Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDUHLN0)

• DOT Name: C-Jun-amino-terminal kinase-interacting protein 2 (MAPK8IP2)
• Synonyms: JIP-2; JNK-interacting protein 2; Islet-brain-2; IB-2; JNK MAP kinase scaffold protein 2; Mitogen-activated protein kinase 8-interacting protein 2
• Gene Name: MAPK8IP2
• Related Disease:
  Endometrial cancer
  Endometrial carcinoma
  Abscess
  Adult glioblastoma
  Autism spectrum disorder
  Cervical cancer
  Cervical carcinoma
  Colorectal carcinoma
  Glioblastoma multiforme
  HER2/NEU overexpressing breast cancer
  Neoplasm
  Non-small-cell lung cancer
  Periodontal disease
  Triple negative breast cancer
  Gastrointestinal stromal tumour
  Pancreatic adenocarcinoma
  Plasma cell myeloma
  Recessive X-linked ichthyosis
  Sarcoma
  Soft tissue sarcoma
  Waldenstrom macroglobulinemia
  Acute myelogenous leukaemia
  Autism
  Cognitive impairment
  Eosinophilic esophagitis
  Melanoma
  Neuroendocrine neoplasm
  Small lymphocytic lymphoma
• UniProt ID: JIP2_HUMAN
• Pfam ID: PF00640 ; PF14604
• Sequence:
  MADRAEMFSLSTFHSLSPPGCRPPQDISLEEFDDEDLSEITDDCGLGLSYDSDHCEKDSL
  SLGRSEQPHPICSFQDDFQEFEMIDDNEEEDDEDEEEEEEEEEGDGEGQEGGDPGSEAPA
  PGPLIPSPSVEEPHKHRPTTLRLTTLGAQDSLNNNGGFDLVRPASWQETALCSPAPEALR
  ELPGPLPATDTGPGGAQSPVRPGCDCEGNRPAEPPAPGGTSPSSDPGIEADLRSRSSGGR
  GGRRSSQELSSPGSDSEDAGGARLGRMISSISETELELSSDGGSSSSGRSSHLTNSIEEA
  SSPASEPEPPREPPRRPAFLPVGPDDTNSEYESGSESEPDLSEDADSPWLLSNLVSRMIS
  EGSSPIRCPGQCLSPAPRPPGEPVSPAGGAAQDSQDPEAAAGPGGVELVDMETLCAPPPP
  APAAPRPGPAQPGPCLFLSNPTRDTITPLWAAPGRAARPGRACSAACSEEEDEEDDEEEE
  DAEDSAGSPGGRGTGPSAPRDASLVYDAVKYTLVVDEHTQLELVSLRRCAGLGHDSEEDS
  GGEASEEEAGAALLGGGQVSGDTSPDSPDLTFSKKFLNVFVNSTSRSSSTESFGLFSCLV
  NGEEREQTHRAVFRFIPRHPDELELDVDDPVLVEAEEDDFWFRGFNMRTGERGVFPAFYA
  HAVPGPAKDLLGSKRSPCWVERFDVQFLGSVEVPCHQGNGILCAAMQKIATARKLTVHLR
  PPASCDLEISLRGVKLSLSGGGPEFQRCSHFFQMKNISFCGCHPRNSCYFGFITKHPLLS
  RFACHVFVSQESMRPVAQSVGRAFLEYYQEHLAYACPTEDIYLE
• 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. JIP2 inhibits IL1 beta-induced apoptosis in insulin-secreting cells. May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins.
• Tissue Specificity: Expressed mainly in the brain and pancreas, including insulin-secreting cells. In the nervous system, more abundantly expressed in the cerebellum, pituitary gland, occipital lobe and the amygdala. Also expressed in fetal brain. Very low levels found in uterus, ovary, prostate, colon, testis, adrenal gland, thyroid gland and salivary gland.
• KEGG Pathway: MAPK sig.ling pathway (hsa04010)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Endometrial cancer	DISW0LMR	Definitive	Biomarker	[1]
Endometrial carcinoma	DISXR5CY	Definitive	Biomarker	[1]
Abscess	DISAP982	Strong	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Genetic Variation	[3]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[4]
Cervical cancer	DISFSHPF	Strong	Biomarker	[5]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[6]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[3]
HER2/NEU overexpressing breast cancer	DISYKID5	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[8]
Periodontal disease	DISJQHVN	Strong	Genetic Variation	[9]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[10]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Biomarker	[11]
Pancreatic adenocarcinoma	DISKHX7S	moderate	Biomarker	[12]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[13]
Recessive X-linked ichthyosis	DISZY56W	moderate	Biomarker	[14]
Sarcoma	DISZDG3U	moderate	Biomarker	[14]
Soft tissue sarcoma	DISSN8XB	moderate	Biomarker	[14]
Waldenstrom macroglobulinemia	DIS9O23I	moderate	Biomarker	[13]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[15]
Autism	DISV4V1Z	Limited	Biomarker	[16]
Cognitive impairment	DISH2ERD	Limited	Genetic Variation	[16]
Eosinophilic esophagitis	DISR8WSB	Limited	Altered Expression	[17]
Melanoma	DIS1RRCY	Limited	Biomarker	[18]
Neuroendocrine neoplasm	DISNPLOO	Limited	Biomarker	[19]
Small lymphocytic lymphoma	DIS30POX	Limited	Biomarker	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of C-Jun-amino-terminal kinase-interacting protein 2 (MAPK8IP2).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of C-Jun-amino-terminal kinase-interacting protein 2 (MAPK8IP2).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of C-Jun-amino-terminal kinase-interacting protein 2 (MAPK8IP2).	[21]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of C-Jun-amino-terminal kinase-interacting protein 2 (MAPK8IP2).	[22]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of C-Jun-amino-terminal kinase-interacting protein 2 (MAPK8IP2).	[23]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of C-Jun-amino-terminal kinase-interacting protein 2 (MAPK8IP2).	[24]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of C-Jun-amino-terminal kinase-interacting protein 2 (MAPK8IP2).	[25]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of C-Jun-amino-terminal kinase-interacting protein 2 (MAPK8IP2).	[26]
PF-3758309	DM36PKZ	Phase 1	PF-3758309 increases the expression of C-Jun-amino-terminal kinase-interacting protein 2 (MAPK8IP2).	[28]

