKAED
  SVLLKKKLEEHLEKLHEANNELQKKRAIIEDLEPRFNNSSLKIEELQEALRKKEEEMKQM
  EERYKKYLEKAKSVIRTLDPKQNQGAAPEIQALKNQLQERDRLFHSLEKEYEKTKSQREM
  EEKYIVSAWYNMGMTLHKKAAEDRLASTGSGQSFLARQRQATSSRRSYPGHVQPATAR
• Function: Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin. Facilitates the interaction between dynein and dynactin and activates dynein processivity (the ability to move along a microtubule for a long distance without falling off the track). Predominantly recruits 2 dyneins, which increases both the force and speed of the microtubule motor. Component of the FTS/Hook/FHIP complex (FHF complex). The FHF complex may function to promote vesicle trafficking and/or fusion via the homotypic vesicular protein sorting complex (the HOPS complex). May regulate clearance of endocytosed receptors such as MSR1. Participates in defining the architecture and localization of the Golgi complex. FHF complex promotes the distribution of AP-4 complex to the perinuclear area of the cell ; (Microbial infection) May serve as a target for the spiC protein from Salmonella typhimurium, which inactivates it, leading to a strong alteration in cellular trafficking.
• KEGG Pathway: Motor proteins (hsa04814)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Limited	Altered Expression	[1]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[1]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Protein Hook homolog 3 (HOOK3).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein Hook homolog 3 (HOOK3).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein Hook homolog 3 (HOOK3).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein Hook homolog 3 (HOOK3).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Protein Hook homolog 3 (HOOK3).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein Hook homolog 3 (HOOK3).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein Hook homolog 3 (HOOK3).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein Hook homolog 3 (HOOK3).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Protein Hook homolog 3 (HOOK3).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Protein Hook homolog 3 (HOOK3).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Protein Hook homolog 3 (HOOK3).	[11]

References

• [1] High-Level HOOK3 Expression Is an Independent Predictor of Poor Prognosis Associated with Genomic Instability in Prostate Cancer.PLoS One. 2015 Jul 31;10(7):e0134614. doi: 10.1371/journal.pone.0134614. eCollection 2015.
• [2] Hook proteins: association with Alzheimer pathology and regulatory role of hook3 in amyloid beta generation.PLoS One. 2015 Mar 23;10(3):e0119423. doi: 10.1371/journal.pone.0119423. eCollection 2015.
• [3] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [4] HOOK3-RET: a novel type of RET/PTC rearrangement in papillary thyroid carcinoma.Endocr Relat Cancer. 2007 Jun;14(2):445-52. doi: 10.1677/ERC-07-0039.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.