Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU24HAU)

• DOT Name: Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D)
• Synonyms: EC 2.7.11.17; CaM kinase I delta; CaM kinase ID; CaM-KI delta; CaMKI delta; CaMKID; CaMKI-like protein kinase; CKLiK
• Gene Name: CAMK1D
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Carcinoma
  Essential hypertension
  Lung adenocarcinoma
  Neoplasm
  Type-1/2 diabetes
  Chronic obstructive pulmonary disease
  Acute myelogenous leukaemia
  Lupus nephritis
  Non-insulin dependent diabetes
  Schizophrenia
  Systemic lupus erythematosus
• UniProt ID: KCC1D_HUMAN
• PDB ID: 2JC6; 6QP5; 6T28; 6T29; 6T6F; 8BFM; 8BFS
• EC Number: 2.7.11.17
• Pfam ID: PF00069
• Sequence:
  MARENGESSSSWKKQAEDIKKIFEFKETLGTGAFSEVVLAEEKATGKLFAVKCIPKKALK
  GKESSIENEIAVLRKIKHENIVALEDIYESPNHLYLVMQLVSGGELFDRIVEKGFYTEKD
  ASTLIRQVLDAVYYLHRMGIVHRDLKPENLLYYSQDEESKIMISDFGLSKMEGKGDVMST
  ACGTPGYVAPEVLAQKPYSKAVDCWSIGVIAYILLCGYPPFYDENDSKLFEQILKAEYEF
  DSPYWDDISDSAKDFIRNLMEKDPNKRYTCEQAARHPWIAGDTALNKNIHESVSAQIRKN
  FAKSKWRQAFNATAVVRHMRKLHLGSSLDSSNASVSSSLSLASQKDCLAPSTLCSFISSS
  SGVSGVGAERRPRPTTVTAVHSGSK
• Function: Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, activates CREB-dependent gene transcription, regulates calcium-mediated granulocyte function and respiratory burst and promotes basal dendritic growth of hippocampal neurons. In neutrophil cells, required for cytokine-induced proliferative responses and activation of the respiratory burst. Activates the transcription factor CREB1 in hippocampal neuron nuclei. May play a role in apoptosis of erythroleukemia cells. In vitro, phosphorylates transcription factor CREM isoform Beta.
• Tissue Specificity: Widely expressed. Highly and mostly expressed in polymorphonuclear leukocytes (neutrophilic and eosinophilic granulocytes) while little or no expression is observed in monocytes and lymphocytes.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Oxytocin sig.ling pathway (hsa04921)
  Aldosterone synthesis and secretion (hsa04925)
  Glioma (hsa05214)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Carcinoma	DISH9F1N	Strong	Altered Expression	[1]
Essential hypertension	DIS7WI98	Strong	Biomarker	[3]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[5]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Genetic Variation	[6]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[7]
Lupus nephritis	DISCVGPZ	Limited	Genetic Variation	[8]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[9]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[10]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[8]

13 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 Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D).	[15]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D).	[15]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D).	[23]

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 Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D).	[20]

References

• [1] CAMK1D amplification implicated in epithelial-mesenchymal transition in basal-like breast cancer.Mol Oncol. 2008 Dec;2(4):327-39. doi: 10.1016/j.molonc.2008.09.004. Epub 2008 Oct 2.
• [2] Alterations of Ca?responsive proteins within cholinergic neurons in aging and Alzheimer's disease.Neurobiol Aging. 2014 Jun;35(6):1325-33. doi: 10.1016/j.neurobiolaging.2013.12.017. Epub 2013 Dec 25.
• [3] Genome-wide association study identifies CAMKID variants involved in blood pressure response to losartan: the SOPHIA study.Pharmacogenomics. 2014 Sep;15(13):1643-52. doi: 10.2217/pgs.14.119.
• [4] Selective secretion of microRNAs from lung cancer cells via extracellular vesicles promotes CAMK1D-mediated tube formation in endothelial cells.Oncotarget. 2017 Aug 7;8(48):83913-83924. doi: 10.18632/oncotarget.19996. eCollection 2017 Oct 13.
• [5] Genetic susceptibility for ischemic infarction and arteriolosclerosis based on neuropathologic evaluations.Cerebrovasc Dis. 2013;36(3):181-188. doi: 10.1159/000352054. Epub 2013 Oct 12.
• [6] Analysis of protein-protein interaction network in chronic obstructive pulmonary disease.Genet Mol Res. 2014 Oct 31;13(4):8862-9. doi: 10.4238/2014.October.31.1.
• [7] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [8] Response to Intravenous Cyclophosphamide Treatment for Lupus Nephritis Associated with Polymorphisms in the FCGR2B-FCRLA Locus.J Rheumatol. 2016 Jun;43(6):1045-9. doi: 10.3899/jrheum.150665. Epub 2016 Mar 15.
• [9] Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population.Nat Genet. 2019 Mar;51(3):379-386. doi: 10.1038/s41588-018-0332-4. Epub 2019 Feb 4.
• [10] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [13] 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.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [16] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [17] 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.
• [18] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [19] 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.
• [20] 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.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [23] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.