Details of Drug Off-Target (DOT)

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

• DOT Name: Calcium-transporting ATPase type 2C member 2 (ATP2C2)
• Synonyms: ATPase 2C2; EC 7.2.2.10; Ca(2+)/Mn(2+)-ATPase 2C2; Secretory pathway Ca(2+)-transporting ATPase type 2; SPCA2
• Gene Name: ATP2C2
• Related Disease:
  Attention deficit hyperactivity disorder
  Breast cancer
  Breast carcinoma
  Chronic obstructive pulmonary disease
  Language disorder
  Pancreatitis
  Specific language impairment
  Acute myelogenous leukaemia
  Breast neoplasm
  Metastatic malignant neoplasm
• UniProt ID: AT2C2_HUMAN
• EC Number: 7.2.2.10
• Pfam ID: PF13246 ; PF00689 ; PF00690 ; PF00122 ; PF00702
• Sequence:
  MVEGRVSEFLKKLGFSGGGRQYQALEKDEEEALIDEQSELKAIEKEKKVTALPPKEACKC
  QKEDLARAFCVDLHTGLSEFSVTQRRLAHGWNEFVADNSEPVWKKYLDQFKNPLILLLLG
  SALVSVLTKEYEDAVSIATAVLVVVTVAFIQEYRSEKSLEELTKLVPPECNCLREGKLQH
  LLARELVPGDVVSLSIGDRIPADIRLTEVTDLLVDESSFTGEAEPCSKTDSPLTGGGDLT
  TLSNIVFMGTLVQYGRGQGVVIGTGESSQFGEVFKMMQAEETPKTPLQKSMDRLGKQLTL
  FSFGIIGLIMLIGWSQGKQLLSMFTIGVSLAVAAIPEGLPIVVMVTLVLGVLRMAKKRVI
  VKKLPIVETLGCCSVLCSDKTGTLTANEMTVTQLVTSDGLRAEVSGVGYDGQGTVCLLPS
  KEVIKEFSNVSVGKLVEAGCVANNAVIRKNAVMGQPTEGALMALAMKMDLSDIKNSYIRK
  KEIPFSSEQKWMAVKCSLKTEDQEDIYFMKGALEEVIRYCTMYNNGGIPLPLTPQQRSFC
  LQEEKRMGSLGLRVLALASGPELGRLTFLGLVGIIDPPRVGVKEAVQVLSESGVSVKMIT
  GDALETALAIGRNIGLCNGKLQAMSGEEVDSVEKGELADRVGKVSVFFRTSPKHKLKIIK
  ALQESGAIVAMTGDGVNDAVALKSADIGIAMGQTGTDVSKEAANMILVDDDFSAIMNAVE
  EGKGIFYNIKNFVRFQLSTSISALSLITLSTVFNLPSPLNAMQILWINIIMDGPPAQSLG
  VEPVDKDAFRQPPRSVRDTILSRALILKILMSAAIIISGTLFIFWKEMPEDRASTPRTTT
  MTFTCFVFFDLFNALTCRSQTKLIFEIGFLRNHMFLYSVLGSILGQLAVIYIPPLQRVFQ
  TENLGALDLLFLTGLASSVFILSELLKLCEKYCCSPKRVQMHPEDV
• Function: ATP-driven pump that supplies the Golgi apparatus with Ca(2+) and Mn(2+) ions, both essential cofactors for processing and trafficking of newly synthesized proteins in the secretory pathway. Within a catalytic cycle, acquires Ca(2+) or Mn(2+) ions on the cytoplasmic side of the membrane and delivers them to the lumenal side. The transfer of ions across the membrane is coupled to ATP hydrolysis and is associated with a transient phosphorylation that shifts the pump conformation from inward-facing to outward-facing state. Induces Ca(2+) influx independently of its ATP-driven pump function. At the basolateral membrane of mammary epithelial cells, interacts with Ca(2+) channel ORAI1 and mediates Ca(2+) entry independently of the Ca(2+) content of endoplasmic reticulum or Golgi stores. May facilitate transepithelial transport of large quantities of Ca(2+) for milk secretion via activation of Ca(2+) influx channels at the plasma membrane and active Ca(2+) transport at the Golgi apparatus.
• Tissue Specificity: Highly expressed in the gastrointestinal and respiratory tracts, prostate, thyroid, salivary, and mammary glands . Expressed in colon epithelial cells (at protein level). Expressed in brain and testis (at protein level) .
• Reactome Pathway: Ion transport by P-type ATPases (R-HSA-936837)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[3]
Language disorder	DISTLKP7	Strong	Genetic Variation	[4]
Pancreatitis	DIS0IJEF	Strong	Altered Expression	[5]
Specific language impairment	DISEKRML	Strong	Biomarker	[6]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[7]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[8]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[8]

8 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 Calcium-transporting ATPase type 2C member 2 (ATP2C2).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Calcium-transporting ATPase type 2C member 2 (ATP2C2).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Calcium-transporting ATPase type 2C member 2 (ATP2C2).	[11]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Calcium-transporting ATPase type 2C member 2 (ATP2C2).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Calcium-transporting ATPase type 2C member 2 (ATP2C2).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Calcium-transporting ATPase type 2C member 2 (ATP2C2).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Calcium-transporting ATPase type 2C member 2 (ATP2C2).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Calcium-transporting ATPase type 2C member 2 (ATP2C2).	[16]

1 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 decreases the methylation of Calcium-transporting ATPase type 2C member 2 (ATP2C2).	[13]

References

• [1] Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies.J Neural Transm (Vienna). 2008 Nov;115(11):1573-85. doi: 10.1007/s00702-008-0119-3. Epub 2008 Oct 7.
• [2] SPCA2 couples Ca(2+) influx via Orai1 to Ca(2+) uptake into the Golgi/secretory pathway.Tissue Cell. 2017 Apr;49(2 Pt A):141-149. doi: 10.1016/j.tice.2016.09.004. Epub 2016 Sep 17.
• [3] Genome-wide association analysis of blood biomarkers in chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2012 Dec 15;186(12):1238-47. doi: 10.1164/rccm.201206-1013OC. Epub 2012 Nov 9.
• [4] Language impairment and dyslexia genes influence language skills in children with autism spectrum disorders.Autism Res. 2015 Apr;8(2):229-34. doi: 10.1002/aur.1436. Epub 2014 Dec 1.
• [5] Atp2c2 Is Transcribed From a Unique Transcriptional Start Site in Mouse Pancreatic Acinar Cells.J Cell Physiol. 2016 Dec;231(12):2768-78. doi: 10.1002/jcp.25391. Epub 2016 Apr 21.
• [6] Deletion of 16q24.1 supports a role for the ATP2C2 gene in specific language impairment.J Child Neurol. 2015 Mar;30(4):517-21. doi: 10.1177/0883073814545113. Epub 2014 Oct 7.
• [7] 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.
• [8] A Ca(2+)-ATPase Regulates E-cadherin Biogenesis and Epithelial-Mesenchymal Transition in Breast Cancer Cells.Mol Cancer Res. 2019 Aug;17(8):1735-1747. doi: 10.1158/1541-7786.MCR-19-0070. Epub 2019 May 10.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [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] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [15] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.