Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0X8ACY)

• DOT Name: C-Jun-amino-terminal kinase-interacting protein 3 (MAPK8IP3)
• Synonyms: JIP-3; JNK-interacting protein 3; JNK MAP kinase scaffold protein 3; Mitogen-activated protein kinase 8-interacting protein 3
• Gene Name: MAPK8IP3
• Related Disease:
  Neurodevelopmental disorder with or without variable brain abnormalities; NEDBA
  Advanced cancer
  Alzheimer disease
  Bipolar disorder
  Brain neoplasm
  Epilepsy
  Hypertrophic cardiomyopathy
  Intellectual disability
  Polycystic ovarian syndrome
  Schizophrenia
  Temporal lobe epilepsy
  Subarachnoid hemorrhage
• UniProt ID: JIP3_HUMAN
• PDB ID: 4PXJ
• Pfam ID: PF16471 ; PF09744 ; PF19056
• Sequence:
  MMEIQMDEGGGVVVYQDDYCSGSVMSERVSGLAGSIYREFERLIHCYDEEVVKELMPLVV
  NVLENLDSVLSENQEHEVELELLREDNEQLLTQYEREKALRRQAEEKFIEFEDALEQEKK
  ELQIQVEHYEFQTRQLELKAKNYADQISRLEERESEMKKEYNALHQRHTEMIQTYVEHIE
  RSKMQQVGGNSQTESSLPGRRKERPTSLNVFPLADGTVRAQIGGKLVPAGDHWHLSDLGQ
  LQSSSSYQCPQDEMSESGQSSAAATPSTTGTKSNTPTSSVPSAAVTPLNESLQPLGDYGV
  GSKNSKRAREKRDSRNMEVQVTQEMRNVSIGMGSSDEWSDVQDIIDSTPELDMCPETRLD
  RTGSSPTQGIVNKAFGINTDSLYHELSTAGSEVIGDVDEGADLLGEFSVRDDFFGMGKEV
  GNLLLENSQLLETKNALNVVKNDLIAKVDQLSGEQEVLRGELEAAKQAKVKLENRIKELE
  EELKRVKSEAIIARREPKEEAEDVSSYLCTESDKIPMAQRRRFTRVEMARVLMERNQYKE
  RLMELQEAVRWTEMIRASREHPSVQEKKKSTIWQFFSRLFSSSSSPPPAKRPYPSVNIHY
  KSPTTAGFSQRRNHAMCPISAGSRPLEFFPDDDCTSSARREQKREQYRQVREHVRNDDGR
  LQACGWSLPAKYKQLSPNGGQEDTRMKNVPVPVYCRPLVEKDPTMKLWCAAGVNLSGWRP
  NEDDAGNGVKPAPGRDPLTCDREGDGEPKSAHTSPEKKKAKELPEMDATSSRVWILTSTL
  TTSKVVIIDANQPGTVVDQFTVCNAHVLCISSIPAASDSDYPPGEMFLDSDVNPEDPGAD
  GVLAGITLVGCATRCNVPRSNCSSRGDTPVLDKGQGEVATIANGKVNPSQSTEEATEATE
  VPDPGPSEPETATLRPGPLTEHVFTDPAPTPSSGPQPGSENGPEPDSSSTRPEPEPSGDP
  TGAGSSAAPTMWLGAQNGWLYVHSAVANWKKCLHSIKLKDSVLSLVHVKGRVLVALADGT
  LAIFHRGEDGQWDLSNYHLMDLGHPHHSIRCMAVVYDRVWCGYKNKVHVIQPKTMQIEKS
  FDAHPRRESQVRQLAWIGDGVWVSIRLDSTLRLYHAHTHQHLQDVDIEPYVSKMLGTGKL
  GFSFVRITALLVAGSRLWVGTGNGVVISIPLTETVVLHRGQLLGLRANKTSPTSGEGARP
  GGIIHVYGDDSSDRAASSFIPYCSMAQAQLCFHGHRDAVKFFVSVPGNVLATLNGSVLDS
  PAEGPGPAAPASEVEGQKLRNVLVLSGGEGYIDFRIGDGEDDETEEGAGDMSQVKPVLSK
  AERSHIIVWQVSYTPE
• 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. May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins. Promotes neuronal axon elongation in a kinesin- and JNK-dependent manner. Activates cofilin at axon tips via local activation of JNK, thereby regulating filopodial dynamics and enhancing axon elongation. Its binding to kinesin heavy chains (KHC), promotes kinesin-1 motility along microtubules and is essential for axon elongation and regeneration. Regulates cortical neuronal migration by mediating NTRK2/TRKB anterograde axonal transport during brain development. Acts as an adapter that bridges the interaction between NTRK2/TRKB and KLC1 and drives NTRK2/TRKB axonal but not dendritic anterograde transport, which is essential for subsequent BDNF-triggered signaling and filopodia formation.
• KEGG Pathway: MAPK sig.ling pathway (hsa04010)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder with or without variable brain abnormalities; NEDBA	DISFYEB6	Definitive	Autosomal dominant	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[4]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[5]
Epilepsy	DISBB28L	Strong	Biomarker	[6]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Altered Expression	[7]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[8]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[9]
Schizophrenia	DISSRV2N	Strong	Biomarker	[4]
Temporal lobe epilepsy	DISNOPXX	Strong	Altered Expression	[6]
Subarachnoid hemorrhage	DISI7I8Y	Limited	Biomarker	[10]

