Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZPZX11)

• DOT Name: Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4)
• Synonyms: MAP kinase kinase 4; MAPKK 4; EC 2.7.12.2; JNK-activating kinase 1; MAPK/ERK kinase 4; MEK 4; SAPK/ERK kinase 1; SEK1; Stress-activated protein kinase kinase 1; SAPK kinase 1; SAPKK-1; SAPKK1; c-Jun N-terminal kinase kinase 1; JNKK
• Gene Name: MAP2K4
• Related Disease:
  Acute myelogenous leukaemia
  Cervical cancer
  Cervical carcinoma
  Epithelial ovarian cancer
  Invasive breast carcinoma
  Lung neoplasm
  Matthew-Wood syndrome
  Neuroblastoma
  Ovarian cancer
  Pancreatic ductal carcinoma
  Adenocarcinoma
  Alzheimer disease
  Atrial fibrillation
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Carcinoma
  Ductal breast carcinoma in situ
  Endometrial cancer
  Endometrial carcinoma
  Huntington disease
  Lung adenocarcinoma
  Nasopharyngeal carcinoma
  Osteoarthritis
  Osteosarcoma
  Ovarian neoplasm
  Ovarian serous adenocarcinoma
  Rheumatoid arthritis
  Breast neoplasm
  Gastric adenocarcinoma
  Laryngeal squamous cell carcinoma
  Lung cancer
  Lung carcinoma
  Obesity
  Pancreatic cancer
  Rhabdomyosarcoma
  Metastatic malignant neoplasm
  Neoplasm
  Castration-resistant prostate carcinoma
  Colonic neoplasm
  Colorectal adenoma
  Colorectal carcinoma
  Gallbladder carcinoma
  Glioma
  Non-small-cell lung cancer
  Prostate cancer
  Prostate carcinoma
• UniProt ID: MP2K4_HUMAN
• PDB ID: 3ALN; 3ALO; 3VUT
• EC Number: 2.7.12.2
• Pfam ID: PF00069
• Sequence:
  MAAPSPSGGGGSGGGSGSGTPGPVGSPAPGHPAVSSMQGKRKALKLNFANPPFKSTARFT
  LNPNPTGVQNPHIERLRTHSIESSGKLKISPEQHWDFTAEDLKDLGEIGRGAYGSVNKMV
  HKPSGQIMAVKRIRSTVDEKEQKQLLMDLDVVMRSSDCPYIVQFYGALFREGDCWICMEL
  MSTSFDKFYKYVYSVLDDVIPEEILGKITLATVKALNHLKENLKIIHRDIKPSNILLDRS
  GNIKLCDFGISGQLVDSIAKTRDAGCRPYMAPERIDPSASRQGYDVRSDVWSLGITLYEL
  ATGRFPYPKWNSVFDQLTQVVKGDPPQLSNSEEREFSPSFINFVNLCLTKDESKRPKYKE
  LLKHPFILMYEERAVEVACYVCKILDQMPATPSSPMYVD
• Function: Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to pro-inflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14.
• Tissue Specificity: Abundant expression is seen in the skeletal muscle. It is also widely expressed in other tissues.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  ErbB sig.ling pathway (hsa04012)
  Toll-like receptor sig.ling pathway (hsa04620)
  Fc epsilon RI sig.ling pathway (hsa04664)
  TNF sig.ling pathway (hsa04668)
  GnRH sig.ling pathway (hsa04912)
  Relaxin sig.ling pathway (hsa04926)
  Growth hormone synthesis, secretion and action (hsa04935)
  Alcoholic liver disease (hsa04936)
  Epithelial cell sig.ling in Helicobacter pylori infection (hsa05120)
  Salmonella infection (hsa05132)
  Yersinia infection (hsa05135)
  Chagas disease (hsa05142)
  Hepatitis B (hsa05161)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Epstein-Barr virus infection (hsa05169)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Lipid and atherosclerosis (hsa05417)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  FCERI mediated MAPK activation (R-HSA-2871796)
  JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 (R-HSA-450321)
  Uptake and function of anthrax toxins (R-HSA-5210891)
  MAP3K8 (TPL2)-dependent MAPK1/3 activation (R-HSA-5684264)
  Oxidative Stress Induced Senescence (R-HSA-2559580)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Genetic Variation	[1]
Cervical cancer	DISFSHPF	Definitive	Genetic Variation	[2]
Cervical carcinoma	DIST4S00	Definitive	Genetic Variation	[2]
Epithelial ovarian cancer	DIS56MH2	Definitive	Altered Expression	[3]
Invasive breast carcinoma	DISANYTW	Definitive	Genetic Variation	[4]
Lung neoplasm	DISVARNB	Definitive	Biomarker	[5]
Matthew-Wood syndrome	DISA7HR7	Definitive	Altered Expression	[6]
Neuroblastoma	DISVZBI4	Definitive	Altered Expression	[7]
Ovarian cancer	DISZJHAP	Definitive	Altered Expression	[3]
Pancreatic ductal carcinoma	DIS26F9Q	Definitive	Genetic Variation	[6]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[8]
Alzheimer disease	DISF8S70	Strong	Biomarker	[9]
Atrial fibrillation	DIS15W6U	Strong	Altered Expression	[10]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[11]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[12]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[12]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[13]
Ductal breast carcinoma in situ	DISLCJY7	Strong	Genetic Variation	[14]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[15]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[15]
Huntington disease	DISQPLA4	Strong	Altered Expression	[16]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[17]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Altered Expression	[18]
Osteoarthritis	DIS05URM	Strong	Biomarker	[19]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[11]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[3]
Ovarian serous adenocarcinoma	DISSU72Z	Strong	Altered Expression	[20]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[21]
Breast neoplasm	DISNGJLM	moderate	Biomarker	[22]
Gastric adenocarcinoma	DISWWLTC	moderate	Biomarker	[23]
Laryngeal squamous cell carcinoma	DIS9UUVF	moderate	Altered Expression	[24]
Lung cancer	DISCM4YA	moderate	Biomarker	[25]
Lung carcinoma	DISTR26C	moderate	Biomarker	[25]
Obesity	DIS47Y1K	moderate	Biomarker	[26]
Pancreatic cancer	DISJC981	moderate	Biomarker	[27]
Rhabdomyosarcoma	DISNR7MS	moderate	Altered Expression	[28]
Metastatic malignant neoplasm	DIS86UK6	Disputed	Biomarker	[29]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[6]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Biomarker	[30]
Colonic neoplasm	DISSZ04P	Limited	Biomarker	[31]
Colorectal adenoma	DISTSVHM	Limited	Biomarker	[32]
Colorectal carcinoma	DIS5PYL0	Limited	Genetic Variation	[33]
Gallbladder carcinoma	DISD6ACL	Limited	Biomarker	[34]
Glioma	DIS5RPEH	Limited	Biomarker	[35]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[5]
Prostate cancer	DISF190Y	Limited	Altered Expression	[36]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[36]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4) increases the response to substance of Arsenic trioxide.	[58]
Afimoxifene	DMFORDT	Phase 2	Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4) decreases the response to substance of Afimoxifene.	[59]

15 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 Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[37]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[38]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[39]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[40]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[41]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[42]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[43]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[44]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[45]
Dactinomycin	DM2YGNW	Approved	Dactinomycin decreases the expression of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[38]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[47]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[48]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[53]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[54]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[55]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[46]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[49]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[50]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[51]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[52]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[56]
LICOAGROCHACONE A	DMWY0TN	Investigative	LICOAGROCHACONE A decreases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[46]
MANGOSTIN	DMYQGDV	Investigative	MANGOSTIN increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4).	[57]

References

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