Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK7GIJ5)

• DOT Name: TIR domain-containing adapter molecule 2 (TICAM2)
• Synonyms: TICAM-2; Putative NF-kappa-B-activating protein 502; TRIF-related adapter molecule; Toll-like receptor adaptor protein 3; Toll/interleukin-1 receptor domain-containing protein; MyD88-4
• Gene Name: TICAM2
• Related Disease:
  Multiple endocrine neoplasia type 1
  Adenoma
  B-cell neoplasm
  Bladder cancer
  Bone osteosarcoma
  Carcinoma of liver and intrahepatic biliary tract
  Cholangiocarcinoma
  Classic Hodgkin lymphoma
  Clear cell renal carcinoma
  Colon cancer
  Endometrial carcinoma
  Epithelial ovarian cancer
  Glioma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Mantle cell lymphoma
  Mesothelioma
  Metastatic malignant neoplasm
  Neuroblastoma
  Non-hodgkin lymphoma
  Non-small-cell lung cancer
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Plasma cell myeloma
  Pulmonary fibrosis
  Renal cell carcinoma
  Small lymphocytic lymphoma
  Thyroid tumor
  Triple negative breast cancer
  Tuberculosis
  Urinary bladder cancer
  Urinary bladder neoplasm
  Acute myelogenous leukaemia
  Glioblastoma multiforme
  Liver cirrhosis
  Esophageal squamous cell carcinoma
  Melanoma
  Thyroid cancer
  Thyroid gland carcinoma
  Adult glioblastoma
  Carcinoma
  Colon carcinoma
  leukaemia
  Leukemia
  Liver cancer
  Nasopharyngeal carcinoma
• UniProt ID: TCAM2_HUMAN
• PDB ID: 2M1W
• Pfam ID: PF13676
• Sequence:
  MGIGKSKINSCPLSLSWGKRHSVDTSPGYHESDSKKSEDLSLCNVAEHSNTTEGPTGKQE
  GAQSVEEMFEEEAEEEVFLKFVILHAEDDTDEALRVQNLLQDDFGIKPGIIFAEMPCGRQ
  HLQNLDDAVNGSAWTILLLTENFLRDTWCNFQFYTSLMNSVNRQHKYNSVIPMRPLNNPL
  PRERTPFALQTINALEEESRGFPTQVERIFQESVYKTQQTIWKETRNMVQRQFIA
• Function: Functions as a sorting adapter in different signaling pathways to facilitate downstream signaling leading to type I interferon induction. In TLR4 signaling, physically bridges TLR4 and TICAM1 and functionally transmits signal to TICAM1 in early endosomes after endocytosis of TLR4. In TLR2 signaling, physically bridges TLR2 and MYD88 and is required for the TLR2-dependent movement of MYD88 to endosomes following ligand engagement. Involved in IL-18 signaling and is proposed to function as a sorting adapter for MYD88 in IL-18 signaling during adaptive immune response. Forms a complex with RAB11FIP2 that is recruited to the phagosomes to promote the activation of the actin-regulatory GTPases RAC1 and CDC42 and subsequent phagocytosis of Gram-negative bacteria ; [Isoform 2]: Proposed to inhibit LPS-TLR4 signaling at the late endosome by interaction with isoform 1 thereby disrupting the association of isoform 1 with TICAM1. May be involved in TLR4 degradation in late endosomes.
• Tissue Specificity: Expressed in spleen, prostate, testis, uterus, small intestine, colon, peripheral blood leukocytes, heart, placenta, lung, liver, skeletal muscle, and pancreas Isoform 2 is ubiquitously expressed (at lower levels than isoform 1).
