Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9WGAFD)

• DOT Name: Mitochondrial inner membrane protease subunit 2 (IMMP2L)
• Synonyms: EC 3.4.21.-; IMP2-like protein
• Gene Name: IMMP2L
• Related Disease:
  Adult glioblastoma
  Breast cancer
  Breast carcinoma
  Epithelial ovarian cancer
  Glioblastoma multiforme
  Ovarian cancer
  Ovarian neoplasm
  Adenoma
  Autism
  Cerebral infarction
  Colon cancer
  Colon carcinoma
  Hepatocellular carcinoma
  Liposarcoma
  Liver cirrhosis
  Neoplasm
  Pervasive developmental disorder
  Schizophrenia
  Tourette syndrome
  Triple negative breast cancer
  Advanced cancer
  Fatty liver disease
  Obesity
  Polycystic ovarian syndrome
  B-cell lymphoma
  Gallbladder carcinoma
  Matthew-Wood syndrome
  Neurodevelopmental disorder
  Non-insulin dependent diabetes
  Pancreatic cancer
  Pancreatic ductal carcinoma
• UniProt ID: IMP2L_HUMAN
• EC Number: 3.4.21.-
• Pfam ID: PF10502
• Sequence:
  MAQSQGWVKRYIKAFCKGFFVAVPVAVTFLDRVACVARVEGASMQPSLNPGGSQSSDVVL
  LNHWKVRNFEVHRGDIVSLVSPKNPEQKIIKRVIALEGDIVRTIGHKNRYVKVPRGHIWV
  EGDHHGHSFDSNSFGPVSLGLLHAHATHILWPPERWQKLESVLPPERLPVQREEE
• Function: Catalyzes the removal of transit peptides required for the targeting of proteins from the mitochondrial matrix, across the inner membrane, into the inter-membrane space. Known to process the nuclear encoded protein DIABLO.
• Tissue Specificity: Expressed in all tissues tested except adult liver and lung.
• KEGG Pathway: Protein export (hsa03060)

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Definitive	Biomarker	[2]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[2]
Epithelial ovarian cancer	DIS56MH2	Definitive	Biomarker	[3]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Ovarian cancer	DISZJHAP	Definitive	Biomarker	[3]
Ovarian neoplasm	DISEAFTY	Definitive	Biomarker	[3]
Adenoma	DIS78ZEV	Strong	Biomarker	[4]
Autism	DISV4V1Z	Strong	Genetic Variation	[5]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[7]
Liposarcoma	DIS8IZVM	Strong	Altered Expression	[8]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[10]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[11]
Tourette syndrome	DISX9D54	Strong	Genetic Variation	[10]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[12]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[13]
Fatty liver disease	DIS485QZ	moderate	Genetic Variation	[7]
Obesity	DIS47Y1K	moderate	Biomarker	[14]
Polycystic ovarian syndrome	DISZ2BNG	moderate	Biomarker	[15]
B-cell lymphoma	DISIH1YQ	Limited	Biomarker	[16]
Gallbladder carcinoma	DISD6ACL	Limited	Biomarker	[9]
Matthew-Wood syndrome	DISA7HR7	Limited	Biomarker	[17]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[18]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[19]
Pancreatic cancer	DISJC981	Limited	Biomarker	[17]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[17]

8 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 Mitochondrial inner membrane protease subunit 2 (IMMP2L).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondrial inner membrane protease subunit 2 (IMMP2L).	[21]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mitochondrial inner membrane protease subunit 2 (IMMP2L).	[22]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Mitochondrial inner membrane protease subunit 2 (IMMP2L).	[23]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Mitochondrial inner membrane protease subunit 2 (IMMP2L).	[24]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Mitochondrial inner membrane protease subunit 2 (IMMP2L).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Mitochondrial inner membrane protease subunit 2 (IMMP2L).	[28]
AM251	DMTAWHL	Investigative	AM251 increases the expression of Mitochondrial inner membrane protease subunit 2 (IMMP2L).	[29]

2 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 decreases the methylation of Mitochondrial inner membrane protease subunit 2 (IMMP2L).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Mitochondrial inner membrane protease subunit 2 (IMMP2L).	[27]

