Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT57KE22)

• DOT Name: Lymphocyte cytosolic protein 2 (LCP2)
• Synonyms: SH2 domain-containing leukocyte protein of 76 kDa; SLP-76 tyrosine phosphoprotein; SLP76
• Gene Name: LCP2
• Related Disease:
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Bladder cancer
  Systemic lupus erythematosus
  Urinary bladder cancer
  Urinary bladder neoplasm
  Adult glioblastoma
  Glioblastoma multiforme
  Small lymphocytic lymphoma
  Follicular lymphoma
  Immunodeficiency 81
• UniProt ID: LCP2_HUMAN
• PDB ID: 1H3H; 1YWO; 2EAP; 2ROR; 6ZCJ
• Pfam ID: PF07647 ; PF00017
• Sequence:
  MALRNVPFRSEVLGWDPDSLADYFKKLNYKDCEKAVKKYHIDGARFLNLTENDIQKFPKL
  RVPILSKLSQEINKNEERRSIFTRKPQVPRFPEETESHEEDNGGWSSFEEDDYESPNDDQ
  DGEDDGDYESPNEEEEAPVEDDADYEPPPSNDEEALQNSILPAKPFPNSNSMYIDRPPSG
  KTPQQPPVPPQRPMAALPPPPAGRNHSPLPPPQTNHEEPSRSRNHKTAKLPAPSIDRSTK
  PPLDRSLAPFDREPFTLGKKPPFSDKPSIPAGRSLGEHLPKIQKPPLPPTTERHERSSPL
  PGKKPPVPKHGWGPDRRENDEDDVHQRPLPQPALLPMSSNTFPSRSTKPSPMNPLPSSHM
  PGAFSESNSSFPQSASLPPYFSQGPSNRPPIRAEGRNFPLPLPNKPRPPSPAEEENSLNE
  EWYVSYITRPEAEAALRKINQDGTFLVRDSSKKTTTNPYVLMVLYKDKVYNIQIRYQKES
  QVYLLGTGLRGKEDFLSVSDIIDYFRKMPLLLIDGKNRGSRYQCTLTHAAGYP
• Function: Involved in T-cell antigen receptor mediated signaling.
• Tissue Specificity: Highly expressed in spleen, thymus and peripheral blood leukocytes. Highly expressed also in T-cell and monocytic cell lines, expressed at lower level in B-cell lines. Not detected in fibroblast or neuroblastoma cell lines.
• KEGG Pathway:
  Rap1 sig.ling pathway (hsa04015)
  Osteoclast differentiation (hsa04380)
  Platelet activation (hsa04611)
  .tural killer cell mediated cytotoxicity (hsa04650)
  T cell receptor sig.ling pathway (hsa04660)
  Fc epsilon RI sig.ling pathway (hsa04664)
  Yersinia infection (hsa05135)
• Reactome Pathway:
  Generation of second messenger molecules (R-HSA-202433)
  DAP12 signaling (R-HSA-2424491)
  FCERI mediated MAPK activation (R-HSA-2871796)
  FCERI mediated Ca+2 mobilization (R-HSA-2871809)
  GPVI-mediated activation cascade (R-HSA-114604)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[2]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[3]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[2]
Adult glioblastoma	DISVP4LU	moderate	Biomarker	[4]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[4]
Small lymphocytic lymphoma	DIS30POX	moderate	Biomarker	[5]
Follicular lymphoma	DISVEUR6	Disputed	Biomarker	[6]
Immunodeficiency 81	DISMX9JC	Limited	Unknown	[7]

8 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 Lymphocyte cytosolic protein 2 (LCP2).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Lymphocyte cytosolic protein 2 (LCP2).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Lymphocyte cytosolic protein 2 (LCP2).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Lymphocyte cytosolic protein 2 (LCP2).	[11]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Lymphocyte cytosolic protein 2 (LCP2).	[12]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Lymphocyte cytosolic protein 2 (LCP2).	[13]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Lymphocyte cytosolic protein 2 (LCP2).	[9]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Lymphocyte cytosolic protein 2 (LCP2).	[14]

1 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 Lymphocyte cytosolic protein 2 (LCP2).	[15]

References

• [1] Retinoic acid and 6-formylindolo(3,2-b)carbazole (FICZ) combination therapy reveals putative targets for enhancing response in non-APL AML.Leuk Lymphoma. 2019 Jul;60(7):1697-1708. doi: 10.1080/10428194.2018.1543880. Epub 2018 Dec 20.
• [2] Implication of vascular endothelial growth factor A and C in revealing diagnostic lymphangiogenic markers in node-positive bladder cancer.Oncotarget. 2017 Mar 28;8(13):21871-21883. doi: 10.18632/oncotarget.15669.
• [3] Prevalence of ZAP-70, LAT, SLP-76, and DNA methyltransferase 1 expression in CD4+ T cells of patients with systemic lupus erythematosus.Clin Rheumatol. 2008 Jan;27(1):21-7. doi: 10.1007/s10067-007-0644-8. Epub 2007 May 11.
• [4] The PPI network and clusters analysis in glioblastoma.Eur Rev Med Pharmacol Sci. 2015 Dec;19(24):4784-90.
• [5] SLP76 integrates into the B-cell receptor signaling cascade in chronic lymphocytic leukemia cells and is associated with an aggressive disease course.Haematologica. 2016 Dec;101(12):1553-1562. doi: 10.3324/haematol.2015.139154. Epub 2016 Jul 21.
• [6] T Cells Expressing Checkpoint Receptor TIGIT Are Enriched in Follicular Lymphoma Tumors and Characterized by Reversible Suppression of T-cell Receptor Signaling.Clin Cancer Res. 2018 Feb 15;24(4):870-881. doi: 10.1158/1078-0432.CCR-17-2337. Epub 2017 Dec 7.
• [7] Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects. J Exp Med. 2021 Mar 1;218(3):e20201062. doi: 10.1084/jem.20201062.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [10] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [11] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [13] Proteomic analysis of anti-cancer effects by paclitaxel treatment in cervical cancer cells. Gynecol Oncol. 2005 Jul;98(1):45-53. doi: 10.1016/j.ygyno.2005.04.010.
• [14] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [15] 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.