Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD1WDQL)

• DOT Name: Sialic acid-binding Ig-like lectin 10 (SIGLEC10)
• Synonyms: Siglec-10; Siglec-like protein 2
• Gene Name: SIGLEC10
• Related Disease:
  Neoplasm
  B-cell neoplasm
  leukaemia
  Leukemia
• UniProt ID: SIG10_HUMAN
• Pfam ID: PF07679 ; PF13927 ; PF07686
• Sequence:
  MLLPLLLSSLLGGSQAMDGRFWIRVQESVMVPEGLCISVPCSFSYPRQDWTGSTPAYGYW
  FKAVTETTKGAPVATNHQSREVEMSTRGRFQLTGDPAKGNCSLVIRDAQMQDESQYFFRV
  ERGSYVRYNFMNDGFFLKVTALTQKPDVYIPETLEPGQPVTVICVFNWAFEECPPPSFSW
  TGAALSSQGTKPTTSHFSVLSFTPRPQDHNTDLTCHVDFSRKGVSAQRTVRLRVAYAPRD
  LVISISRDNTPALEPQPQGNVPYLEAQKGQFLRLLCAADSQPPATLSWVLQNRVLSSSHP
  WGPRPLGLELPGVKAGDSGRYTCRAENRLGSQQRALDLSVQYPPENLRVMVSQANRTVLE
  NLGNGTSLPVLEGQSLCLVCVTHSSPPARLSWTQRGQVLSPSQPSDPGVLELPRVQVEHE
  GEFTCHARHPLGSQHVSLSLSVHYSPKLLGPSCSWEAEGLHCSCSSQASPAPSLRWWLGE
  ELLEGNSSQDSFEVTPSSAGPWANSSLSLHGGLSSGLRLRCEAWNVHGAQSGSILQLPDK
  KGLISTAFSNGAFLGIGITALLFLCLALIIMKILPKRRTQTETPRPRFSRHSTILDYINV
  VPTAGPLAQKRNQKATPNSPRTPLPPGAPSPESKKNQKKQYQLPSFPEPKSSTQAPESQE
  SQEELHYATLNFPGVRPRPEARMPKGTQADYAEVKFQ
• Function: Putative adhesion molecule that mediates sialic-acid dependent binding to cells. Preferentially binds to alpha-2,3- or alpha-2,6-linked sialic acid. The sialic acid recognition site may be masked by cis interactions with sialic acids on the same cell surface. In the immune response, seems to act as an inhibitory receptor upon ligand induced tyrosine phosphorylation by recruiting cytoplasmic phosphatase(s) via their SH2 domain(s) that block signal transduction through dephosphorylation of signaling molecules. Involved in negative regulation of B-cell antigen receptor signaling. The inhibition of B cell activation is dependent on PTPN6/SHP-1. In association with CD24 may be involved in the selective suppression of the immune response to danger-associated molecular patterns (DAMPs) such as HMGB1, HSP70 and HSP90. In association with CD24 may regulate the immune repsonse of natural killer (NK) cells. Plays a role in the control of autoimmunity. During initiation of adaptive immune responses by CD8-alpha(+) dendritic cells inhibits cross-presentation by impairing the formation of MHC class I-peptide complexes. The function seems to implicate recruitment of PTPN6/SHP-1, which dephosphorylates NCF1 of the NADPH oxidase complex consequently promoting phagosomal acidification.
• Tissue Specificity: Expressed by peripheral blood leukocytes (eosinophils, monocytes and a natural killer cell subpopulation). Isoform 5 is found to be the most abundant isoform. Found in lymph node, lung, ovary and appendix. Isoform 1 is found at high levels and isoform 2 at lower levels in bone marrow, spleen and spinal chord. Isoform 2 is also found in brain. Isoform 4 is specifically found in natural killer cells.
• KEGG Pathway: Efferocytosis (hsa04148)
• 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
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
B-cell neoplasm	DISVY326	moderate	Biomarker	[2]
leukaemia	DISS7D1V	moderate	Altered Expression	[2]
Leukemia	DISNAKFL	moderate	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Sialic acid-binding Ig-like lectin 10 (SIGLEC10).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Sialic acid-binding Ig-like lectin 10 (SIGLEC10).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sialic acid-binding Ig-like lectin 10 (SIGLEC10).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Sialic acid-binding Ig-like lectin 10 (SIGLEC10).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Sialic acid-binding Ig-like lectin 10 (SIGLEC10).	[7]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Sialic acid-binding Ig-like lectin 10 (SIGLEC10).	[8]

References

• [1] Malignant ascite-derived extracellular vesicles inhibit T cell activity by upregulating Siglec-10 expression.Cancer Manag Res. 2019 Jul 29;11:7123-7134. doi: 10.2147/CMAR.S210568. eCollection 2019.
• [2] SIGLEC-G deficiency increases susceptibility to develop B-cell lymphoproliferative disorders.Haematologica. 2014 Aug;99(8):1356-64. doi: 10.3324/haematol.2013.100230. Epub 2014 May 23.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] 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.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] 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.
• [7] 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.
• [8] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.