3 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 3 (MAPK8IP3).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of C-Jun-amino-terminal kinase-interacting protein 3 (MAPK8IP3).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of C-Jun-amino-terminal kinase-interacting protein 3 (MAPK8IP3).	[16]

4 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 3 (MAPK8IP3).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of C-Jun-amino-terminal kinase-interacting protein 3 (MAPK8IP3).	[13]
Sertraline	DM0FB1J	Approved	Sertraline increases the expression of C-Jun-amino-terminal kinase-interacting protein 3 (MAPK8IP3).	[14]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of C-Jun-amino-terminal kinase-interacting protein 3 (MAPK8IP3).	[17]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] ARF6-JIP3/4 regulate endosomal tubules for MT1-MMP exocytosis in cancer invasion.J Cell Biol. 2015 Oct 26;211(2):339-58. doi: 10.1083/jcb.201506002.
• [3] Impaired JIP3-dependent axonal lysosome transport promotes amyloid plaque pathology.J Cell Biol. 2017 Oct 2;216(10):3291-3305. doi: 10.1083/jcb.201612148. Epub 2017 Aug 7.
• [4] Neurochemical changes and neurotoxic effects of an acute treatment with sydnocarb, a novel psychostimulant: comparison with D-amphetamine.Ann N Y Acad Sci. 2002 Jun;965:180-92. doi: 10.1111/j.1749-6632.2002.tb04160.x.
• [5] JSAP1/JIP3 cooperates with focal adhesion kinase to regulate c-Jun N-terminal kinase and cell migration.J Biol Chem. 2005 Nov 11;280(45):37772-81. doi: 10.1074/jbc.M505241200. Epub 2005 Sep 2.
• [6] Effects of JIP3 on epileptic seizures: Evidence from temporal lobe epilepsy patients, kainic-induced acute seizures and pentylenetetrazole-induced kindled seizures.Neuroscience. 2015 Aug 6;300:314-24. doi: 10.1016/j.neuroscience.2015.05.008. Epub 2015 May 19.
• [7] JIP3 deficiency attenuates cardiac hypertrophy by suppression of JNK pathway.Biochem Biophys Res Commun. 2018 Sep 3;503(1):1-7. doi: 10.1016/j.bbrc.2018.03.208. Epub 2018 Jun 15.
• [8] De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies. Am J Hum Genet. 2019 Feb 7;104(2):203-212. doi: 10.1016/j.ajhg.2018.12.008. Epub 2019 Jan 3.
• [9] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [10] DLK silencing attenuated neuron apoptosis through JIP3/MA2K7/JNK pathway in early brain injury after SAH in rats.Neurobiol Dis. 2017 Jul;103:133-143. doi: 10.1016/j.nbd.2017.04.006. Epub 2017 Apr 8.
• [11] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [12] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] Sertraline induces endoplasmic reticulum stress in hepatic cells. Toxicology. 2014 Aug 1;322:78-88. doi: 10.1016/j.tox.2014.05.007. Epub 2014 May 24.
• [15] 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.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.