Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTATV63W)

• DOT Name: TYRO protein tyrosine kinase-binding protein
• Synonyms: DNAX-activation protein 12; Killer-activating receptor-associated protein; KAR-associated protein
• Gene Name: TYROBP
• Related Disease:
  Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1
  Polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly
• UniProt ID: TYOBP_HUMAN
• PDB ID: 2L34; 2L35; 4WO1; 4WOL; 7Q5W
• Sequence:
  MGGLEPCSRLLLLPLLLAVSGLRPVQAQAQSDCSCSTVSPGVLAGIVMGDLVLTVLIALA
  VYFLGRLVPRGRGAAEAATRKQRITETESPYQELQGQRSDVYSDLNTQRPYYK
• Function: Adapter protein which non-covalently associates with activating receptors found on the surface of a variety of immune cells to mediate signaling and cell activation following ligand binding by the receptors. TYROBP is tyrosine-phosphorylated in the ITAM domain following ligand binding by the associated receptors which leads to activation of additional tyrosine kinases and subsequent cell activation. Also has an inhibitory role in some cells. Non-covalently associates with activating receptors of the CD300 family to mediate cell activation. Also mediates cell activation through association with activating receptors of the CD200R family. Required for neutrophil activation mediated by integrin. Required for the activation of myeloid cells mediated by the CLEC5A/MDL1 receptor. Associates with natural killer (NK) cell receptors such as KIR2DS2 and the KLRD1/KLRC2 heterodimer to mediate NK cell activation. Also enhances trafficking and cell surface expression of NK cell receptors KIR2DS1, KIR2DS2 and KIR2DS4 and ensures their stability at the cell surface. Associates with SIRPB1 to mediate activation of myeloid cells such as monocytes and dendritic cells. Associates with TREM1 to mediate activation of neutrophils and monocytes. Associates with TREM2 on monocyte-derived dendritic cells to mediate up-regulation of chemokine receptor CCR7 and dendritic cell maturation and survival. Association with TREM2 mediates cytokine-induced formation of multinucleated giant cells which are formed by the fusion of macrophages. Stabilizes the TREM2 C-terminal fragment (TREM2-CTF) produced by TREM2 ectodomain shedding which suppresses the release of pro-inflammatory cytokines. In microglia, required with TREM2 for phagocytosis of apoptotic neurons. Required with ITGAM/CD11B in microglia to control production of microglial superoxide ions which promote the neuronal apoptosis that occurs during brain development. Promotes pro-inflammatory responses in microglia following nerve injury which accelerates degeneration of injured neurons. Positively regulates the expression of the IRAK3/IRAK-M kinase and IL10 production by liver dendritic cells and inhibits their T cell allostimulatory ability. Negatively regulates B cell proliferation. Required for CSF1-mediated osteoclast cytoskeletal organization. Positively regulates multinucleation during osteoclast development.
• Tissue Specificity: Expressed at low levels in the early development of the hematopoietic system and in the promonocytic stage and at high levels in mature monocytes. Expressed in hematological cells and tissues such as peripheral blood leukocytes and spleen. Also found in bone marrow, lymph nodes, placenta, lung and liver. Expressed at lower levels in different parts of the brain especially in the basal ganglia and corpus callosum.
• KEGG Pathway:
  Osteoclast differentiation (hsa04380)
  .tural killer cell mediated cytotoxicity (hsa04650)
• Reactome Pathway:
  DAP12 interactions (R-HSA-2172127)
  DAP12 signaling (R-HSA-2424491)
  Signal regulatory protein family interactions (R-HSA-391160)
  Other semaphorin interactions (R-HSA-416700)
  Neutrophil degranulation (R-HSA-6798695)
  Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1	DIS8D6P6	Strong	Autosomal recessive	[1]
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly	DIS6AABL	Supportive	Autosomal recessive	[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 TYRO protein tyrosine kinase-binding protein.	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of TYRO protein tyrosine kinase-binding protein.	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of TYRO protein tyrosine kinase-binding protein.	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of TYRO protein tyrosine kinase-binding protein.	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of TYRO protein tyrosine kinase-binding protein.	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of TYRO protein tyrosine kinase-binding protein.	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of TYRO protein tyrosine kinase-binding protein.	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of TYRO protein tyrosine kinase-binding protein.	[9]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of TYRO protein tyrosine kinase-binding protein.	[10]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of TYRO protein tyrosine kinase-binding protein.	[12]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy. 2002 Jan 24 [updated 2020 Dec 10]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] Comparison of the gene expression profiles of monocytic versus granulocytic lineages of HL-60 leukemia cell differentiation by DNA microarray analysis. Life Sci. 2003 Aug 15;73(13):1705-19. doi: 10.1016/s0024-3205(03)00515-0.
• [6] 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.
• [7] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [8] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [9] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [10] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [11] 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.
• [12] 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.