Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK13JKC)

• DOT Name: Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6)
• Synonyms: MAP kinase kinase 6; MAPKK 6; EC 2.7.12.2; MAPK/ERK kinase 6; MEK 6; Stress-activated protein kinase kinase 3; SAPK kinase 3; SAPKK-3; SAPKK3
• Gene Name: MAP2K6
• Related Disease:
  Hepatocellular carcinoma
  Myocardial infarction
  Adrenocortical carcinoma
  Adult glioblastoma
  Advanced cancer
  Allergy
  Amyloidosis
  Carcinoma of esophagus
  Colon carcinoma
  Epithelial ovarian cancer
  Esophageal adenocarcinoma
  Esophageal cancer
  Glioblastoma multiforme
  Huntington disease
  Hyperglycemia
  Hypertrichosis lanuginosa congenita
  Influenza
  Intervertebral disc degeneration
  Knee osteoarthritis
  Lung cancer
  Lung carcinoma
  Muscular dystrophy
  Nasopharyngeal carcinoma
  Neoplasm
  Neoplasm of esophagus
  Obesity
  Ovarian cancer
  Ovarian neoplasm
  Type-1/2 diabetes
  Colon cancer
  Arthritis
  Isolated Pierre-Robin syndrome
  Cardiomyopathy
  Colon adenocarcinoma
  Colonic neoplasm
  Parkinson disease
• UniProt ID: MP2K6_HUMAN
• PDB ID: 2Y8O; 3ENM; 3FME; 3VN9; 5ETF; 8A8M; 8P7J; 8PM3
• EC Number: 2.7.12.2
• Pfam ID: PF00069
• Sequence:
  MSQSKGKKRNPGLKIPKEAFEQPQTSSTPPRDLDSKACISIGNQNFEVKADDLEPIMELG
  RGAYGVVEKMRHVPSGQIMAVKRIRATVNSQEQKRLLMDLDISMRTVDCPFTVTFYGALF
  REGDVWICMELMDTSLDKFYKQVIDKGQTIPEDILGKIAVSIVKALEHLHSKLSVIHRDV
  KPSNVLINALGQVKMCDFGISGYLVDSVAKTIDAGCKPYMAPERINPELNQKGYSVKSDI
  WSLGITMIELAILRFPYDSWGTPFQQLKQVVEEPSPQLPADKFSAEFVDFTSQCLKKNSK
  ERPTYPELMQHPFFTLHESKGTDVASFVKLILGD
• Function: Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. With MAP3K3/MKK3, catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 and MAPK14 and plays an important role in the regulation of cellular responses to cytokines and all kinds of stresses. Especially, MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 and MAPK13 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK11 activator in response to TNF. MAP2K6/MKK6 also phosphorylates and activates PAK6. The p38 MAP kinase signal transduction pathway leads to direct activation of transcription factors. Nuclear targets of p38 MAP kinase include the transcription factors ATF2 and ELK1. Within the p38 MAPK signal transduction pathway, MAP3K6/MKK6 mediates phosphorylation of STAT4 through MAPK14 activation, and is therefore required for STAT4 activation and STAT4-regulated gene expression in response to IL-12 stimulation. The pathway is also crucial for IL-6-induced SOCS3 expression and down-regulation of IL-6-mediated gene induction; and for IFNG-dependent gene transcription. Has a role in osteoclast differentiation through NF-kappa-B transactivation by TNFSF11, and in endochondral ossification and since SOX9 is another likely downstream target of the p38 MAPK pathway. MAP2K6/MKK6 mediates apoptotic cell death in thymocytes. Acts also as a regulator for melanocytes dendricity, through the modulation of Rho family GTPases.
• Tissue Specificity: Isoform 2 is only expressed in skeletal muscle. Isoform 1 is expressed in skeletal muscle, heart, and in lesser extent in liver or pancreas.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Rap1 sig.ling pathway (hsa04015)
  Cellular senescence (hsa04218)
  Osteoclast differentiation (hsa04380)
  Toll-like receptor sig.ling pathway (hsa04620)
  Fc epsilon RI sig.ling pathway (hsa04664)
  TNF sig.ling pathway (hsa04668)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  GnRH sig.ling pathway (hsa04912)
  Growth hormone synthesis, secretion and action (hsa04935)
  Alcoholic liver disease (hsa04936)
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Salmonella infection (hsa05132)
  Yersinia infection (hsa05135)
  Toxoplasmosis (hsa05145)
  Hepatitis B (hsa05161)
  Human cytomegalovirus infection (hsa05163)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
  Lipid and atherosclerosis (hsa05417)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  Oxidative Stress Induced Senescence (R-HSA-2559580)
  activated TAK1 mediates p38 MAPK activation (R-HSA-450302)
  Myogenesis (R-HSA-525793)
  PI5P Regulates TP53 Acetylation (R-HSA-6811555)
  Interleukin-1 signaling (R-HSA-9020702)
  PKR-mediated signaling (R-HSA-9833482)
  NOD1/2 Signaling Pathway (R-HSA-168638)

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Altered Expression	[1]
Myocardial infarction	DIS655KI	Definitive	Altered Expression	[2]
Adrenocortical carcinoma	DISZF4HX	Strong	Biomarker	[3]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Allergy	DIS48ZAP	Strong	Therapeutic	[6]
Amyloidosis	DISHTAI2	Strong	Biomarker	[7]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[8]
Colon carcinoma	DISJYKUO	Strong	Genetic Variation	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[10]
Esophageal adenocarcinoma	DISODWFP	Strong	Biomarker	[11]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[8]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[4]
Huntington disease	DISQPLA4	Strong	Altered Expression	[12]
Hyperglycemia	DIS0BZB5	Strong	Biomarker	[13]
Hypertrichosis lanuginosa congenita	DISX1C1I	Strong	Genetic Variation	[14]
Influenza	DIS3PNU3	Strong	Biomarker	[15]
Intervertebral disc degeneration	DISG3AIM	Strong	Biomarker	[16]
Knee osteoarthritis	DISLSNBJ	Strong	Genetic Variation	[17]
Lung cancer	DISCM4YA	Strong	Altered Expression	[18]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[18]
Muscular dystrophy	DISJD6P7	Strong	Biomarker	[19]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Biomarker	[20]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[8]
Obesity	DIS47Y1K	Strong	Biomarker	[21]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[10]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[10]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[21]
Colon cancer	DISVC52G	moderate	Altered Expression	[22]
Arthritis	DIST1YEL	Disputed	Biomarker	[23]
Isolated Pierre-Robin syndrome	DISVEHG7	Disputed	Biomarker	[24]
Cardiomyopathy	DISUPZRG	Limited	Altered Expression	[25]
Colon adenocarcinoma	DISDRE0J	Limited	Biomarker	[26]
Colonic neoplasm	DISSZ04P	Limited	Therapeutic	[9]
Parkinson disease	DISQVHKL	Limited	Altered Expression	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6) decreases the response to substance of Afimoxifene.	[60]

31 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 6 (MAP2K6).	[28]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[29]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[30]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[31]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the activity of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[32]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[33]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[34]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[35]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[36]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[37]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[38]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[39]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[40]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[41]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[42]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[43]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[44]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[45]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[46]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[40]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[47]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[49]
Acocantherin	DM7JT24	Approved	Acocantherin increases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[50]
Atazanavir	DMSYRBX	Approved	Atazanavir decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[52]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[53]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[54]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[56]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[57]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[58]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[59]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[48]
Sevoflurane	DMC9O43	Approved	Sevoflurane increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[51]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6).	[55]

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