Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEKL45T)

• DOT Name: KH domain-containing, RNA-binding, signal transduction-associated protein 2 (KHDRBS2)
• Synonyms: Sam68-like mammalian protein 1; SLM-1; hSLM-1
• Gene Name: KHDRBS2
• Related Disease:
  Alzheimer disease
  Esophageal adenocarcinoma
  Lung adenocarcinoma
  Melanoma
• UniProt ID: KHDR2_HUMAN
• Pfam ID: PF00013 ; PF16274 ; PF16568
• Sequence:
  MEEEKYLPELMAEKDSLDPSFVHASRLLAEEIEKFQGSDGKKEDEEKKYLDVISNKNIKL
  SERVLIPVKQYPKFNFVGKLLGPRGNSLKRLQEETGAKMSILGKGSMRDKAKEEELRKSG
  EAKYAHLSDELHVLIEVFAPPGEAYSRMSHALEEIKKFLVPDYNDEIRQEQLRELSYLNG
  SEDSGRGRGIRGRGIRIAPTAPSRGRGGAIPPPPPPGRGVLTPRGSTVTRGALPVPPVAR
  GVPTPRARGAPTVPGYRAPPPPAHEAYEEYGYDDGYGGEYDDQTYETYDNSYATQTQSVP
  EYYDYGHGVSEDAYDSYAPEEWATTRSSLKAPPQRSARGGYREHPYGRY
• Function: RNA-binding protein that plays a role in the regulation of alternative splicing and influences mRNA splice site selection and exon inclusion. Binds both poly(A) and poly(U) homopolymers. Phosphorylation by PTK6 inhibits its RNA-binding ability. Induces an increased concentration-dependent incorporation of exon in CD44 pre-mRNA by direct binding to purine-rich exonic enhancer. Can regulate alternative splicing of NRXN1 in the laminin G-like domain 6 containing the evolutionary conserved neurexin alternative spliced segment 4 (AS4) involved in neurexin selective targeting to postsynaptic partners. Regulates cell-type specific alternative splicing of NRXN1 at AS4 and acts synergystically with SAM68 in exon skipping. In contrast acts antagonistically with SAM68 in NRXN3 exon skipping at AS4. Its phosphorylation by FYN inhibits its ability to regulate splice site selection. May function as an adapter protein for Src kinases during mitosis.
• Tissue Specificity: Highly expressed in brain, lung, kidney and small intestine. Weakly expressed in placenta, liver, spleen, thymus, ovary and colon.
• Reactome Pathway: PTK6 Regulates Proteins Involved in RNA Processing (R-HSA-8849468)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Esophageal adenocarcinoma	DISODWFP	Strong	Genetic Variation	[2]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[3]
Melanoma	DIS1RRCY	Strong	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of KH domain-containing, RNA-binding, signal transduction-associated protein 2 (KHDRBS2).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of KH domain-containing, RNA-binding, signal transduction-associated protein 2 (KHDRBS2).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of KH domain-containing, RNA-binding, signal transduction-associated protein 2 (KHDRBS2).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 2 (KHDRBS2).	[6]

References

• [1] Genome-wide association interaction analysis for Alzheimer's disease.Neurobiol Aging. 2014 Nov;35(11):2436-2443. doi: 10.1016/j.neurobiolaging.2014.05.014. Epub 2014 May 28.
• [2] Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis.Lancet Oncol. 2016 Oct;17(10):1363-1373. doi: 10.1016/S1470-2045(16)30240-6. Epub 2016 Aug 12.
• [3] Genomic aberrations in lung adenocarcinoma in never smokers.PLoS One. 2010 Dec 6;5(12):e15145. doi: 10.1371/journal.pone.0015145.
• [4] Exome sequencing identifies GRIN2A as frequently mutated in melanoma.Nat Genet. 2011 May;43(5):442-6. doi: 10.1038/ng.810. Epub 2011 Apr 15.
• [5] 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.
• [6] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [7] 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.
• [8] 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.