Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQID87L)

• DOT Name: Tyrosine-protein kinase SYK (SYK)
• Synonyms: EC 2.7.10.2; Spleen tyrosine kinase; p72-Syk
• Gene Name: SYK
• Related Disease: Immunodeficiency 82 with systemic inflammation
• UniProt ID: KSYK_HUMAN
• PDB ID: 1A81 ; 1CSY ; 1CSZ ; 1XBA ; 1XBB ; 1XBC ; 3BUW ; 3EMG ; 3FQE ; 3FQH ; 3FQS ; 3SRV ; 3TUB ; 3TUC ; 3TUD ; 3VF8 ; 3VF9 ; 4DFL ; 4DFN ; 4F4P ; 4FL1 ; 4FL2 ; 4FL3 ; 4FYN ; 4FYO ; 4FZ6 ; 4FZ7 ; 4GFG ; 4I0R ; 4I0S ; 4I0T ; 4PUZ ; 4PV0 ; 4PX6 ; 4RSS ; 4RX7 ; 4RX8 ; 4RX9 ; 4WNM ; 4XG2 ; 4XG3 ; 4XG4 ; 4XG6 ; 4XG7 ; 4XG8 ; 4XG9 ; 4YJO ; 4YJP ; 4YJQ ; 4YJR ; 4YJS ; 4YJT ; 4YJU ; 4YJV ; 5C26 ; 5C27 ; 5CXH ; 5CXZ ; 5CY3 ; 5GHV ; 5LMA ; 5LMB ; 5T68 ; 5TIU ; 5TR6 ; 5TT7 ; 5Y5T ; 5Y5U ; 6HM6 ; 6HM7 ; 6SSB ; 6VOV ; 6ZC0 ; 6ZCP ; 6ZCQ ; 6ZCR ; 6ZCS ; 6ZCU ; 6ZCX ; 6ZCY ; 7Q5T ; 7Q5U ; 7Q5W ; 7Q63 ; 7SA7 ; 8BI2
• EC Number: 2.7.10.2
• Pfam ID: PF07714 ; PF00017
• Sequence:
  MASSGMADSANHLPFFFGNITREEAEDYLVQGGMSDGLYLLRQSRNYLGGFALSVAHGRK
  AHHYTIERELNGTYAIAGGRTHASPADLCHYHSQESDGLVCLLKKPFNRPQGVQPKTGPF
  EDLKENLIREYVKQTWNLQGQALEQAIISQKPQLEKLIATTAHEKMPWFHGKISREESEQ
  IVLIGSKTNGKFLIRARDNNGSYALCLLHEGKVLHYRIDKDKTGKLSIPEGKKFDTLWQL
  VEHYSYKADGLLRVLTVPCQKIGTQGNVNFGGRPQLPGSHPATWSAGGIISRIKSYSFPK
  PGHRKSSPAQGNRQESTVSFNPYEPELAPWAADKGPQREALPMDTEVYESPYADPEEIRP
  KEVYLDRKLLTLEDKELGSGNFGTVKKGYYQMKKVVKTVAVKILKNEANDPALKDELLAE
  ANVMQQLDNPYIVRMIGICEAESWMLVMEMAELGPLNKYLQQNRHVKDKNIIELVHQVSM
  GMKYLEESNFVHRDLAARNVLLVTQHYAKISDFGLSKALRADENYYKAQTHGKWPVKWYA
  PECINYYKFSSKSDVWSFGVLMWEAFSYGQKPYRGMKGSEVTAMLEKGERMGCPAGCPRE
  MYDLMNLCWTYDVENRPGFAAVELRLRNYYYDVVN
• Function: Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include DEPTOR, VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. In addition to its function downstream of BCR also plays a role in T-cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Required for the stimulation of neutrophil phagocytosis by IL15. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Involved in interleukin-3/IL3-mediated signaling pathway in basophils. Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Also plays a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen. Together with CEACAM20, enhances production of the cytokine CXCL8/IL-8 via the NFKB pathway and may thus have a role in the intestinal immune response.
• Tissue Specificity: Widely expressed in hematopoietic cells (at protein level) . Expressed in neutrophils (at protein level) . Within the B-cell compartment, expressed from pro- and pre-B cells to plasma cells .
• KEGG Pathway:
  NF-kappa B sig.ling pathway (hsa04064)
  Phospholipase D sig.ling pathway (hsa04072)
  PI3K-Akt sig.ling pathway (hsa04151)
  Osteoclast differentiation (hsa04380)
  Platelet activation (hsa04611)
  Neutrophil extracellular trap formation (hsa04613)
  C-type lectin receptor sig.ling pathway (hsa04625)
  .tural killer cell mediated cytotoxicity (hsa04650)
  B cell receptor sig.ling pathway (hsa04662)
  Fc epsilon RI sig.ling pathway (hsa04664)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Tuberculosis (hsa05152)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Coro.virus disease - COVID-19 (hsa05171)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  FCGR activation (R-HSA-2029481)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)
  Role of phospholipids in phagocytosis (R-HSA-2029485)
  DAP12 signaling (R-HSA-2424491)
  Fc epsilon receptor (FCERI) signaling (R-HSA-2454202)
  Role of LAT2/NTAL/LAB on calcium mobilization (R-HSA-2730905)
  FCERI mediated MAPK activation (R-HSA-2871796)
  FCERI mediated Ca+2 mobilization (R-HSA-2871809)
  Integrin signaling (R-HSA-354192)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  Dectin-2 family (R-HSA-5621480)
  Interleukin-2 signaling (R-HSA-9020558)
  Regulation of signaling by CBL (R-HSA-912631)
  FCGR3A-mediated IL10 synthesis (R-HSA-9664323)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Signaling by CSF3 (G-CSF) (R-HSA-9674555)
  Potential therapeutics for SARS (R-HSA-9679191)
  Inactivation of CSF3 (G-CSF) signaling (R-HSA-9705462)
  FLT3 signaling through SRC family kinases (R-HSA-9706374)
  Antigen activates B Cell Receptor (BCR) leading to generation of second messengers (R-HSA-983695)
  GPVI-mediated activation cascade (R-HSA-114604)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Immunodeficiency 82 with systemic inflammation	DISYW6N0	Strong	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Tyrosine-protein kinase SYK (SYK).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tyrosine-protein kinase SYK (SYK).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tyrosine-protein kinase SYK (SYK).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Tyrosine-protein kinase SYK (SYK).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Tyrosine-protein kinase SYK (SYK).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Tyrosine-protein kinase SYK (SYK).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Tyrosine-protein kinase SYK (SYK).	[8]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline decreases the expression of Tyrosine-protein kinase SYK (SYK).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Tyrosine-protein kinase SYK (SYK).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Tyrosine-protein kinase SYK (SYK).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tyrosine-protein kinase SYK (SYK).	[13]
Scriptaid	DM9JZ21	Preclinical	Scriptaid affects the expression of Tyrosine-protein kinase SYK (SYK).	[14]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Tyrosine-protein kinase SYK (SYK).	[12]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Tyrosine-protein kinase SYK (SYK).	[16]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl increases the expression of Tyrosine-protein kinase SYK (SYK).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the phosphorylation of Tyrosine-protein kinase SYK (SYK).	[10]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the phosphorylation of Tyrosine-protein kinase SYK (SYK).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Tyrosine-protein kinase SYK (SYK).	[15]
Uric acid	DMA1MKT	Investigative	Uric acid increases the phosphorylation of Tyrosine-protein kinase SYK (SYK).	[17]

