Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT47RDGV)

• DOT Name: Calcium/calmodulin-dependent protein kinase type IV (CAMK4)
• Synonyms: CaMK IV; EC 2.7.11.17; CaM kinase-GR
• Gene Name: CAMK4
• Related Disease:
  Ovarian neoplasm
  Acute myelogenous leukaemia
  Advanced cancer
  Alzheimer disease
  Amyloidosis
  Asthma
  Autism spectrum disorder
  Autoimmune disease, susceptibility to, 6
  Carcinoma of liver and intrahepatic biliary tract
  Cognitive impairment
  Colitis
  Endometrial carcinoma
  Epilepsy
  Familial Alzheimer disease
  Hypoplastic left heart syndrome 1
  Hypothyroidism
  Inflammatory bowel disease
  leukaemia
  Leukemia
  Liver cancer
  Neoplasm
  Nephropathy
  Neuroblastoma
  Nicotine dependence
  Psoriatic arthritis
  Skin disease
  STAT3-related early-onset multisystem autoimmune disease
  Ulcerative colitis
  High blood pressure
  Lupus
  Amyotrophic lateral sclerosis
  Complex neurodevelopmental disorder
  Focal segmental glomerulosclerosis
  Lupus nephritis
  Nephritis
  Systemic lupus erythematosus
• UniProt ID: KCC4_HUMAN
• PDB ID: 2W4O
• EC Number: 2.7.11.17
• Pfam ID: PF00069
• Sequence:
  MLKVTVPSCSASSCSSVTASAAPGTASLVPDYWIDGSNRDALSDFFEVESELGRGATSIV
  YRCKQKGTQKPYALKVLKKTVDKKIVRTEIGVLLRLSHPNIIKLKEIFETPTEISLVLEL
  VTGGELFDRIVEKGYYSERDAADAVKQILEAVAYLHENGIVHRDLKPENLLYATPAPDAP
  LKIADFGLSKIVEHQVLMKTVCGTPGYCAPEILRGCAYGPEVDMWSVGIITYILLCGFEP
  FYDERGDQFMFRRILNCEYYFISPWWDEVSLNAKDLVRKLIVLDPKKRLTTFQALQHPWV
  TGKAANFVHMDTAQKKLQEFNARRKLKAAVKAVVASSRLGSASSSHGSIQESHKASRDPS
  PIQDGNEDMKAIPEGEKIQGDGAQAAVKGAQAELMKVQALEKVKGADINAEEAPKMVPKA
  VEDGIKVADLELEEGLAEEKLKTVEEAAAPREGQGSSAVGFEVPQQDVILPEY
• Function: Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK4 signaling cascade and regulates, mainly by phosphorylation, the activity of several transcription activators, such as CREB1, MEF2D, JUN and RORA, which play pivotal roles in immune response, inflammation, and memory consolidation. In the thymus, regulates the CD4(+)/CD8(+) double positive thymocytes selection threshold during T-cell ontogeny. In CD4 memory T-cells, is required to link T-cell antigen receptor (TCR) signaling to the production of IL2, IFNG and IL4 (through the regulation of CREB and MEF2). Regulates the differentiation and survival phases of osteoclasts and dendritic cells (DCs). Mediates DCs survival by linking TLR4 and the regulation of temporal expression of BCL2. Phosphorylates the transcription activator CREB1 on 'Ser-133' in hippocampal neuron nuclei and contribute to memory consolidation and long term potentiation (LTP) in the hippocampus. Can activate the MAP kinases MAPK1/ERK2, MAPK8/JNK1 and MAPK14/p38 and stimulate transcription through the phosphorylation of ELK1 and ATF2. Can also phosphorylate in vitro CREBBP, PRM2, MEF2A and STMN1/OP18.
• Tissue Specificity: Expressed in brain, thymus, CD4 T-cells, testis and epithelial ovarian cancer tissue.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cAMP sig.ling pathway (hsa04024)
  Longevity regulating pathway (hsa04211)
  Apelin sig.ling pathway (hsa04371)
  Osteoclast differentiation (hsa04380)
  Long-term potentiation (hsa04720)
  Neurotrophin sig.ling pathway (hsa04722)
  Cholinergic sy.pse (hsa04725)
  Oxytocin sig.ling pathway (hsa04921)
  Aldosterone synthesis and secretion (hsa04925)
  Amphetamine addiction (hsa05031)
  Alcoholism (hsa05034)
  Glioma (hsa05214)
• Reactome Pathway:
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)
  CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde (R-HSA-442729)
  Loss of phosphorylation of MECP2 at T308 (R-HSA-9022535)
  Regulation of MECP2 expression and activity (R-HSA-9022692)
  Negative regulation of NMDA receptor-mediated neuronal transmission (R-HSA-9617324)
  CaMK IV-mediated phosphorylation of CREB (R-HSA-111932)

