Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8QE6EU)

• DOT Name: PRKCA-binding protein (PICK1)
• Synonyms: Protein interacting with C kinase 1; Protein kinase C-alpha-binding protein
• Gene Name: PICK1
• Related Disease:
  Alzheimer disease
  Cardiac failure
  Congestive heart failure
  Epilepsy
  Hyperinsulinemia
  Male infertility
  Prostate cancer
  Prostate carcinoma
  Psychotic disorder
  Glioblastoma multiforme
  Neoplasm
  Male infertility due to globozoospermia
  Amyotrophic lateral sclerosis
  Diabetic kidney disease
  Hyperglycemia
  Nervous system disease
  Spinocerebellar ataxia type 3
• UniProt ID: PICK1_HUMAN
• PDB ID: 2GZV; 6AR4; 6BJN; 6BJO
• Pfam ID: PF06456 ; PF00595
• Sequence:
  MFADLDYDIEEDKLGIPTVPGKVTLQKDAQNLIGISIGGGAQYCPCLYIVQVFDNTPAAL
  DGTVAAGDEITGVNGRSIKGKTKVEVAKMIQEVKGEVTIHYNKLQADPKQGMSLDIVLKK
  VKHRLVENMSSGTADALGLSRAILCNDGLVKRLEELERTAELYKGMTEHTKNLLRAFYEL
  SQTHRAFGDVFSVIGVREPQPAASEAFVKFADAHRSIEKFGIRLLKTIKPMLTDLNTYLN
  KAIPDTRLTIKKYLDVKFEYLSYCLKVKEMDDEEYSCIALGEPLYRVSTGNYEYRLILRC
  RQEARARFSQMRKDVLEKMELLDQKHVQDIVFQLQRLVSTMSKYYNDCYAVLRDADVFPI
  EVDLAHTTLAYGLNQEEFTDGEEEEEEEDTAAGEPSRDTRGAAGPLDKGGSWCDS
• Function: Probable adapter protein that bind to and organize the subcellular localization of a variety of membrane proteins containing some PDZ recognition sequence. Involved in the clustering of various receptors, possibly by acting at the receptor internalization level. Plays a role in synaptic plasticity by regulating the trafficking and internalization of AMPA receptors. May be regulated upon PRKCA activation. May regulate ASIC1/ASIC3 channel. Regulates actin polymerization by inhibiting the actin-nucleating activity of the Arp2/3 complex; the function is competitive with nucleation promoting factors and is linked to neuronal morphology regulation and AMPA receptor (AMPAR) endocytosis. Via interaction with the Arp2/3 complex involved in regulation of synaptic plasicity of excitatory synapses and required for spine shrinkage during long-term depression (LTD). Involved in regulation of astrocyte morphology, antagonistic to Arp2/3 complex activator WASL/N-WASP function.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway:
  Trafficking of GluR2-containing AMPA receptors (R-HSA-416993)
  Cell surface interactions at the vascular wall (R-HSA-202733)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Cardiac failure	DISDC067	Strong	Biomarker	[2]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[2]
Epilepsy	DISBB28L	Strong	Altered Expression	[3]
Hyperinsulinemia	DISIDWT6	Strong	Altered Expression	[4]
Male infertility	DISY3YZZ	Strong	Biomarker	[5]
Prostate cancer	DISF190Y	Strong	Biomarker	[6]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[6]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[7]
Glioblastoma multiforme	DISK8246	moderate	Altered Expression	[8]
Neoplasm	DISZKGEW	moderate	Altered Expression	[8]
Male infertility due to globozoospermia	DIS7EMCO	Supportive	Autosomal recessive	[9]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[10]
Diabetic kidney disease	DISJMWEY	Limited	Biomarker	[11]
Hyperglycemia	DIS0BZB5	Limited	Biomarker	[11]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[10]
Spinocerebellar ataxia type 3	DISQBQID	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methamphetamine	DMPM4SK	Approved	PRKCA-binding protein (PICK1) increases the response to substance of Methamphetamine.	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of PRKCA-binding protein (PICK1).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of PRKCA-binding protein (PICK1).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of PRKCA-binding protein (PICK1).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of PRKCA-binding protein (PICK1).	[17]

2 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 PRKCA-binding protein (PICK1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of PRKCA-binding protein (PICK1).	[18]

References

• [1] Genetic Analysis of PICK1 Gene in Alzheimer's Disease: A Study for Finding a New Gene Target.Front Neurol. 2019 Jan 9;9:1169. doi: 10.3389/fneur.2018.01169. eCollection 2018.
• [2] Multiple faces of protein interacting with C kinase 1 (PICK1): Structure, function, and diseases.Neurochem Int. 2016 Sep;98:115-21. doi: 10.1016/j.neuint.2016.03.001. Epub 2016 Mar 9.
• [3] PICK1 facilitates lasting reduction in GluA2 concentration in the hippocampus during chronic epilepsy.Epilepsy Res. 2017 Nov;137:25-32. doi: 10.1016/j.eplepsyres.2017.08.012. Epub 2017 Aug 31.
• [4] PICK1 attenuates high glucose-induced pancreatic -cell death through the PI3K/Akt pathway and is negatively regulated by miR-139-5p.Biochem Biophys Res Commun. 2020 Jan 29;522(1):14-20. doi: 10.1016/j.bbrc.2019.11.051. Epub 2019 Nov 15.
• [5] Rescuing infertility of Pick1 knockout mice by generating testis-specific transgenic mice via testicular infection.Sci Rep. 2013 Oct 8;3:2842. doi: 10.1038/srep02842.
• [6] The TGF- signalling negative regulator PICK1 represses prostate cancer metastasis to bone.Br J Cancer. 2017 Aug 22;117(5):685-694. doi: 10.1038/bjc.2017.212. Epub 2017 Jul 11.
• [7] Identification of functional polymorphisms in the promoter region of the human PICK1 gene and their association with methamphetamine psychosis. Am J Psychiatry. 2007 Jul;164(7):1105-14. doi: 10.1176/ajp.2007.164.7.1105.
• [8] Protein interacting with C kinase 1 suppresses invasion and anchorage-independent growth of astrocytic tumor cells.Mol Biol Cell. 2015 Dec 15;26(25):4552-61. doi: 10.1091/mbc.E15-05-0270. Epub 2015 Oct 14.
• [9] A newly discovered mutation in PICK1 in a human with globozoospermia. Asian J Androl. 2010 Jul;12(4):556-60. doi: 10.1038/aja.2010.47. Epub 2010 Jun 21.
• [10] Protein interacting with C kinase and neurological disorders.Synapse. 2013 Aug;67(8):532-40. doi: 10.1002/syn.21657. Epub 2013 Mar 20.
• [11] PKC alpha mediates beta-arrestin2-dependent nephrin endocytosis in hyperglycemia.J Biol Chem. 2011 Apr 15;286(15):12959-70. doi: 10.1074/jbc.M110.204024. Epub 2011 Feb 14.
• [12] Protein interacting with C kinase (PICK1) is a suppressor of spinocerebellar ataxia 3-associated neurodegeneration in Drosophila.Hum Mol Genet. 2012 Jan 1;21(1):76-84. doi: 10.1093/hmg/ddr439. Epub 2011 Sep 23.
• [13] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [14] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [15] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [16] 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.
• [17] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [18] 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.
• [19] Identification of functional polymorphisms in the promoter region of the human PICK1 gene and their association with methamphetamine psychosis. Am J Psychiatry. 2007 Jul;164(7):1105-14. doi: 10.1176/ajp.2007.164.7.1105.