References

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• [12] A Phase Ib/II Study of the JAK1 Inhibitor, Itacitinib, plus nab-Paclitaxel and Gemcitabine in Advanced Solid Tumors.Oncologist. 2019 Jan;24(1):14-e10. doi: 10.1634/theoncologist.2017-0665. Epub 2018 Aug 16.
• [13] A Phase Ib/II Study of Oprozomib in Patients with Advanced Multiple Myeloma and Waldenstrm Macroglobulinemia.Clin Cancer Res. 2019 Aug 15;25(16):4907-4916. doi: 10.1158/1078-0432.CCR-18-3728. Epub 2019 May 29.
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• [15] Venetoclax Combined With Low-Dose Cytarabine for Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase Ib/II Study.J Clin Oncol. 2019 May 20;37(15):1277-1284. doi: 10.1200/JCO.18.01600. Epub 2019 Mar 20.
• [16] Behavioral and cerebellar transmission deficits in mice lacking the autism-linked gene islet brain-2.J Neurosci. 2010 Nov 3;30(44):14805-16. doi: 10.1523/JNEUROSCI.1161-10.2010.
• [17] RNA sequencing confirms similarities between PPI-responsive oesophageal eosinophilia and eosinophilic oesophagitis.Aliment Pharmacol Ther. 2018 Jul;48(2):219-225. doi: 10.1111/apt.14825. Epub 2018 Jun 4.
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• [19] Surufatinib in Advanced Well-Differentiated Neuroendocrine Tumors: A Multicenter, Single-Arm, Open-Label, Phase Ib/II Trial.Clin Cancer Res. 2019 Jun 15;25(12):3486-3494. doi: 10.1158/1078-0432.CCR-18-2994. Epub 2019 Mar 4.
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• [21] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [22] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [23] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
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• [25] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [26] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [27] 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.
• [28] Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4. Oncol Rep. 2017 Nov;38(5):2705-2716. doi: 10.3892/or.2017.5989. Epub 2017 Sep 22.