General Information of Drug Off-Target (DOT) (ID: OTRN55RE)

DOT Name Calcium/calmodulin-dependent protein kinase type 1 (CAMK1)
Synonyms EC 2.7.11.17; CaM kinase I; CaM-KI; CaM kinase I alpha; CaMKI-alpha
Gene Name CAMK1
Related Disease
Neoplasm ( )
Acute myelogenous leukaemia ( )
B-cell lymphoma ( )
Burkitt lymphoma ( )
Medulloblastoma ( )
Breast cancer ( )
Breast carcinoma ( )
Non-small-cell lung cancer ( )
UniProt ID
KCC1A_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
4FG7; 4FG8; 4FG9; 4FGB
EC Number
2.7.11.17
Pfam ID
PF00069
Sequence
MLGAVEGPRWKQAEDIRDIYDFRDVLGTGAFSEVILAEDKRTQKLVAIKCIAKEALEGKE
GSMENEIAVLHKIKHPNIVALDDIYESGGHLYLIMQLVSGGELFDRIVEKGFYTERDASR
LIFQVLDAVKYLHDLGIVHRDLKPENLLYYSLDEDSKIMISDFGLSKMEDPGSVLSTACG
TPGYVAPEVLAQKPYSKAVDCWSIGVIAYILLCGYPPFYDENDAKLFEQILKAEYEFDSP
YWDDISDSAKDFIRHLMEKDPEKRFTCEQALQHPWIAGDTALDKNIHQSVSEQIKKNFAK
SKWKQAFNATAVVRHMRKLQLGTSQEGQGQTASHGELLTPVAGGPAAGCCCRDCCVEPGT
ELSPTLPHQL
Function
Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, regulates transcription activators activity, cell cycle, hormone production, cell differentiation, actin filament organization and neurite outgrowth. Recognizes the substrate consensus sequence [MVLIF]-x-R-x(2)-[ST]-x(3)-[MVLIF]. Regulates axonal extension and growth cone motility in hippocampal and cerebellar nerve cells. Upon NMDA receptor-mediated Ca(2+) elevation, promotes dendritic growth in hippocampal neurons and is essential in synapses for full long-term potentiation (LTP) and ERK2-dependent translational activation. Downstream of NMDA receptors, promotes the formation of spines and synapses in hippocampal neurons by phosphorylating ARHGEF7/BETAPIX on 'Ser-694', which results in the enhancement of ARHGEF7 activity and activation of RAC1. Promotes neuronal differentiation and neurite outgrowth by activation and phosphorylation of MARK2 on 'Ser-91', 'Ser-92', 'Ser-93' and 'Ser-294'. Promotes nuclear export of HDAC5 and binding to 14-3-3 by phosphorylation of 'Ser-259' and 'Ser-498' in the regulation of muscle cell differentiation. Regulates NUMB-mediated endocytosis by phosphorylation of NUMB on 'Ser-276' and 'Ser-295'. Involved in the regulation of basal and estrogen-stimulated migration of medulloblastoma cells through ARHGEF7/BETAPIX phosphorylation. Is required for proper activation of cyclin-D1/CDK4 complex during G1 progression in diploid fibroblasts. Plays a role in K(+) and ANG2-mediated regulation of the aldosterone synthase (CYP11B2) to produce aldosterone in the adrenal cortex. Phosphorylates EIF4G3/eIF4GII. In vitro phosphorylates CREB1, ATF1, CFTR, MYL9 and SYN1/synapsin I.
Tissue Specificity Widely expressed. Expressed in cells of the zona glomerulosa of the adrenal cortex.
KEGG Pathway
Calcium sig.ling pathway (hsa04020 )
Oxytocin sig.ling pathway (hsa04921 )
Aldosterone synthesis and secretion (hsa04925 )
Glioma (hsa05214 )
Reactome Pathway
Activation of RAC1 downstream of NMDARs (R-HSA-9619229 )
Negative regulation of NMDA receptor-mediated neuronal transmission (R-HSA-9617324 )

