Details of Drug Off-Target (DOT)

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

• DOT Name: KICSTOR complex protein kaptin (KPTN)
• Synonyms: Actin-associated protein 2E4
• Gene Name: KPTN
• Related Disease:
  Macrocephaly-developmental delay syndrome
  Intellectual disability
  Megalencephaly
• UniProt ID: KPTN_HUMAN
• Sequence:
  MMGEAAVAAGPCPLREDSFTRFSSQSNVYGLAGGAGGRGELLAATLKGKVLGFRYQDLRQ
  KIRPVAKELQFNYIPVDAEIVSIDTFNKSPPKRGLVVGITFIKDSGDKGSPFLNIYCDYE
  PGSEYNLDSIAQSCLNLELQFTPFQLCHAEVQVGDQLETVFLLSGNDPAIHLYKENEGLH
  QFEEQPVENLFPELTNLTSSVLWLDVHNFPGTSRRLSALGCQSGYVRVAHVDQRSREVLQ
  MWSVLQDGPISRVIVFSLSAAKETKDRPLQDEYSVLVASMLEPAVVYRDLLNRGLEDQLL
  LPGSDQFDSVLCSLVTDVDLDGRPEVLVATYGQELLCYKYRGPESGLPEAQHGFHLLWQR
  SFSSPLLAMAHVDLTGDGLQELAVVSLKGVHILQHSLIQASELVLTRLRHQVEQRRRRLQ
  GLEDGAGAGPAENAAS
• Function: As part of the KICSTOR complex functions in the amino acid-sensing branch of the TORC1 signaling pathway. Recruits, in an amino acid-independent manner, the GATOR1 complex to the lysosomal membranes and allows its interaction with GATOR2 and the RAG GTPases. Functions upstream of the RAG GTPases and is required to negatively regulate mTORC1 signaling in absence of amino acids. In absence of the KICSTOR complex mTORC1 is constitutively localized to the lysosome and activated. The KICSTOR complex is also probably involved in the regulation of mTORC1 by glucose.
• Reactome Pathway: Amino acids regulate mTORC1 (R-HSA-9639288)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Macrocephaly-developmental delay syndrome	DISEELAR	Strong	Autosomal recessive	[1]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[2]
Megalencephaly	DISYW5SV	Limited	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of KICSTOR complex protein kaptin (KPTN).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of KICSTOR complex protein kaptin (KPTN).	[4]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of KICSTOR complex protein kaptin (KPTN).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of KICSTOR complex protein kaptin (KPTN).	[5]

References

• [1] Mutations in KPTN cause macrocephaly, neurodevelopmental delay, and seizures. Am J Hum Genet. 2014 Jan 2;94(1):87-94. doi: 10.1016/j.ajhg.2013.10.001. Epub 2013 Nov 14.
• [2] Novel homozygous mutation in KPTN gene causing a familial intellectual disability-macrocephaly syndrome.Am J Med Genet A. 2015 Aug;167A(8):1913-5. doi: 10.1002/ajmg.a.37105. Epub 2015 Apr 5.
• [3] 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.
• [4] 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.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] 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.