• Reactome Pathway:
  Toll Like Receptor 4 (TLR4) Cascade (R-HSA-166016)
  MyD88-independent TLR4 cascade (R-HSA-166166)
  TRIF-mediated programmed cell death (R-HSA-2562578)
  Neutrophil degranulation (R-HSA-6798695)
  Activation of IRF3, IRF7 mediated by TBK1, IKK (IKBKE) (R-HSA-936964)
  IKK complex recruitment mediated by RIP1 (R-HSA-937041)
  TRAF6-mediated induction of TAK1 complex within TLR4 complex (R-HSA-937072)
  IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation (R-HSA-975163)
  Caspase activation via Death Receptors in the presence of ligand (R-HSA-140534)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple endocrine neoplasia type 1	DIS0RJRK	Definitive	Genetic Variation	[1]
Adenoma	DIS78ZEV	Strong	Biomarker	[2]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[3]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[4]
Bone osteosarcoma	DIST1004	Strong	Posttranslational Modification	[5]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[6]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[7]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Altered Expression	[8]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[9]
Colon cancer	DISVC52G	Strong	Biomarker	[10]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[11]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[12]
Glioma	DIS5RPEH	Strong	Biomarker	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[14]
Lung cancer	DISCM4YA	Strong	Altered Expression	[15]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[15]
Mantle cell lymphoma	DISFREOV	Strong	Biomarker	[16]
Mesothelioma	DISKWK9M	Strong	Biomarker	[17]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[18]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[19]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Altered Expression	[20]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[21]
Osteosarcoma	DISLQ7E2	Strong	Posttranslational Modification	[5]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[12]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[12]
Plasma cell myeloma	DIS0DFZ0	Strong	Posttranslational Modification	[22]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[23]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[9]
Small lymphocytic lymphoma	DIS30POX	Strong	Altered Expression	[24]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[25]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[26]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[27]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[4]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[4]
Acute myelogenous leukaemia	DISCSPTN	moderate	Altered Expression	[28]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[29]
Liver cirrhosis	DIS4G1GX	moderate	Biomarker	[30]
Esophageal squamous cell carcinoma	DIS5N2GV	Disputed	Altered Expression	[31]
Melanoma	DIS1RRCY	Disputed	Biomarker	[32]
Thyroid cancer	DIS3VLDH	Disputed	Biomarker	[25]
Thyroid gland carcinoma	DISMNGZ0	Disputed	Biomarker	[25]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[29]
Carcinoma	DISH9F1N	Limited	Biomarker	[33]
Colon carcinoma	DISJYKUO	Limited	Biomarker	[10]
leukaemia	DISS7D1V	Limited	Biomarker	[34]
Leukemia	DISNAKFL	Limited	Biomarker	[34]
Liver cancer	DISDE4BI	Limited	Altered Expression	[6]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of TIR domain-containing adapter molecule 2 (TICAM2).	[36]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of TIR domain-containing adapter molecule 2 (TICAM2).	[37]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of TIR domain-containing adapter molecule 2 (TICAM2).	[38]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of TIR domain-containing adapter molecule 2 (TICAM2).	[39]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of TIR domain-containing adapter molecule 2 (TICAM2).	[40]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of TIR domain-containing adapter molecule 2 (TICAM2).	[41]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of TIR domain-containing adapter molecule 2 (TICAM2).	[42]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of TIR domain-containing adapter molecule 2 (TICAM2).	[42]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of TIR domain-containing adapter molecule 2 (TICAM2).	[43]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of TIR domain-containing adapter molecule 2 (TICAM2).	[44]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of TIR domain-containing adapter molecule 2 (TICAM2).	[37]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of TIR domain-containing adapter molecule 2 (TICAM2).	[45]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of TIR domain-containing adapter molecule 2 (TICAM2).	[46]

References

• [1] Hyperparathyroid genes: sequences reveal answers and questions.Endocr Pract. 2011 Jul-Aug;17 Suppl 3(Suppl 3):18-27. doi: 10.4158/EP11067.RA.
• [2] Expression of Cyclin E/Cdk2/p27(Kip1) in Growth Hormone Adenomas.World Neurosurg. 2019 Jan;121:e45-e53. doi: 10.1016/j.wneu.2018.08.209. Epub 2018 Sep 6.
• [3] Lost expression of cell adhesion molecule 1 is associated with bladder cancer progression and recurrence and its overexpression inhibited tumor cell malignant behaviors.Oncol Lett. 2019 Feb;17(2):2047-2056. doi: 10.3892/ol.2018.9845. Epub 2018 Dec 18.
• [4] Transcriptional and post-transcriptional upregulation of p27 mediates growth inhibition of isorhapontigenin (ISO) on human bladder cancer cells.Carcinogenesis. 2018 Mar 8;39(3):482-492. doi: 10.1093/carcin/bgy015.
• [5] p27/Kip1 functions as a tumor suppressor and oncoprotein in osteosarcoma.Sci Rep. 2019 Apr 16;9(1):6161. doi: 10.1038/s41598-019-42450-0.
