Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXNF0NQ)

• DOT Name: Cytotoxic and regulatory T-cell molecule (CRTAM)
• Synonyms: Class-I MHC-restricted T-cell-associated molecule; CD antigen CD355
• Gene Name: CRTAM
• Related Disease:
  Malignant mesothelioma
  Potassium-aggravated myotonia
  Neoplasm
  Asthma
• UniProt ID: CRTAM_HUMAN
• PDB ID: 3RBG; 4H5S
• Pfam ID: PF08205 ; PF07686
• Sequence:
  MWWRVLSLLAWFPLQEASLTNHTETITVEEGQTLTLKCVTSLRKNSSLQWLTPSGFTIFL
  NEYPALKNSKYQLLHHSANQLSITVPNVTLQDEGVYKCLHYSDSVSTKEVKVIVLATPFK
  PILEASVIRKQNGEEHVVLMCSTMRSKPPPQITWLLGNSMEVSGGTLHEFETDGKKCNTT
  STLIIHTYGKNSTVDCIIRHRGLQGRKLVAPFRFEDLVTDEETASDALERNSLSSQDPQQ
  PTSTVSVTEDSSTSEIDKEEKEQTTQDPDLTTEANPQYLGLARKKSGILLLTLVSFLIFI
  LFIIVQLFIMKLRKAHVIWKKENEVSEHTLESYRSRSNNEETSSEEKNGQSSHPMRCMNY
  ITKLYSEAKTKRKENVQHSKLEEKHIQVPESIV
• Function: Mediates heterophilic cell-cell adhesion which regulates the activation, differentiation and tissue retention of various T-cell subsets. Interaction with CADM1 promotes natural killer (NK) cell cytotoxicity and IFNG/interferon-gamma secretion by CD8+ T-cells in vitro as well as NK cell-mediated rejection of tumors expressing CADM1 in vivo. Regulates CD8+ T-cell proliferation in response to T-cell receptor (TCR) activation. Appears to be dispensable for CD8+ T-cell-mediated cytotoxicity. Interaction with SCRIB promotes the late phase of cellular polarization of a subset of CD4+ T-cells, which in turn regulates TCR-mediated proliferation and IFNG, IL17 and IL22 production. By interacting with CADM1 on CD8+ dendritic cells, regulates the retention of activated CD8+ T-cells within the draining lymph node. Required for the intestinal retention of intraepithelial CD4+ CD8+ T-cells and, to a lesser extent, intraepithelial and lamina propria CD8+ T-cells and CD4+ T-cells. Interaction with CADM1 promotes the adhesion to gut-associated CD103+ dendritic cells, which may facilitate the expression of gut-homing and adhesion molecules on T-cells and the conversion of CD4+ T-cells into CD4+ CD8+ T-cells.
• Tissue Specificity: In the immune system, expression is restricted to activated class-I MHC-restricted cells, including NKT and CD8 T-cells . Strongly expressed in spleen, thymus, small intestine, peripheral blood leukocyte, and in Purkinje neurons in cerebellum. Expressed at much lower levels in testis, ovary, colon, lung and lymphoid tissues .
• Reactome Pathway: Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Malignant mesothelioma	DISTHJGH	Strong	Genetic Variation	[1]
Potassium-aggravated myotonia	DISRO6ZH	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Disputed	Biomarker	[3]
Asthma	DISW9QNS	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cytotoxic and regulatory T-cell molecule (CRTAM).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cytotoxic and regulatory T-cell molecule (CRTAM).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Cytotoxic and regulatory T-cell molecule (CRTAM).	[6]

References

• [1] A genome-wide association study for malignant mesothelioma risk.Lung Cancer. 2013 Oct;82(1):1-8. doi: 10.1016/j.lungcan.2013.04.018. Epub 2013 Jul 1.
• [2] Transcriptome of porcine alveolar macrophages activated by interferon-gamma and lipopolysaccharide.Biochem Biophys Res Commun. 2018 Sep 18;503(4):2666-2672. doi: 10.1016/j.bbrc.2018.08.021. Epub 2018 Aug 4.
• [3] The role of NK cell recognition of nectin and nectin-like proteins in tumor immunosurveillance.Semin Cancer Biol. 2006 Oct;16(5):359-66. doi: 10.1016/j.semcancer.2006.07.002. Epub 2006 Jul 7.
• [4] Genome-wide association study reveals class I MHC-restricted T cell-associated molecule gene (CRTAM) variants interact with vitamin D levels to affect asthma exacerbations.J Allergy Clin Immunol. 2012 Feb;129(2):368-73, 373.e1-5. doi: 10.1016/j.jaci.2011.09.034. Epub 2011 Nov 1.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [7] 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.