Details of Drug Off-Target (DOT)

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

• DOT Name: Cas scaffolding protein family member 4 (CASS4)
• Synonyms: HEF-like protein; HEF1-EFS-p130Cas-like protein; HEPL
• Gene Name: CASS4
• Related Disease:
  Autonomic nervous system disorder
  Dysautonomia
  Familial Alzheimer disease
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Parkinson disease
  Alzheimer disease
• UniProt ID: CASS4_HUMAN
• PDB ID: 2CRE
• Pfam ID: PF12026 ; PF08824 ; PF14604
• Sequence:
  MKGTGIMDCAPKALLARALYDNCPDCSDELAFSRGDILTILEQHVPESEGWWKCLLHGRQ
  GLAPANRLQILTEVAADRPCPPFLRGLEEAPASSEETYQVPTLPRPPTPGPVYEQMRSWA
  EGPQPPTAQVYEFPDPPTSARIICEKTLSFPKQAILTLPRPVRASLPTLPSQVYDVPTQH
  RGPVVLKEPEKQQLYDIPASPKKAGLHPPDSQASGQGVPLISVTTLRRGGYSTLPNPQKS
  EWIYDTPVSPGKASVRNTPLTSFAEESRPHALPSSSSTFYNPPSGRSRSLTPQLNNNVPM
  QKKLSLPEIPSYGFLVPRGTFPLDEDVSYKVPSSFLIPRVEQQNTKPNIYDIPKATSSVS
  QAGKELEKAKEVSENSAGHNSSWFSRRTTSPSPEPDRLSGSSSDSRASIVSSCSTTSTDD
  SSSSSSEESAKELSLDLDVAKETVMALQHKVVSSVAGLMLFVSRKWRFRDYLEANIDAIH
  RSTDHIEESVREFLDFARGVHGTACNLTDSNLQNRIRDQMQTISNSYRILLETKESLDNR
  NWPLEVLVTDSVQNSPDDLERFVMVARMLPEDIKRFASIVIANGRLLFKRNCEKEETVQL
  TPNAEFKCEKYIQPPQRETESHQKSTPSTKQREDEHSSELLKKNRANICGQNPGPLIPQP
  SSQQTPERKPRLSEHCRLYFGALFKAISAFHGSLSSSQPAEIITQSKLVIMVGQKLVDTL
  CMETQERDVRNEILRGSSHLCSLLKDVALATKNAVLTYPSPAALGHLQAEAEKLEQHTRQ
  FRGTLG
• Function: Docking protein that plays a role in tyrosine kinase-based signaling related to cell adhesion and cell spreading. Regulates PTK2/FAK1 activity, focal adhesion integrity, and cell spreading.
• Tissue Specificity: Expressed abundantly in lung and spleen. Also highly expressed in ovarian and leukemia cell lines.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autonomic nervous system disorder	DIS6JLTA	Strong	Biomarker	[1]
Dysautonomia	DISF4MT6	Strong	Biomarker	[1]
Familial Alzheimer disease	DISE75U4	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[3]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[1]
Alzheimer disease	DISF8S70	moderate	Genetic Variation	[4]

1 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 Cas scaffolding protein family member 4 (CASS4).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cas scaffolding protein family member 4 (CASS4).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cas scaffolding protein family member 4 (CASS4).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Cas scaffolding protein family member 4 (CASS4).	[8]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Cas scaffolding protein family member 4 (CASS4).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cas scaffolding protein family member 4 (CASS4).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cas scaffolding protein family member 4 (CASS4).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Cas scaffolding protein family member 4 (CASS4).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cas scaffolding protein family member 4 (CASS4).	[13]

References

• [1] Dysautonomia is associated with structural and functional alterations in Parkinson disease.Neurology. 2019 Mar 26;92(13):e1456-e1467. doi: 10.1212/WNL.0000000000007181. Epub 2019 Feb 22.
• [2] Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers.J Alzheimers Dis. 2018;66(2):639-652. doi: 10.3233/JAD-180512.
• [3] Overexpression of CASS4 promotes invasion in non-small cell lung cancer by activating the AKT signaling pathway and inhibiting E-cadherin expression.Tumour Biol. 2016 Nov;37(11):15157-15164. doi: 10.1007/s13277-016-5411-5. Epub 2016 Sep 27.
• [4] Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.Nat Genet. 2019 Mar;51(3):404-413. doi: 10.1038/s41588-018-0311-9. Epub 2019 Jan 7.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] 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.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.