Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHD9KJG)

• DOT Name: Calcium/calmodulin-dependent protein kinase type II subunit gamma (CAMK2G)
• Synonyms: CaM kinase II subunit gamma; CaMK-II subunit gamma; EC 2.7.11.17
• Gene Name: CAMK2G
• Related Disease:
  Intellectual disability
  Non-insulin dependent diabetes
  Advanced cancer
  Amyloidosis
  Anxiety
  Anxiety disorder
  Breast neoplasm
  Depression
  Familial multiple trichoepithelioma
  Glioblastoma multiforme
  Glioma
  Hypoplastic left heart syndrome 1
  Intellectual developmental disorder 59
  Neuroblastoma
  Post-traumatic stress disorder
  Infantile epileptic-dyskinetic encephalopathy
  Infantile spasm
  Myeloid leukaemia
  Psoriasis
• UniProt ID: KCC2G_HUMAN
• PDB ID: 2UX0; 2V7O
• EC Number: 2.7.11.17
• Pfam ID: PF08332 ; PF00069
• Sequence:
  MATTATCTRFTDDYQLFEELGKGAFSVVRRCVKKTSTQEYAAKIINTKKLSARDHQKLER
  EARICRLLKHPNIVRLHDSISEEGFHYLVFDLVTGGELFEDIVAREYYSEADASHCIHQI
  LESVNHIHQHDIVHRDLKPENLLLASKCKGAAVKLADFGLAIEVQGEQQAWFGFAGTPGY
  LSPEVLRKDPYGKPVDIWACGVILYILLVGYPPFWDEDQHKLYQQIKAGAYDFPSPEWDT
  VTPEAKNLINQMLTINPAKRITADQALKHPWVCQRSTVASMMHRQETVECLRKFNARRKL
  KGAILTTMLVSRNFSAAKSLLNKKSDGGVKKRKSSSSVHLMPQSNNKNSLVSPAQEPAPL
  QTAMEPQTTVVHNATDGIKGSTESCNTTTEDEDLKGRVPEGRSSRDRTAPSAGMQPQPSL
  CSSAMRKQEIIKITEQLIEAINNGDFEAYTKICDPGLTSFEPEALGNLVEGMDFHKFYFE
  NLLSKNSKPIHTTILNPHVHVIGEDAACIAYIRLTQYIDGQGRPRTSQSEETRVWHRRDG
  KWLNVHYHCSGAPAAPLQ
• Function: Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in sarcoplasmic reticulum Ca(2+) transport in skeletal muscle and may function in dendritic spine and synapse formation and neuronal plasticity. 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 the ryanodine receptor-coupling factor triadin. In the central nervous system, it is involved in the regulation of neurite formation and arborization. It may participate in the promotion of dendritic spine and synapse formation and maintenance of synaptic plasticity which enables long-term potentiation (LTP) and hippocampus-dependent learning. In response to interferon-gamma (IFN-gamma) stimulation, catalyzes phosphorylation of STAT1, stimulating the JAK-STAT signaling pathway.
• Tissue Specificity: 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

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Genetic Variation	[1]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Amyloidosis	DISHTAI2	Strong	Genetic Variation	[4]
Anxiety	DISIJDBA	Strong	Biomarker	[5]
Anxiety disorder	DISBI2BT	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[6]
Depression	DIS3XJ69	Strong	Altered Expression	[5]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Biomarker	[7]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[8]
Glioma	DIS5RPEH	Strong	Biomarker	[9]
Hypoplastic left heart syndrome 1	DISW3OY8	Strong	Altered Expression	[10]
Intellectual developmental disorder 59	DIS3QPZB	Strong	Autosomal dominant	[11]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[6]
Post-traumatic stress disorder	DISHL1EY	Strong	Altered Expression	[5]
Infantile epileptic-dyskinetic encephalopathy	DISD2ZNC	Limited	Biomarker	[12]
Infantile spasm	DISZSKDG	Limited	Autosomal dominant	[13]
Myeloid leukaemia	DISMN944	Limited	Biomarker	[14]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[15]

