Details of Drug Off-Target (DOT)

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

• DOT Name: Transmembrane and immunoglobulin domain-containing protein 2 (TMIGD2)
• Synonyms: CD28 homolog; Immunoglobulin and proline-rich receptor 1; IGPR-1
• Gene Name: TMIGD2
• Related Disease:
  Neoplasm
  Pancreatic cancer
  Pancreatic ductal carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal neoplasm
  Myocardial ischemia
  Squamous cell carcinoma
• UniProt ID: TMIG2_HUMAN
• Pfam ID: PF07686
• Sequence:
  MGSPGMVLGLLVQIWALQEASSLSVQQGPNLLQVRQGSQATLVCQVDQATAWERLRVKWT
  KDGAILCQPYITNGSLSLGVCGPQGRLSWQAPSHLTLQLDPVSLNHSGAYVCWAAVEIPE
  LEEAEGNITRLFVDPDDPTQNRNRIASFPGFLFVLLGVGSMGVAAIVWGAWFWGRRSCQQ
  RDSGNSPGNAFYSNVLYRPRGAPKKSEDCSGEGKDQRGQSIYSTSFPQPAPRQPHLASRP
  CPSPRPCPSPRPGHPVSMVRVSPRPSPTQQPRPKGFPKVGEE
• Function: Plays a role in cell-cell interaction, cell migration, and angiogenesis. Through interaction with HHLA2, costimulates T-cells in the context of TCR-mediated activation. Enhances T-cell proliferation and cytokine production via an AKT-dependent signaling cascade.
• Tissue Specificity: Widely expressed, mainly by epithelial and endothelial cells, including bronchial epithelial cells of lung, breast glandular and lobular epithelia cells, urothelium of the bladder, skin epidermis, epithelium of gastrointestinal, rectum, endometrial glands of the uterus, ureter, fallopian tube epithelium, colonic epithelium, small bowl epithelium, stomach epithelium, including both chief and parietal cells, trophoblastic epithelium of placenta, and pancreatic acinar cells (at protein level). Consistently expressed in veins and arteries (at protein level). Not detected in thyroid, cerebellum, cerebral cortex and thymus (at protein level). Expressed in lymphoid organs, with highest levels in thymus, spleen, peripheral blood lymphocytes and liver. In the thymus, expressed in CD4+ and CD8+ single- and double-positive cells, but not in immature CD4- and CD8- double-negative cells (at protein level). In peripheral blood mononuclear cells, highly expressed on CD56+ or CD16+ natural killer cells and CD3+ T-cells(at protein level). Not detected on B-cells(at protein level). Expressed in tonsils (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Pancreatic cancer	DISJC981	Definitive	Altered Expression	[2]
Pancreatic ductal carcinoma	DIS26F9Q	Definitive	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Altered Expression	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[3]
Myocardial ischemia	DISFTVXF	moderate	Biomarker	[4]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transmembrane and immunoglobulin domain-containing protein 2 (TMIGD2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Transmembrane and immunoglobulin domain-containing protein 2 (TMIGD2).	[7]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Transmembrane and immunoglobulin domain-containing protein 2 (TMIGD2).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transmembrane and immunoglobulin domain-containing protein 2 (TMIGD2).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Transmembrane and immunoglobulin domain-containing protein 2 (TMIGD2).	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Transmembrane and immunoglobulin domain-containing protein 2 (TMIGD2).	[10]

References

• [1] CD28H expression identifies resident memory CD8+T cells with less cytotoxicity in human peripheral tissues and cancers.Oncoimmunology. 2018 Nov 5;8(2):e1538440. doi: 10.1080/2162402X.2018.1538440. eCollection 2019.
• [2] B7-H5/CD28H is a co-stimulatory pathway and correlates with improved prognosis in pancreatic ductal adenocarcinoma.Cancer Sci. 2019 Feb;110(2):530-539. doi: 10.1111/cas.13914. Epub 2019 Jan 16.
• [3] Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy.Oncogenesis. 2017 Sep 18;6(9):e378. doi: 10.1038/oncsis.2017.77.
• [4] The cell adhesion molecule IGPR-1 is activated by and regulates responses of endothelial cells to shear stress.J Biol Chem. 2019 Sep 13;294(37):13671-13680. doi: 10.1074/jbc.RA119.008548. Epub 2019 Jul 24.
• [5] The Expression Patterns and Associated Clinical Parameters of Human Endogenous Retrovirus-H Long Terminal Repeat-Associating Protein 2 and Transmembrane and Immunoglobulin Domain Containing 2 in Oral Squamous Cell Carcinoma.Dis Markers. 2019 Apr 7;2019:5421985. doi: 10.1155/2019/5421985. eCollection 2019.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [9] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [10] 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.