Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG1Z6TY)

• DOT Name: STE20-related kinase adapter protein alpha (STRADA)
• Synonyms: STRAD alpha; STE20-related adapter protein; Serologically defined breast cancer antigen NY-BR-96
• Gene Name: STRADA
• Related Disease:
  Polyhydramnios, megalencephaly, and symptomatic epilepsy
  Alzheimer disease
  Childhood epilepsy with centrotemporal spikes
  Epilepsy
  Epilepsy syndrome
  Medulloblastoma
  Neurodevelopmental disorder
  Adenocarcinoma
  Peutz-Jeghers syndrome
• UniProt ID: STRAA_HUMAN
• PDB ID: 1UPK; 2WTK; 3GNI
• Pfam ID: PF00069
• Sequence:
  MSFLVSKPERIRRWVSEKFIVEGLRDLELFGEQPPGDTRRKTNDASSESIASFSKQEVMS
  SFLPEGGCYELLTVIGKGFEDLMTVNLARYKPTGEYVTVRRINLEACSNEMVTFLQGELH
  VSKLFNHPNIVPYRATFIADNELWVVTSFMAYGSAKDLICTHFMDGMNELAIAYILQGVL
  KALDYIHHMGYVHRSVKASHILISVDGKVYLSGLRSNLSMISHGQRQRVVHDFPKYSVKV
  LPWLSPEVLQQNLQGYDAKSDIYSVGITACELANGHVPFKDMPATQMLLEKLNGTVPCLL
  DTSTIPAEELTMSPSRSVANSGLSDSLTTSTPRPSNGDSPSHPYHRTFSPHFHHFVEQCL
  QRNPDARPSASTLLNHSFFKQIKRRASEALPELLRPVTPITNFEGSQSQDHSGIFGLVTN
  LEELEVDDWEF
• Function: Pseudokinase which, in complex with CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta), binds to and activates STK11/LKB1. Adopts a closed conformation typical of active protein kinases and binds STK11/LKB1 as a pseudosubstrate, promoting conformational change of STK11/LKB1 in an active conformation.
• KEGG Pathway:
  mTOR sig.ling pathway (hsa04150)
  AMPK sig.ling pathway (hsa04152)
• Reactome Pathway: Energy dependent regulation of mTOR by LKB1-AMPK (R-HSA-380972)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Polyhydramnios, megalencephaly, and symptomatic epilepsy	DISH85FR	Definitive	Autosomal recessive	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Childhood epilepsy with centrotemporal spikes	DISKT2L5	Strong	CausalMutation	[3]
Epilepsy	DISBB28L	Strong	Genetic Variation	[4]
Epilepsy syndrome	DISLYXJ3	Strong	Genetic Variation	[1]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[5]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[6]
Adenocarcinoma	DIS3IHTY	moderate	Biomarker	[7]
Peutz-Jeghers syndrome	DISF27ZJ	moderate	Genetic Variation	[7]

2 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 STE20-related kinase adapter protein alpha (STRADA).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of STE20-related kinase adapter protein alpha (STRADA).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of STE20-related kinase adapter protein alpha (STRADA).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of STE20-related kinase adapter protein alpha (STRADA).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of STE20-related kinase adapter protein alpha (STRADA).	[11]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of STE20-related kinase adapter protein alpha (STRADA).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of STE20-related kinase adapter protein alpha (STRADA).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of STE20-related kinase adapter protein alpha (STRADA).	[15]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of STE20-related kinase adapter protein alpha (STRADA).	[16]

References

• [1] Whole exome sequencing identifies the first STRADA point mutation in a patient with polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE). Am J Med Genet A. 2016 Aug;170(8):2181-5. doi: 10.1002/ajmg.a.37727. Epub 2016 May 12.
• [2] Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.Mol Psychiatry. 2016 Nov;21(11):1608-1612. doi: 10.1038/mp.2015.218. Epub 2016 Feb 2.
• [3] Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy.Eur J Hum Genet. 2018 Feb;26(2):258-264. doi: 10.1038/s41431-017-0034-x. Epub 2018 Jan 22.
• [4] Impact of clinical exomes in neurodevelopmental and neurometabolic disorders. Mol Genet Metab. 2017 Aug;121(4):297-307. doi: 10.1016/j.ymgme.2017.06.014. Epub 2017 Jun 30.
• [5] A sensitized RNA interference screen identifies a novel role for the PI3K p110 isoform in medulloblastoma cell proliferation and chemoresistance. Mol Cancer Res. 2011 Jul;9(7):925-35. doi: 10.1158/1541-7786.MCR-10-0200. Epub 2011 Jun 7.
• [6] Novel Homozygous Deletion in STRADA Gene Associated With Polyhydramnios, Megalencephaly, and Epilepsy in 2 Siblings: Implications for Diagnosis and Treatment.J Child Neurol. 2018 Dec;33(14):925-929. doi: 10.1177/0883073818802724. Epub 2018 Oct 12.
• [7] STRAD in Peutz-Jeghers syndrome and sporadic cancers.J Clin Pathol. 2005 Oct;58(10):1091-5. doi: 10.1136/jcp.2005.026013.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [11] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [13] 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.
• [14] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [15] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.