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 gamma (CAMK2G).	[16]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Calcium/calmodulin-dependent protein kinase type II subunit gamma (CAMK2G).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Calcium/calmodulin-dependent protein kinase type II subunit gamma (CAMK2G).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Calcium/calmodulin-dependent protein kinase type II subunit gamma (CAMK2G).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit gamma (CAMK2G).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Calcium/calmodulin-dependent protein kinase type II subunit gamma (CAMK2G).	[19]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Calcium/calmodulin-dependent protein kinase type II subunit gamma (CAMK2G).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit gamma (CAMK2G).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Calcium/calmodulin-dependent protein kinase type II subunit gamma (CAMK2G).	[22]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Calcium/calmodulin-dependent protein kinase type II subunit gamma (CAMK2G).	[23]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Calcium/calmodulin-dependent protein kinase type II subunit gamma (CAMK2G).	[24]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit gamma (CAMK2G).	[25]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Calcium/calmodulin-dependent protein kinase type II subunit gamma (CAMK2G).	[28]

References

• [1] The intellectual disability-associated CAMK2G p.Arg292Pro mutation acts as a pathogenic gain-of-function.Hum Mutat. 2018 Dec;39(12):2008-2024. doi: 10.1002/humu.23647. Epub 2018 Sep 19.
• [2] Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes.Nat Commun. 2018 Jul 27;9(1):2941. doi: 10.1038/s41467-018-04951-w.
• [3] CAMK2 in intestinal epithelial cells modulates colitis-associated colorectal carcinogenesis via enhancing STAT3 activation.Oncogene. 2017 Jul 13;36(28):4060-4071. doi: 10.1038/onc.2017.16. Epub 2017 Mar 20.
• [4] Optogenetics-induced activation of glutamate receptors improves memory function in mice with Alzheimer's disease.Neural Regen Res. 2019 Dec;14(12):2147-2155. doi: 10.4103/1673-5374.262593.
• [5] 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.
• [6] 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.
• [7] RNA sequencing of esophageal adenocarcinomas identifies novel fusion transcripts, including NPC1-MELK, arising from a complex chromosomal rearrangement.Cancer. 2017 Oct 15;123(20):3916-3924. doi: 10.1002/cncr.30837. Epub 2017 Jun 22.
• [8] Characterization of gene expression profiles associated with glioma progression using oligonucleotide-based microarray analysis and real-time reverse transcription-polymerase chain reaction.Am J Pathol. 2003 Sep;163(3):1033-43. doi: 10.1016/S0002-9440(10)63463-3.
• [9] 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.
• [10] Gene expression and -adrenergic signaling are altered in hypoplastic left heart syndrome.J Heart Lung Transplant. 2014 Aug;33(8):785-93. doi: 10.1016/j.healun.2014.02.030. Epub 2014 Mar 5.
• [11] Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012 Nov 15;367(20):1921-9. doi: 10.1056/NEJMoa1206524. Epub 2012 Oct 3.
• [12] Integrated network analysis reveals potentially novel molecular mechanisms and therapeutic targets of refractory epilepsies.PLoS One. 2017 Apr 7;12(4):e0174964. doi: 10.1371/journal.pone.0174964. eCollection 2017.
• [13] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [14] Activated Ca2+/calmodulin-dependent protein kinase IIgamma is a critical regulator of myeloid leukemia cell proliferation.Cancer Res. 2008 May 15;68(10):3733-42. doi: 10.1158/0008-5472.CAN-07-2509.
• [15] Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci.Nat Commun. 2015 May 5;6:7001. doi: 10.1038/ncomms8001.
• [16] 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.
• [17] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [18] 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.
• [19] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [20] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [21] 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.
• [22] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [23] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [24] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.