• [6] High GSTP1 inhibits cell proliferation by reducing Akt phosphorylation and is associated with a better prognosis in hepatocellular carcinoma.Oncotarget. 2017 Dec 19;9(10):8957-8971. doi: 10.18632/oncotarget.23420. eCollection 2018 Feb 6.
• [7] Phosphorylation of P27 by AKT is required for inhibition of cell cycle progression in cholangiocarcinoma.Dig Liver Dis. 2018 May;50(5):501-506. doi: 10.1016/j.dld.2017.12.021. Epub 2018 Jan 4.
• [8] Expression of Foxo3a in non-Hodgkin's lymphomas is correlated with cell cycle inhibitor p27.Eur J Haematol. 2008 Aug;81(2):83-93. doi: 10.1111/j.1600-0609.2008.01077.x. Epub 2008 Mar 19.
• [9] The long noncoding RNA KCNQ1DN suppresses the survival of renal cell carcinoma cells through downregulating c-Myc.J Cancer. 2019 Aug 19;10(19):4662-4670. doi: 10.7150/jca.29280. eCollection 2019.
• [10] Construction and characterization of regulated cycle inhibiting factors induced upon Tet-On system in human colon cancer cell lines.Anticancer Drugs. 2018 Oct;29(9):854-860. doi: 10.1097/CAD.0000000000000654.
• [11] Loss of p27 Associated with Risk for Endometrial Carcinoma Arising in the Setting of Obesity.Curr Mol Med. 2016;16(3):252-65. doi: 10.2174/1566524016666160225153307.
• [12] Cell Cycle Regulator p27 Mediates Body Mass Index Effects in Ovarian Cancer in FIGO-stages I-II.Cancer Genomics Proteomics. 2019 Nov-Dec;16(6):443-450. doi: 10.21873/cgp.20148.
• [13] TRIM44 is indispensable for glioma cell proliferation and cell cycle progression through AKT/p21/p27 signaling pathway.J Neurooncol. 2019 Nov;145(2):211-222. doi: 10.1007/s11060-019-03301-0. Epub 2019 Oct 11.
• [14] Gold nanoparticles-loaded anti-miR221 enhances antitumor effect of sorafenib in hepatocellular carcinoma cells.Int J Med Sci. 2019 Oct 21;16(12):1541-1548. doi: 10.7150/ijms.37427. eCollection 2019.
• [15] Overexpression of TRPV3 Correlates with Tumor Progression in Non-Small Cell Lung Cancer.Int J Mol Sci. 2016 Mar 24;17(4):437. doi: 10.3390/ijms17040437.
• [16] Molecular signatures for CCN1, p21 and p27 in progressive mantle cell lymphoma.J Cell Commun Signal. 2019 Sep;13(3):421-434. doi: 10.1007/s12079-018-0494-y. Epub 2018 Nov 21.
• [17] miR-182 and miR-183 Promote Cell Proliferation and Invasion by Targeting FOXO1 in Mesothelioma.Front Oncol. 2018 Oct 22;8:446. doi: 10.3389/fonc.2018.00446. eCollection 2018.
• [18] Cytoplasmic p27 promotes epithelial-mesenchymal transition and tumor metastasis via STAT3-mediated Twist1 upregulation.Oncogene. 2015 Oct;34(43):5447-59. doi: 10.1038/onc.2014.473. Epub 2015 Feb 16.
• [19] TIPE? suppresses growth and aggressiveness of hepatocellular carcinoma cells through downregulation of the phosphoinositide 3kinase/AKT signaling pathway.Mol Med Rep. 2018 May;17(5):7017-7026. doi: 10.3892/mmr.2018.8789. Epub 2018 Mar 20.
• [20] Reciprocal Cdc25A and p27 expression in B-cell non-Hodgkin lymphomas.Diagn Mol Pathol. 2003 Sep;12(3):128-32. doi: 10.1097/00019606-200309000-00003.
• [21] Cytoplasmic p27(Kip1) promotes tumorigenesis via suppression of RhoB activity.J Pathol. 2019 Jan;247(1):60-71. doi: 10.1002/path.5167. Epub 2018 Dec 11.
