Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2A6FSA)

• DOT Name: Integrin-linked kinase-associated serine/threonine phosphatase 2C (ILKAP)
• Synonyms: ILKAP; EC 3.1.3.16
• Gene Name: ILKAP
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Gastric cancer
  Melanoma
  Stomach cancer
  Acute myelogenous leukaemia
• UniProt ID: ILKAP_HUMAN
• EC Number: 3.1.3.16
• Pfam ID: PF00481
• Sequence:
  MDLFGDLPEPERSPRPAAGKEAQKGPLLFDDLPPASSTDSGSGGPLLFDDLPPASSGDSG
  SLATSISQMVKTEGKGAKRKTSEEEKNGSEELVEKKVCKASSVIFGLKGYVAERKGEREE
  MQDAHVILNDITEECRPPSSLITRVSYFAVFDGHGGIRASKFAAQNLHQNLIRKFPKGDV
  ISVEKTVKRCLLDTFKHTDEEFLKQASSQKPAWKDGSTATCVLAVDNILYIANLGDSRAI
  LCRYNEESQKHAALSLSKEHNPTQYEERMRIQKAGGNVRDGRVLGVLEVSRSIGDGQYKR
  CGVTSVPDIRRCQLTPNDRFILLACDGLFKVFTPEEAVNFILSCLEDEKIQTREGKSAAD
  ARYEAACNRLANKAVQRGSADNVTVMVVRIGH
• Function: Protein phosphatase that may play a role in regulation of cell cycle progression via dephosphorylation of its substrates whose appropriate phosphorylation states might be crucial for cell proliferation. Selectively associates with integrin linked kinase (ILK), to modulate cell adhesion and growth factor signaling. Inhibits the ILK-GSK3B signaling axis and may play an important role in inhibiting oncogenic transformation.
• Tissue Specificity: Widely expressed. Highest levels expressed in striated muscle. Much lower levels evident in various smooth muscle tissues.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Gastric cancer	DISXGOUK	moderate	Biomarker	[2]
Melanoma	DIS1RRCY	moderate	Biomarker	[3]
Stomach cancer	DISKIJSX	moderate	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Daunorubicin	DMQUSBT	Approved	Integrin-linked kinase-associated serine/threonine phosphatase 2C (ILKAP) affects the response to substance of Daunorubicin.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Integrin-linked kinase-associated serine/threonine phosphatase 2C (ILKAP).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Integrin-linked kinase-associated serine/threonine phosphatase 2C (ILKAP).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Integrin-linked kinase-associated serine/threonine phosphatase 2C (ILKAP).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Integrin-linked kinase-associated serine/threonine phosphatase 2C (ILKAP).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Integrin-linked kinase-associated serine/threonine phosphatase 2C (ILKAP).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Integrin-linked kinase-associated serine/threonine phosphatase 2C (ILKAP).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Integrin-linked kinase-associated serine/threonine phosphatase 2C (ILKAP).	[10]

References

• [1] PP2C inhibits p300-mediated p53 acetylation via ATM/BRCA1 pathway to impede DNA damage response in breast cancer.Sci Adv. 2019 Oct 16;5(10):eaaw8417. doi: 10.1126/sciadv.aaw8417. eCollection 2019 Oct.
• [2] MAEL contributes to gastric cancer progression by promoting ILKAP degradation.Oncotarget. 2017 Dec 6;8(69):113331-113344. doi: 10.18632/oncotarget.22970. eCollection 2017 Dec 26.
• [3] Involvement of ANXA5 and ILKAP in susceptibility to malignant melanoma.PLoS One. 2014 Apr 17;9(4):e95522. doi: 10.1371/journal.pone.0095522. eCollection 2014.
• [4] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [7] Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Mapping genes that contribute to daunorubicin-induced cytotoxicity. Cancer Res. 2007 Jun 1;67(11):5425-33. doi: 10.1158/0008-5472.CAN-06-4431.