References

• [1] Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice. Nat Genet. 2021 Apr;53(4):500-510. doi: 10.1038/s41588-021-00803-4. Epub 2021 Mar 29.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [7] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [8] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [9] Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers. J Allergy Clin Immunol. 2016 Dec;138(6):1690-1700. doi: 10.1016/j.jaci.2016.02.038. Epub 2016 Apr 24.
• [10] Gnetin H isolated from Paeonia anomala inhibits FcRI-mediated mast cell signaling and degranulation. J Ethnopharmacol. 2014 Jul 3;154(3):798-806.
• [11] Rigosertib as a selective anti-tumor agent can ameliorate multiple dysregulated signaling transduction pathways in high-grade myelodysplastic syndrome. Sci Rep. 2014 Dec 4;4:7310. doi: 10.1038/srep07310.
• [12] Inhibition of CXCL12-mediated chemotaxis of Jurkat cells by direct immunotoxicants. Arch Toxicol. 2016 Jul;90(7):1685-94. doi: 10.1007/s00204-015-1585-7. Epub 2015 Aug 28.
• [13] 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.
• [14] Histone deacetylase inhibitor scriptaid induces cell cycle arrest and epigenetic change in colon cancer cells. Int J Oncol. 2008 Oct;33(4):767-76.
• [15] 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.
• [16] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [17] Flavonoids interfere with NLRP3 inflammasome activation. Toxicol Appl Pharmacol. 2018 Sep 15;355:93-102. doi: 10.1016/j.taap.2018.06.022. Epub 2018 Jun 28.