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Neoplasm DISZKGEW Definitive Biomarker [1]
Acute myelogenous leukaemia DISCSPTN Strong Biomarker [2]
B-cell lymphoma DISIH1YQ Strong Biomarker [3]
Burkitt lymphoma DIS9D5XU Strong Biomarker [3]
Medulloblastoma DISZD2ZL Strong Biomarker [4]
Breast cancer DIS7DPX1 moderate Biomarker [5]
Breast carcinoma DIS2UE88 moderate Biomarker [5]
Non-small-cell lung cancer DIS5Y6R9 Limited Biomarker [6]
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⏷ Show the Full List of 8 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
This DOT Affected the Drug Response of 2 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Topotecan DMP6G8T Approved Calcium/calmodulin-dependent protein kinase type 1 (CAMK1) affects the response to substance of Topotecan. [17]
Afimoxifene DMFORDT Phase 2 Calcium/calmodulin-dependent protein kinase type 1 (CAMK1) decreases the response to substance of Afimoxifene. [18]
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9 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 1 (CAMK1). [7]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate decreases the expression of Calcium/calmodulin-dependent protein kinase type 1 (CAMK1). [8]
Cisplatin DMRHGI9 Approved Cisplatin increases the expression of Calcium/calmodulin-dependent protein kinase type 1 (CAMK1). [9]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Calcium/calmodulin-dependent protein kinase type 1 (CAMK1). [10]
Quercetin DM3NC4M Approved Quercetin decreases the expression of Calcium/calmodulin-dependent protein kinase type 1 (CAMK1). [11]
Tamibarotene DM3G74J Phase 3 Tamibarotene increases the expression of Calcium/calmodulin-dependent protein kinase type 1 (CAMK1). [7]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 decreases the expression of Calcium/calmodulin-dependent protein kinase type 1 (CAMK1). [14]
Bisphenol A DM2ZLD7 Investigative Bisphenol A increases the expression of Calcium/calmodulin-dependent protein kinase type 1 (CAMK1). [15]
KN-93 DMPTMKH Investigative KN-93 decreases the activity of Calcium/calmodulin-dependent protein kinase type 1 (CAMK1). [16]
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⏷ Show the Full List of 9 Drug(s)
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
phorbol 12-myristate 13-acetate DMJWD62 Phase 2 phorbol 12-myristate 13-acetate increases the phosphorylation of Calcium/calmodulin-dependent protein kinase type 1 (CAMK1). [12]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of Calcium/calmodulin-dependent protein kinase type 1 (CAMK1). [13]
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References

1 Aldosterone producing adrenal adenomas are characterized by activation of calcium/calmodulin-dependent protein kinase (CaMK) dependent pathways.Horm Metab Res. 2011 Feb;43(2):106-11. doi: 10.1055/s-0030-1269899. Epub 2011 Jan 19.
2 The ITIM-containing receptor LAIR1 is essential for acute myeloid leukaemia development.Nat Cell Biol. 2015 May;17(5):665-77. doi: 10.1038/ncb3158. Epub 2015 Apr 27.
3 Comparison of gene expression profiles of lymphoma cell lines from transformed follicular lymphoma, Burkitt's lymphoma and de novo diffuse large B-cell lymphoma.Cancer Sci. 2003 Sep;94(9):774-81. doi: 10.1111/j.1349-7006.2003.tb01518.x.
4 Calmodulin-kinases regulate basal and estrogen stimulated medulloblastoma migration via Rac1.J Neurooncol. 2011 Aug;104(1):65-82. doi: 10.1007/s11060-010-0472-6. Epub 2010 Nov 24.
5 Calcium/calmodulin-dependent kinase I and calcium/calmodulin-dependent kinase kinase participate in the control of cell cycle progression in MCF-7 human breast cancer cells. Cancer Res. 2005 Jun 15;65(12):5408-16. doi: 10.1158/0008-5472.CAN-05-0271.
6 Cloning, expression and chromosomal localization of human Ca2+/calmodulin-dependent protein kinase kinase.J Biomed Sci. 1998;5(2):141-9. doi: 10.1007/BF02258368.
7 Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
8 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
9 Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
10 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.
11 Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
12 Metformin blocks migration and invasion of tumour cells by inhibition of matrix metalloproteinase-9 activation through a calcium and protein kinase Calpha-dependent pathway: phorbol-12-myristate-13-acetate-induced/extracellular signal-regulated kinase/activator protein-1. Br J Pharmacol. 2010 Jul;160(5):1195-211. doi: 10.1111/j.1476-5381.2010.00762.x.
13 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.
14 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.
15 Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
16 Calmodulin-dependent kinase I regulates adrenal cell expression of aldosterone synthase. Endocrinology. 2002 Sep;143(9):3651-7. doi: 10.1210/en.2001-211359.
17 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.
18 High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.