References

• [1] The RNA Binding Protein IMP2 Preserves Glioblastoma Stem Cells by Preventing let-7 Target Gene Silencing.Cell Rep. 2016 May 24;15(8):1634-47. doi: 10.1016/j.celrep.2016.04.086. Epub 2016 May 12.
• [2] p62/IMP2 stimulates cell migration and reduces cell adhesion in breast cancer.Oncotarget. 2015 Oct 20;6(32):32656-68. doi: 10.18632/oncotarget.5328.
• [3] Humoral autoimmune responses to insulin-like growth factor II mRNA-binding proteins IMP1 and p62/IMP2 in ovarian cancer.J Immunol Res. 2014;2014:326593. doi: 10.1155/2014/326593. Epub 2014 Apr 27.
• [4] Humoral autoimmune response to IGF2 mRNA-binding protein (IMP2/p62) and its tissue-specific expression in colon cancer.Scand J Immunol. 2013 Apr;77(4):255-60. doi: 10.1111/sji.12032.
• [5] Family-based association study of ZNF533, DOCK4 and IMMP2L gene polymorphisms linked to autism in a northeastern Chinese Han population.J Zhejiang Univ Sci B. 2014 Mar;15(3):264-71. doi: 10.1631/jzus.B1300133.
• [6] Suppression of Inner Mitochondrial Membrane Peptidase 2-Like (IMMP2L) Gene Exacerbates Hypoxia-Induced Neural Death Under High Glucose Condition.Neurochem Res. 2017 May;42(5):1504-1514. doi: 10.1007/s11064-017-2207-y. Epub 2017 Mar 18.
• [7] IGF2 mRNA Binding Protein 2 Transgenic Mice Are More Prone to Develop a Ductular Reaction and to Progress Toward Cirrhosis.Front Med (Lausanne). 2019 Sep 4;6:179. doi: 10.3389/fmed.2019.00179. eCollection 2019.
• [8] HMGA2 regulates transcription of the Imp2 gene via an intronic regulatory element in cooperation with nuclear factor-kappaB.Mol Cancer Res. 2007 Apr;5(4):363-72. doi: 10.1158/1541-7786.MCR-06-0331.
• [9] IMP2/IGF2BP2 expression, but not IMP1 and IMP3, predicts poor outcome in patients and high tumor growth rate in xenograft models of gallbladder cancer.Oncotarget. 2017 Sep 21;8(52):89736-89745. doi: 10.18632/oncotarget.21116. eCollection 2017 Oct 27.
• [10] First behavioural assessment of a novel Immp2l knockdown mouse model with relevance for Gilles de la Tourette syndrome and Autism spectrum disorder.Behav Brain Res. 2019 Nov 18;374:112057. doi: 10.1016/j.bbr.2019.112057. Epub 2019 Jun 21.
• [11] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [12] IMP2 and IMP3 cooperate to promote the metastasis of triple-negative breast cancer through destabilization of progesterone receptor.Cancer Lett. 2018 Feb 28;415:30-39. doi: 10.1016/j.canlet.2017.11.039. Epub 2017 Dec 5.
• [13] Transgenic expression of the RNA binding protein IMP2 stabilizes miRNA targets in murine microsteatosis.Biochim Biophys Acta Mol Basis Dis. 2018 Oct;1864(10):3099-3108. doi: 10.1016/j.bbadis.2018.05.024. Epub 2018 May 30.
• [14] Liver-specific deletion of IGF2 mRNA binding protein-2/IMP2 reduces hepatic fatty acid oxidation and increases hepatic triglyceride accumulation.J Biol Chem. 2019 Aug 2;294(31):11944-11951. doi: 10.1074/jbc.RA119.008778. Epub 2019 Jun 17.
• [15] The HMGA2-IMP2 Pathway Promotes Granulosa Cell Proliferation in Polycystic Ovary Syndrome.J Clin Endocrinol Metab. 2019 Apr 1;104(4):1049-1059. doi: 10.1210/jc.2018-00544.
• [16] Novel IGH and MYC Translocation Partners in Diffuse Large B-Cell Lymphomas.Genes Chromosomes Cancer. 2016 Dec;55(12):932-943. doi: 10.1002/gcc.22391. Epub 2016 Jul 12.
• [17] The Insulin-Like Growth Factor 2 mRNA Binding Protein IMP2/IGF2BP2 is Overexpressed and Correlates with Poor Survival in Pancreatic Cancer.Int J Mol Sci. 2019 Jun 29;20(13):3204. doi: 10.3390/ijms20133204.
• [18] Association of IMMP2L deletions with autism spectrum disorder: A trio family study and meta-analysis.Am J Med Genet B Neuropsychiatr Genet. 2018 Jan;177(1):93-100. doi: 10.1002/ajmg.b.32608. Epub 2017 Nov 20.
• [19] IGF2 mRNA-binding protein 2: biological function and putative role in type 2 diabetes.J Mol Endocrinol. 2009 Nov;43(5):187-95. doi: 10.1677/JME-09-0016. Epub 2009 May 8.
• [20] 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.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [23] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [24] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] 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.
• [27] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [28] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [29] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.