Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1E21HI)

• DOT Name: Mitogen-activated protein kinase kinase kinase 15 (MAP3K15)
• Synonyms: EC 2.7.11.25; Apoptosis signal-regulating kinase 3; MAPK/ERK kinase kinase 15; MEK kinase 15; MEKK 15
• Gene Name: MAP3K15
• Related Disease:
  High blood pressure
  Female hypogonadism
  Polycystic ovarian syndrome
• UniProt ID: M3K15_HUMAN
• PDB ID: 6V0M
• EC Number: 2.7.11.25
• Pfam ID: PF19039 ; PF20309 ; PF20302 ; PF13281 ; PF00069
• Sequence:
  MESGGGNAPAGALGAASESPQCPPPPGVEGAAGPAEPDGAAEGAAGGSGEGESGGGPRRA
  LRAVYVRSESSQGGAAGGPEAGARQCLLRACEAEGAHLTSVPFGELDFGETAVLDAFYDA
  DVAVVDMSDVSRQPSLFYHLGVRESFDMANNVILYHDTDADTALSLKDMVTQKNTASSGN
  YYFIPYIVTPCADYFCCESDAQRRASEYMQPNWDNILGPLCMPLVDRFISLLKDIHVTSC
  VYYKETLLNDIRKAREKYQGEELAKELARIKLRMDNTEVLTSDIIINLLLSYRDIQDYDA
  MVKLVETLEMLPTCDLADQHNIKFHYAFALNRRNSTGDREKALQIMLQVLQSCDHPGPDM
  FCLCGRIYKDIFLDSDCKDDTSRDSAIEWYRKGFELQSSLYSGINLAVLLIVAGQQFETS
  LELRKIGVRLNSLLGRKGSLEKMNNYWDVGQFFSVSMLAHDVGKAVQAAERLFKLKPPVW
  YLRSLVQNLLLIRRFKKTIIEHSPRQERLNFWLDIIFEATNEVTNGLRFPVLVIEPTKVY
  QPSYVSINNEAEERTVSLWHVSPTEMKQMHEWNFTASSIKGISLSKFDERCCFLYVHDNS
  DDFQIYFSTEEQCSRFFSLVKEMITNTAGSTVELEGETDGDTLEYEYDHDANGERVVLGK
  GTYGIVYAGRDLSNQVRIAIKEIPERDSRYSQPLHEEIALHKYLKHRNIVQYLGSVSENG
  YIKIFMEQVPGGSLSALLRSKWGPMKEPTIKFYTKQILEGLKYLHENQIVHRDIKGDNVL
  VNTYSGVVKISDFGTSKRLAGVNPCTETFTGTLQYMAPEIIDQGPRGYGAPADIWSLGCT
  IIEMATSKPPFHELGEPQAAMFKVGMFKIHPEIPEALSAEARAFILSCFEPDPHKRATTA
  ELLREGFLRQVNKGKKNRIAFKPSEGPRGVVLALPTQGEPMATSSSEHGSVSPDSDAQPD
  ALFERTRAPRHHLGHLLSVPDESSALEDRGLASSPEDRDQGLFLLRKDSERRAILYKILW
  EEQNQVASNLQECVAQSSEELHLSVGHIKQIIGILRDFIRSPEHRVMATTISKLKVDLDF
  DSSSISQIHLVLFGFQDAVNKILRNHLIRPHWMFAMDNIIRRAVQAAVTILIPELRAHFE
  PTCETEGVDKDMDEAEEGYPPATGPGQEAQPHQQHLSLQLGELRQETNRLLEHLVEKERE
  YQNLLRQTLEQKTQELYHLQLKLKSNCITENPAGPYGQRTDKELIDWLRLQGADAKTIEK
  IVEEGYTLSDILNEITKEDLRYLRLRGGLLCRLWSAVSQYRRAQEASETKDKA
• Function: Serine/threonine kinase which acts as a component of the MAP kinase signal transduction pathway. Once activated, acts as an upstream activator of the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases. May function in a signal transduction pathway that is activated by various cell stresses and leads to apoptosis. Involved in phosphorylation of WNK4 in response to osmotic stress or hypotonic low-chloride stimulation via the p38 MAPK signal transduction cascade.
• Tissue Specificity: Isoform 2 and isoform 3 are widely expressed. Isoform 2 highest levels are observed in fetal brain, and isoform 3 highest levels in pancreas, peripheral blood leukocytes, fetal brain and spleen.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
High blood pressure	DISY2OHH	Strong	Biomarker	[1]
Female hypogonadism	DISWASB4	Limited	Biomarker	[2]
Polycystic ovarian syndrome	DISZ2BNG	Limited	Biomarker	[2]

2 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitogen-activated protein kinase kinase kinase 15 (MAP3K15).	[3]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Mitogen-activated protein kinase kinase kinase 15 (MAP3K15).	[4]

1 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 affects the methylation of Mitogen-activated protein kinase kinase kinase 15 (MAP3K15).	[5]

References

• [1] MAP3K kinases and kidney injury.Nefrologia (Engl Ed). 2019 Nov-Dec;39(6):568-580. doi: 10.1016/j.nefro.2019.03.004. Epub 2019 Jun 10.
• [2] The transcriptional regulator CBX2 and ovarian function: A whole genome and whole transcriptome approach.Sci Rep. 2019 Nov 19;9(1):17033. doi: 10.1038/s41598-019-53370-4.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [5] 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.