Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNVE666)

• DOT Name: Src-like-adapter 2 (SLA2)
• Synonyms: Modulator of antigen receptor signaling; MARS; Src-like adapter protein 2; SLAP-2
• Gene Name: SLA2
• Related Disease:
  Epilepsy
  Acute liver failure
  Alzheimer disease
  Alzheimer disease 3
  Charcot marie tooth disease
  Depression
  Liver failure
  Major depressive disorder
  Renal hypodysplasia/aplasia 1
  Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency
  Stroke
  Charcot-Marie-Tooth disease axonal type 2U
  Hypercholesterolemia, familial, 1
  Subarachnoid hemorrhage
• UniProt ID: SLAP2_HUMAN
• PDB ID: 4M4Z
• Pfam ID: PF00017 ; PF00018
• Sequence:
  MGSLPSRRKSLPSPSLSSSVQGQGPVTMEAERSKATAVALGSFPAGGPAELSLRLGEPLT
  IVSEDGDWWTVLSEVSGREYNIPSVHVAKVSHGWLYEGLSREKAEELLLLPGNPGGAFLI
  RESQTRRGSYSLSVRLSRPASWDRIRHYRIHCLDNGWLYISPRLTFPSLQALVDHYSELA
  DDICCLLKEPCVLQRAGPLPGKDIPLPVTVQRTPLNWKELDSSLLFSEAATGEESLLSEG
  LRESLSFYISLNDEAVSLDDA
• Function: Adapter protein, which negatively regulates T-cell receptor (TCR) signaling. Inhibits T-cell antigen-receptor induced activation of nuclear factor of activated T-cells. May act by linking signaling proteins such as ZAP70 with CBL, leading to a CBL dependent degradation of signaling proteins.
• Tissue Specificity: Predominantly expressed in immune system, with highest levels in peripheral blood leukocytes. Expressed in spleen, thymus and lymph nodes. Expressed in T-cells as well as in monocytes, and at low level in B-cells. Also detected in placenta, prostate, skin, retina and colon.
• Reactome Pathway: Negative regulation of FLT3 (R-HSA-9706369)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Definitive	Biomarker	[1]
Acute liver failure	DIS5EZKX	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Alzheimer disease 3	DISVT69G	Strong	Genetic Variation	[3]
Charcot marie tooth disease	DIS3BT2L	Strong	Biomarker	[4]
Depression	DIS3XJ69	Strong	Biomarker	[5]
Liver failure	DISLGEL6	Strong	Biomarker	[6]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[7]
Renal hypodysplasia/aplasia 1	DISOH8XN	Strong	Biomarker	[8]
Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency	DIS9EFIT	Strong	Genetic Variation	[4]
Stroke	DISX6UHX	Strong	Biomarker	[5]
Charcot-Marie-Tooth disease axonal type 2U	DISRCJLT	moderate	Genetic Variation	[9]
Hypercholesterolemia, familial, 1	DISU411W	moderate	Biomarker	[10]
Subarachnoid hemorrhage	DISI7I8Y	Limited	Biomarker	[11]

3 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 Src-like-adapter 2 (SLA2).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Src-like-adapter 2 (SLA2).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Src-like-adapter 2 (SLA2).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Src-like-adapter 2 (SLA2).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Src-like-adapter 2 (SLA2).	[14]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Src-like-adapter 2 (SLA2).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Src-like-adapter 2 (SLA2).	[15]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Src-like-adapter 2 (SLA2).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Src-like-adapter 2 (SLA2).	[18]

References

• [1] Effectiveness of a multicomponent self-management intervention for adults with epilepsy (ZMILE study): A randomized controlled trial.Epilepsy Behav. 2018 Mar;80:259-265. doi: 10.1016/j.yebeh.2018.01.019. Epub 2018 Feb 12.
• [2] Molecular Adsorbent Recirculating System Effectively Replaces Hepatic Function in Severe Acute Liver Failure.Ann Surg. 2017 Oct;266(4):677-684. doi: 10.1097/SLA.0000000000002361.
• [3] Histopathological features of a patient with Charcot-Marie-Tooth disease type 2U/AD-CMTax-MARS.J Peripher Nerv Syst. 2016 Dec;21(4):370-374. doi: 10.1111/jns.12193.
• [4] MARS variant associated with both recessive interstitial lung and liver disease and dominant Charcot-Marie-Tooth disease.Eur J Med Genet. 2018 Oct;61(10):616-620. doi: 10.1016/j.ejmg.2018.04.005. Epub 2018 Apr 12.
• [5] Validation of the 5-Item Medication Adherence Report Scale in Older Stroke Patients in Iran.J Cardiovasc Nurs. 2018 Nov/Dec;33(6):536-543. doi: 10.1097/JCN.0000000000000488.
• [6] Targeting Albumin Binding Function as a Therapy Goal in Liver Failure: Development of a Novel Adsorbent for Albumin Dialysis.Ther Apher Dial. 2018 Apr;22(2):196-204. doi: 10.1111/1744-9987.12645. Epub 2017 Dec 20.
• [7] Treatment response classes in major depressive disorder identified by model-based clustering and validated by clinical prediction models.Transl Psychiatry. 2019 Aug 5;9(1):187. doi: 10.1038/s41398-019-0524-4.
• [8] Indications for MARS-MRI in Patients Treated With Metal-on-Metal Hip Resurfacing Arthroplasty.J Arthroplasty. 2018 Jun;33(6):1919-1925. doi: 10.1016/j.arth.2018.01.024. Epub 2018 Feb 2.
• [9] Whole-exome sequencing reveals a novel missense mutation in the MARS gene related to a rare Charcot-Marie-Tooth neuropathy type 2U.J Peripher Nerv Syst. 2018 Jun;23(2):138-142. doi: 10.1111/jns.12264. Epub 2018 May 9.
• [10] The development and first results of a health-related outcomes set in familial hypercholesterolemia (FH) patients: Knowledge is health.Atherosclerosis. 2020 Jan;293:11-17. doi: 10.1016/j.atherosclerosis.2019.11.030. Epub 2019 Nov 30.
• [11] Aneurysms in relatives of patients with subarachnoid hemorrhage: frequency and risk factors. MARS Study Group. Magnetic Resonance Angiography in Relatives of patients with Subarachnoid hemorrhage.Neurology. 1999 Sep 22;53(5):982-8. doi: 10.1212/wnl.53.5.982.
• [12] 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.
• [13] 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.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [17] 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.
• [18] 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.
• [19] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.