Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT5XJST)

• DOT Name: T-cell-specific surface glycoprotein CD28 (CD28)
• Synonyms: TP44; CD antigen CD28
• Gene Name: CD28
• UniProt ID: CD28_HUMAN
• PDB ID: 1YJD; 3WA4; 5AUL; 5GJH; 5GJI; 6O8D; 7PPN; 7VU5
• Pfam ID: PF15910
• Sequence:
  MLRLLLALNLFPSIQVTGNKILVKQSPMLVAYDNAVNLSCKYSYNLFSREFRASLHKGLD
  SAVEVCVVYGNYSQQLQVYSKTGFNCDGKLGNESVTFYLQNLYVNQTDIYFCKIEVMYPP
  PYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVR
  SKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
• Function: Involved in T-cell activation, the induction of cell proliferation and cytokine production and promotion of T-cell survival. Enhances the production of IL4 and IL10 in T-cells in conjunction with TCR/CD3 ligation and CD40L costimulation. Isoform 3 enhances CD40L-mediated activation of NF-kappa-B and kinases MAPK8 and PAK2 in T-cells.
• Tissue Specificity: Expressed in T-cells and plasma cells, but not in less mature B-cells.
• KEGG Pathway:
  Cell adhesion molecules (hsa04514)
  T cell receptor sig.ling pathway (hsa04660)
  Intesti.l immune network for IgA production (hsa04672)
  Type I diabetes mellitus (hsa04940)
  Measles (hsa05162)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
  Autoimmune thyroid disease (hsa05320)
  Systemic lupus erythematosus (hsa05322)
  Rheumatoid arthritis (hsa05323)
  Allograft rejection (hsa05330)
  Graft-versus-host disease (hsa05332)
  Viral myocarditis (hsa05416)
• Reactome Pathway:
  Nef mediated downregulation of CD28 cell surface expression (R-HSA-164939)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  CD28 co-stimulation (R-HSA-389356)
  CD28 dependent PI3K/Akt signaling (R-HSA-389357)
  CD28 dependent Vav1 pathway (R-HSA-389359)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  PIP3 activates AKT signaling (R-HSA-1257604)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Nitric Oxide	DM1RBYG	Approved	T-cell-specific surface glycoprotein CD28 (CD28) increases the abundance of Nitric Oxide.	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of T-cell-specific surface glycoprotein CD28 (CD28).	[1]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of T-cell-specific surface glycoprotein CD28 (CD28).	[2]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of T-cell-specific surface glycoprotein CD28 (CD28).	[4]
GSK618334	DMJPXZ4	Phase 1	GSK618334 decreases the expression of T-cell-specific surface glycoprotein CD28 (CD28).	[5]

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 increases the methylation of T-cell-specific surface glycoprotein CD28 (CD28).	[3]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of T-cell-specific surface glycoprotein CD28 (CD28).	[6]

References

• [1] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [2] Immunobiology of CD28 expression on human neutrophils. I. CD28 regulates neutrophil migration by modulating CXCR-1 expression. Eur J Immunol. 2001 May;31(5):1536-43. doi: 10.1002/1521-4141(200105)31:5<1536::AID-IMMU1536>3.0.CO;2-8.
• [3] 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.
• [4] BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol. 2012 Dec;92(6):1147-54. doi: 10.1189/jlb.0312165. Epub 2012 Jul 16.
• [5] Phase IIa trial of fingolimod for amyotrophic lateral sclerosis demonstrates acceptable acute safety and tolerability. Muscle Nerve. 2017 Dec;56(6):1077-1084. doi: 10.1002/mus.25733. Epub 2017 Aug 29.
• [6] 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.
• [7] T cell activation-induced mitochondrial hyperpolarization is mediated by Ca2+- and redox-dependent production of nitric oxide. J Immunol. 2003 Nov 15;171(10):5188-97.