Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS9YK3E)

• DOT Name: Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B)
• Synonyms: CaM kinase II subunit beta; CaMK-II subunit beta; EC 2.7.11.17
• Gene Name: CAMK2B
• Related Disease:
  Intellectual disability, autosomal dominant 40
  Nervous system disease
  Advanced cancer
  Breast neoplasm
  Cocaine addiction
  Colorectal carcinoma
  Constipation
  Depression
  Eye disorder
  Glioma
  Influenza
  Intellectual disability, autosomal dominant 54
  Melanoma
  Microcephaly
  Movement disorder
  Neuroblastoma
  Breast cancer
  Breast carcinoma
  Intellectual disability
  Osteoarthritis
  Schizophrenia
  Autosomal dominant non-syndromic intellectual disability
  Adult glioblastoma
  Glioblastoma multiforme
  Neoplasm
• UniProt ID: KCC2B_HUMAN
• PDB ID: 3BHH; 7URW; 7URY; 7URZ
• EC Number: 2.7.11.17
• Pfam ID: PF08332 ; PF00069
• Sequence:
  MATTVTCTRFTDEYQLYEDIGKGAFSVVRRCVKLCTGHEYAAKIINTKKLSARDHQKLER
  EARICRLLKHSNIVRLHDSISEEGFHYLVFDLVTGGELFEDIVAREYYSEADASHCIQQI
  LEAVLHCHQMGVVHRDLKPENLLLASKCKGAAVKLADFGLAIEVQGDQQAWFGFAGTPGY
  LSPEVLRKEAYGKPVDIWACGVILYILLVGYPPFWDEDQHKLYQQIKAGAYDFPSPEWDT
  VTPEAKNLINQMLTINPAKRITAHEALKHPWVCQRSTVASMMHRQETVECLKKFNARRKL
  KGAILTTMLATRNFSVGRQTTAPATMSTAASGTTMGLVEQAKSLLNKKADGVKPQTNSTK
  NSAAATSPKGTLPPAALEPQTTVIHNPVDGIKESSDSANTTIEDEDAKAPRVPDILSSVR
  RGSGAPEAEGPLPCPSPAPFSPLPAPSPRISDILNSVRRGSGTPEAEGPLSAGPPPCLSP
  ALLGPLSSPSPRISDILNSVRRGSGTPEAEGPSPVGPPPCPSPTIPGPLPTPSRKQEIIK
  TTEQLIEAVNNGDFEAYAKICDPGLTSFEPEALGNLVEGMDFHRFYFENLLAKNSKPIHT
  TILNPHVHVIGEDAACIAYIRLTQYIDGQGRPRTSQSEETRVWHRRDGKWQNVHFHCSGA
  PVAPLQ
• Function: Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in dendritic spine and synapse formation, neuronal plasticity and regulation of sarcoplasmic reticulum Ca(2+) transport in skeletal muscle. In neurons, plays an essential structural role in the reorganization of the actin cytoskeleton during plasticity by binding and bundling actin filaments in a kinase-independent manner. This structural function is required for correct targeting of CaMK2A, which acts downstream of NMDAR to promote dendritic spine and synapse formation and maintain synaptic plasticity which enables long-term potentiation (LTP) and hippocampus-dependent learning. In developing hippocampal neurons, promotes arborization of the dendritic tree and in mature neurons, promotes dendritic remodeling. Also regulates the migration of developing neurons. Participates in the modulation of skeletal muscle function in response to exercise. In slow-twitch muscles, is involved in regulation of sarcoplasmic reticulum (SR) Ca(2+) transport and in fast-twitch muscle participates in the control of Ca(2+) release from the SR through phosphorylation of triadin, a ryanodine receptor-coupling factor, and phospholamban (PLN/PLB), an endogenous inhibitor of SERCA2A/ATP2A2. In response to interferon-gamma (IFN-gamma) stimulation, catalyzes phosphorylation of STAT1, stimulating the JAK-STAT signaling pathway. Phosphorylates reticulophagy regulator RETREG1 at 'Ser-151' under endoplasmic reticulum stress conditions which enhances RETREG1 oligomerization and its membrane scission and reticulophagy activity.
• Tissue Specificity: Widely expressed. Expressed in adult and fetal brain. Expression is slightly lower in fetal brain. Expressed in skeletal muscle.