• [22] ADP-ribosylation factor 1 (ARF1) takes part in cell proliferation and cell adhesion-mediated drug resistance (CAM-DR).Ann Hematol. 2017 May;96(5):847-858. doi: 10.1007/s00277-017-2949-2. Epub 2017 Feb 25.
• [23] P27 Promotes TGF--Mediated Pulmonary Fibrosis via Interacting with MTORC2.Can Respir J. 2019 Sep 19;2019:7157861. doi: 10.1155/2019/7157861. eCollection 2019.
• [24] High p27 protein levels in chronic lymphocytic leukemia are associated to low Myc and Skp2 expression, confer resistance to apoptosis and antagonize Myc effects on cell cycle.Oncotarget. 2014 Jul 15;5(13):4694-708. doi: 10.18632/oncotarget.2100.
• [25] Rewiring of the apoptotic TGF--SMAD/NFB pathway through an oncogenic function of p27 in human papillary thyroid cancer.Oncogene. 2017 Feb 2;36(5):652-666. doi: 10.1038/onc.2016.233. Epub 2016 Jul 25.
• [26] Role of mitochondria in rescuing glycolytically inhibited subpopulation of triple negative but not hormone-responsive breast cancer cells.Sci Rep. 2019 Sep 24;9(1):13748. doi: 10.1038/s41598-019-50141-z.
• [27] Polymorphisms in TICAM2 and IL1B are associated with TB.Genes Immun. 2015 Mar;16(2):127-133. doi: 10.1038/gene.2014.77. Epub 2014 Dec 18.
• [28] c-Myc represses FOXO3a-mediated transcription of the gene encoding the p27(Kip1) cyclin dependent kinase inhibitor.J Cell Biochem. 2008 Aug 15;104(6):2091-106. doi: 10.1002/jcb.21765.
• [29] PKM2 uses control of HuR localization to regulate p27 and cell cycle progression in human glioblastoma cells.Int J Cancer. 2016 Jul 1;139(1):99-111. doi: 10.1002/ijc.30041. Epub 2016 Mar 2.
• [30] miR-181b promotes hepatic stellate cells proliferation by targeting p27 and is elevated in the serum of cirrhosis patients.Biochem Biophys Res Commun. 2012 Apr 27;421(1):4-8. doi: 10.1016/j.bbrc.2012.03.025. Epub 2012 Mar 13.
• [31] Targeted therapy of the AKT kinase inhibits esophageal squamous cell carcinoma growth in vitro and in vivo.Int J Cancer. 2019 Aug 15;145(4):1007-1019. doi: 10.1002/ijc.32285. Epub 2019 Apr 3.
• [32] Loss of tumor suppressors KAI1 and p27 identifies a unique subgroup of primary melanoma patients with poor prognosis.Oncotarget. 2015 Sep 8;6(26):23026-35. doi: 10.18632/oncotarget.4854.
• [33] Predictive value of FHIT, p27, and pERK1/ERK2 in salivary gland carcinomas: a retrospective study.Clin Oral Investig. 2019 Oct;23(10):3801-3809. doi: 10.1007/s00784-019-02809-z. Epub 2019 Jan 23.
• [34] CD244 maintains the proliferation ability of leukemia initiating cells through SHP-2/p27(kip1) signaling.Haematologica. 2017 Apr;102(4):707-718. doi: 10.3324/haematol.2016.151555. Epub 2017 Jan 25.
• [35] Cyclin-Dependent Kinase Inhibitor 3 Promotes Cancer Cell Proliferation and Tumorigenesis in Nasopharyngeal Carcinoma by Targeting p27.Oncol Res. 2017 Nov 2;25(9):1431-1440. doi: 10.3727/096504017X14835311718295. Epub 2017 Jan 20.
• [36] 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.
• [37] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [38] 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.
• [39] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [40] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [41] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [42] Synergistic antiproliferative effect of arsenic trioxide combined with bortezomib in HL60 cell line and primary blasts from patients affected by myeloproliferative disorders. Cancer Genet Cytogenet. 2010 Jun;199(2):110-20. doi: 10.1016/j.cancergencyto.2010.02.010.
• [43] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [44] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [45] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [46] Global gene expression analysis reveals novel transcription factors associated with long-term low-level exposure of EA.hy926 human endothelial cells to bisphenol A. Chem Biol Interact. 2023 Aug 25;381:110571. doi: 10.1016/j.cbi.2023.110571. Epub 2023 May 25.