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ovarian neoplasm	DISEAFTY	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Amyloidosis	DISHTAI2	Strong	Genetic Variation	[5]
Asthma	DISW9QNS	Strong	Genetic Variation	[6]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[7]
Autoimmune disease, susceptibility to, 6	DISHNUXI	Strong	Genetic Variation	[8]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[9]
Cognitive impairment	DISH2ERD	Strong	Genetic Variation	[10]
Colitis	DISAF7DD	Strong	Altered Expression	[11]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[12]
Epilepsy	DISBB28L	Strong	Biomarker	[13]
Familial Alzheimer disease	DISE75U4	Strong	Biomarker	[14]
Hypoplastic left heart syndrome 1	DISW3OY8	Strong	Altered Expression	[15]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[8]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[11]
leukaemia	DISS7D1V	Strong	Altered Expression	[2]
Leukemia	DISNAKFL	Strong	Altered Expression	[2]
Liver cancer	DISDE4BI	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[16]
Nephropathy	DISXWP4P	Strong	Biomarker	[17]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[18]
Nicotine dependence	DISZD9W7	Strong	Biomarker	[19]
Psoriatic arthritis	DISLWTG2	Strong	Biomarker	[20]
Skin disease	DISDW8R6	Strong	Biomarker	[21]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	Strong	Genetic Variation	[8]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[11]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[22]
Lupus	DISOKJWA	moderate	Altered Expression	[17]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[23]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal dominant	[24]
Focal segmental glomerulosclerosis	DISJNHH0	Limited	Biomarker	[25]
Lupus nephritis	DISCVGPZ	Limited	Biomarker	[26]
Nephritis	DISQZQ70	Limited	Biomarker	[25]
Systemic lupus erythematosus	DISI1SZ7	Limited	Altered Expression	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cocaine	DMSOX7I	Approved	Calcium/calmodulin-dependent protein kinase type IV (CAMK4) increases the response to substance of Cocaine.	[38]

11 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 IV (CAMK4).	[28]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Calcium/calmodulin-dependent protein kinase type IV (CAMK4).	[29]
Estradiol	DMUNTE3	Approved	Estradiol increases the activity of Calcium/calmodulin-dependent protein kinase type IV (CAMK4).	[30]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Calcium/calmodulin-dependent protein kinase type IV (CAMK4).	[31]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Calcium/calmodulin-dependent protein kinase type IV (CAMK4).	[28]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Calcium/calmodulin-dependent protein kinase type IV (CAMK4).	[32]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the activity of Calcium/calmodulin-dependent protein kinase type IV (CAMK4).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Calcium/calmodulin-dependent protein kinase type IV (CAMK4).	[33]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Calcium/calmodulin-dependent protein kinase type IV (CAMK4).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Calcium/calmodulin-dependent protein kinase type IV (CAMK4).	[36]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Calcium/calmodulin-dependent protein kinase type IV (CAMK4).	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Calcium/calmodulin-dependent protein kinase type IV (CAMK4).	[35]

References

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