• KEGG Pathway:
  ErbB sig.ling pathway (hsa04012)
  Calcium sig.ling pathway (hsa04020)
  cAMP sig.ling pathway (hsa04024)
  HIF-1 sig.ling pathway (hsa04066)
  Oocyte meiosis (hsa04114)
  Efferocytosis (hsa04148)
  Necroptosis (hsa04217)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Wnt sig.ling pathway (hsa04310)
  Axon guidance (hsa04360)
  Circadian entrainment (hsa04713)
  Long-term potentiation (hsa04720)
  Neurotrophin sig.ling pathway (hsa04722)
  Cholinergic sy.pse (hsa04725)
  Dopaminergic sy.pse (hsa04728)
  Olfactory transduction (hsa04740)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Insulin secretion (hsa04911)
  GnRH sig.ling pathway (hsa04912)
  Melanogenesis (hsa04916)
  Oxytocin sig.ling pathway (hsa04921)
  Glucagon sig.ling pathway (hsa04922)
  Aldosterone synthesis and secretion (hsa04925)
  Cushing syndrome (hsa04934)
  Gastric acid secretion (hsa04971)
  Parkinson disease (hsa05012)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Amphetamine addiction (hsa05031)
  Tuberculosis (hsa05152)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  Glioma (hsa05214)
  Diabetic cardiomyopathy (hsa05415)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  HSF1-dependent transactivation (R-HSA-3371571)
  Trafficking of AMPA receptors (R-HSA-399719)
  Unblocking of NMDA receptors, glutamate binding and activation (R-HSA-438066)
  CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde (R-HSA-442729)
  Ras activation upon Ca2+ influx through NMDA receptor (R-HSA-442982)
  Phase 0 - rapid depolarisation (R-HSA-5576892)
  Ion homeostasis (R-HSA-5578775)
  RAF activation (R-HSA-5673000)
  RAF/MAP kinase cascade (R-HSA-5673001)
  Signaling by moderate kinase activity BRAF mutants (R-HSA-6802946)
  Signaling by BRAF and RAF1 fusions (R-HSA-6802952)
  Paradoxical activation of RAF signaling by kinase inactive BRAF (R-HSA-6802955)
  Interferon gamma signaling (R-HSA-877300)
  Regulation of MECP2 expression and activity (R-HSA-9022692)
  Ion transport by P-type ATPases (R-HSA-936837)
  Assembly and cell surface presentation of NMDA receptors (R-HSA-9609736)
  Negative regulation of NMDA receptor-mediated neuronal transmission (R-HSA-9617324)
  Long-term potentiation (R-HSA-9620244)
  Signaling downstream of RAS mutants (R-HSA-9649948)
  Signaling by RAF1 mutants (R-HSA-9656223)
  CaMK IV-mediated phosphorylation of CREB (R-HSA-111932)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, autosomal dominant 40	DISAI0IH	Definitive	Autosomal dominant	[1]
Nervous system disease	DISJ7GGT	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Cocaine addiction	DISHTRXG	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[6]
Constipation	DISRQXWI	Strong	CausalMutation	[1]
Depression	DIS3XJ69	Strong	Altered Expression	[7]
Eye disorder	DISB52BH	Strong	CausalMutation	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[8]
Influenza	DIS3PNU3	Strong	Biomarker	[9]
Intellectual disability, autosomal dominant 54	DIS6J0JB	Strong	Autosomal dominant	[1]
Melanoma	DIS1RRCY	Strong	Altered Expression	[10]
Microcephaly	DIS2GRD8	Strong	CausalMutation	[1]
Movement disorder	DISOJJ2D	Strong	CausalMutation	[1]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[11]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[11]
Intellectual disability	DISMBNXP	moderate	Biomarker	[12]
Osteoarthritis	DIS05URM	moderate	Altered Expression	[13]
Schizophrenia	DISSRV2N	moderate	Biomarker	[14]
Autosomal dominant non-syndromic intellectual disability	DISD6L06	Supportive	Autosomal dominant	[1]
Adult glioblastoma	DISVP4LU	Limited	Altered Expression	[15]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[15]
Neoplasm	DISZKGEW	Limited	Altered Expression	[16]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B) affects the response to substance of Paclitaxel.	[34]

3 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 Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B).	[17]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B).	[20]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B).	[22]
Selenium	DM25CGV	Approved	Selenium increases the expression of Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B).	[23]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B).	[24]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B).	[25]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B).	[5]
Acocantherin	DM7JT24	Approved	Acocantherin increases the expression of Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B).	[27]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B).	[28]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B).	[23]
AMEP	DMFELMQ	Phase 1	AMEP decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B).	[31]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B).	[32]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B).	[30]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B).	[5]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B).	[33]

References

• [1] De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability. Am J Hum Genet. 2017 Nov 2;101(5):768-788. doi: 10.1016/j.ajhg.2017.10.003.
