Details of Drug Off-Target (DOT)

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

• DOT Name: C-Jun-amino-terminal kinase-interacting protein 1 (MAPK8IP1)
• Synonyms: JIP-1; JNK-interacting protein 1; Islet-brain 1; IB-1; JNK MAP kinase scaffold protein 1; Mitogen-activated protein kinase 8-interacting protein 1
• Gene Name: MAPK8IP1
• Related Disease: Obsolete diabetes mellitus, noninsulin-dependent
• UniProt ID: JIP1_HUMAN
• PDB ID: 2G01; 2GMX; 2H96; 3OXI; 3PTG; 3VUD; 3VUG; 3VUH; 3VUI; 3VUK; 3VUL; 3VUM; 4E73; 4G1W; 4H39; 4HYS; 4HYU; 4IZY; 5LW1; 6FUZ; 7NYK; 7NYL; 7NYM; 7NYN; 7NYO; 7NZB
• Pfam ID: PF00640 ; PF14604
• Sequence:
  MAERESGGLGGGAASPPAASPFLGLHIASPPNFRLTHDISLEEFEDEDLSEITDECGISL
  QCKDTLSLRPPRAGLLSAGGGGAGSRLQAEMLQMDLIDATGDTPGAEDDEEDDDEERAAR
  RPGAGPPKAESGQEPASRGQGQSQGQSQGPGSGDTYRPKRPTTLNLFPQVPRSQDTLNNN
  SLGKKHSWQDRVSRSSSPLKTGEQTPPHEHICLSDELPPQSGPAPTTDRGTSTDSPCRRS
  TATQMAPPGGPPAAPPGGRGHSHRDRIHYQADVRLEATEEIYLTPVQRPPDAAEPTSAFL
  PPTESRMSVSSDPDPAAYPSTAGRPHPSISEEEEGFDCLSSPERAEPPGGGWRGSLGEPP
  PPPRASLSSDTSALSYDSVKYTLVVDEHAQLELVSLRPCFGDYSDESDSATVYDNCASVS
  SPYESAIGEEYEEAPRPQPPACLSEDSTPDEPDVHFSKKFLNVFMSGRSRSSSAESFGLF
  SCIINGEEQEQTHRAIFRFVPRHEDELELEVDDPLLVELQAEDYWYEAYNMRTGARGVFP
  AYYAIEVTKEPEHMAALAKNSDWVDQFRVKFLGSVQVPYHKGNDVLCAAMQKIATTRRLT
  VHFNPPSSCVLEISVRGVKIGVKADDSQEAKGNKCSHFFQLKNISFCGYHPKNNKYFGFI
  TKHPADHRFACHVFVSEDSTKALAESVGRAFQQFYKQFVEYTCPTEDIYLE
• Function: The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module. Required for JNK activation in response to excitotoxic stress. Cytoplasmic MAPK8IP1 causes inhibition of JNK-regulated activity by retaining JNK in the cytoplasm and inhibiting JNK phosphorylation of c-Jun. May also participate in ApoER2-specific reelin signaling. Directly, or indirectly, regulates GLUT2 gene expression and beta-cell function. Appears to have a role in cell signaling in mature and developing nerve terminals. May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins. Functions as an anti-apoptotic protein and whose level seems to influence the beta-cell death or survival response. Acts as a scaffold protein that coordinates with SH3RF1 in organizing different components of the JNK pathway, including RAC1 or RAC2, MAP3K11/MLK3 or MAP3K7/TAK1, MAP2K7/MKK7, MAPK8/JNK1 and/or MAPK9/JNK2 into a functional multiprotein complex to ensure the effective activation of the JNK signaling pathway. Regulates the activation of MAPK8/JNK1 and differentiation of CD8(+) T-cells.
• Tissue Specificity: Highly expressed in brain. Expressed in neurons, localizing to neurite tips in differentiating cells. Also expressed in the pancreas, testis and prostate. Low levels in heart, ovary and small intestine. Decreased levels in pancreatic beta cells sensitize cells to IL-1-beta-induced apoptosis.
• KEGG Pathway: MAPK sig.ling pathway (hsa04010)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Obsolete diabetes mellitus, noninsulin-dependent	DISS46MZ	Limited	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Dexamethasone	DMMWZET	Approved	C-Jun-amino-terminal kinase-interacting protein 1 (MAPK8IP1) increases the Multiple myeloma ADR of Dexamethasone.	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of C-Jun-amino-terminal kinase-interacting protein 1 (MAPK8IP1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of C-Jun-amino-terminal kinase-interacting protein 1 (MAPK8IP1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of C-Jun-amino-terminal kinase-interacting protein 1 (MAPK8IP1).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of C-Jun-amino-terminal kinase-interacting protein 1 (MAPK8IP1).	[5]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of C-Jun-amino-terminal kinase-interacting protein 1 (MAPK8IP1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of C-Jun-amino-terminal kinase-interacting protein 1 (MAPK8IP1).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of C-Jun-amino-terminal kinase-interacting protein 1 (MAPK8IP1).	[8]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Arsenic trioxide decreases AKT protein in a caspase-dependent manner. Mol Cancer Ther. 2008 Jun;7(6):1680-7. doi: 10.1158/1535-7163.MCT-07-2164.
• [6] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [7] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [8] 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.
• [9] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.