• [2] A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability.Elife. 2018 May 22;7:e32451. doi: 10.7554/eLife.32451.
• [3] Downregulation of ARFGEF1 and CAMK2B by promoter hypermethylation in breast cancer cells.BMB Rep. 2011 Aug;44(8):523-8. doi: 10.5483/bmbrep.2011.44.8.523.
• [4] Identification of novel human tumor cell-specific CaMK-II variants.Biochim Biophys Acta. 1997 Mar 1;1355(3):281-92. doi: 10.1016/s0167-4889(96)00141-3.
• [5] Transcriptional changes common to human cocaine, cannabis and phencyclidine abuse. PLoS One. 2006 Dec 27;1(1):e114. doi: 10.1371/journal.pone.0000114.
• [6] Alteration of microRNA-4474/4717 expression and CREB-binding protein in human colorectal cancer tissues infected with Fusobacterium nucleatum.PLoS One. 2019 Apr 5;14(4):e0215088. doi: 10.1371/journal.pone.0215088. eCollection 2019.
• [7] Expression of the PPM1F Gene Is Regulated by Stress and Associated With Anxiety and Depression.Biol Psychiatry. 2018 Feb 1;83(3):284-295. doi: 10.1016/j.biopsych.2017.08.013. Epub 2017 Aug 30.
• [8] Insilico analysis identified miRNAbased therapeutic agents against glioblastoma multiforme.Oncol Rep. 2019 Apr;41(4):2194-2208. doi: 10.3892/or.2019.7022. Epub 2019 Feb 19.
• [9] Human host factors required for influenza virus replication.Nature. 2010 Feb 11;463(7282):813-7. doi: 10.1038/nature08699.
• [10] Comparison of calmodulin gene expression in human neonatal melanocytes and metastatic melanoma cell lines.J Invest Dermatol. 1992 Dec;99(6):764-73. doi: 10.1111/1523-1747.ep12614725.
• [11] Phosphorylation of calcium/calmodulin-stimulated protein kinase II at T286 enhances invasion and migration of human breast cancer cells.Sci Rep. 2016 Sep 8;6:33132. doi: 10.1038/srep33132.
• [12] De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders.Ann Clin Transl Neurol. 2018 Jan 29;5(3):280-296. doi: 10.1002/acn3.528. eCollection 2018 Mar.
• [13] Basic Calcium Phosphate Crystals Induce Osteoarthritis-Associated Changes in Phenotype Markers in Primary Human Chondrocytes by a Calcium/Calmodulin Kinase 2-Dependent Mechanism.Calcif Tissue Int. 2019 Mar;104(3):331-343. doi: 10.1007/s00223-018-0494-1. Epub 2018 Nov 19.
• [14] Hyperactive mice show elevated D2(High) receptors, a model for schizophrenia: Calcium/calmodulin-dependent kinase II alpha knockouts.Synapse. 2010 Oct;64(10):794-800. doi: 10.1002/syn.20786.
• [15] Trifluoperazine, a Well-Known Antipsychotic, Inhibits Glioblastoma Invasion by Binding to Calmodulin and Disinhibiting Calcium Release Channel IP3R.Mol Cancer Ther. 2017 Jan;16(1):217-227. doi: 10.1158/1535-7163.MCT-16-0169-T. Epub 2016 Nov 9.
• [16] Expression analysis of genes involved in brain tumor progression driven by retroviral insertional mutagenesis in mice.Oncogene. 2005 Jun 2;24(24):3896-905. doi: 10.1038/sj.onc.1208553.
• [17] 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.
• [18] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [23] 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.
• [24] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [25] Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells. Int J Mol Sci. 2016 Dec 23;18(1):26. doi: 10.3390/ijms18010026.
• [26] Transcriptional changes common to human cocaine, cannabis and phencyclidine abuse. PLoS One. 2006 Dec 27;1(1):e114. doi: 10.1371/journal.pone.0000114.
• [27] Ouabain induces apoptotic cell death in human prostate DU 145 cancer cells through DNA damage and TRAIL pathways. Environ Toxicol. 2019 Dec;34(12):1329-1339. doi: 10.1002/tox.22834. Epub 2019 Aug 21.
• [28] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [29] 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.
• [30] Use of human neuroblastoma SH-SY5Y cells to evaluate glyphosate-induced effects on oxidative stress, neuronal development and cell death signaling pathways. Environ Int. 2020 Feb;135:105414. doi: 10.1016/j.envint.2019.105414. Epub 2019 Dec 23.
• [31] 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.
• [32] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [33] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [34] 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.