Details of Drug Off-Target (DOT)

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

• DOT Name: Neurabin-2 (PPP1R9B)
• Synonyms: Neurabin-II; Protein phosphatase 1 regulatory subunit 9B; Spinophilin
• Gene Name: PPP1R9B
• Related Disease:
  Glioma
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Colon adenocarcinoma
  Colon carcinoma
  Colorectal carcinoma
  Craniosynostosis
  Hepatocellular carcinoma
  Lung neoplasm
  Major depressive disorder
  Metastatic malignant neoplasm
  Mood disorder
  Obsessive compulsive disorder
  Parkinson disease
  Schizophrenia
  Advanced cancer
  High blood pressure
  Neoplasm
  Anxiety
  Anxiety disorder
  Breast neoplasm
  Lung cancer
  Lung carcinoma
  Sinusitis
• UniProt ID: NEB2_HUMAN
• Pfam ID: PF00595 ; PF17817
• Sequence:
  MMKTEPRGPGGPLRSASPHRSAYEAGIQALKPPDAPGPDEAPKGAHHKKYGSNVHRIKSM
  FLQMGTTAGPSGEAGGGAGLAEAPRASERGVRLSLPRASSLNENVDHSALLKLGTSVSER
  VSRFDSKPAPSAQPAPPPHPPSRLQETRKLFERSAPAAAGGDKEAAARRLLRQERAGLQD
  RKLDVVVRFNGSTEALDKLDADAVSPTVSQLSAVFEKADSRTGLHRGPGLPRAAGVPQVN
  SKLVSKRSRVFQPPPPPPPAPSGDAPAEKERCPAGQQPPQHRVAPARPPPKPREVRKIKP
  VEVEESGESEAESAPGEVIQAEVTVHAALENGSTVATAASPAPEEPKAQAAPEKEAAAVA
  PPERGVGNGRAPDVAPEEVDESKKEDFSEADLVDVSAYSGLGEDSAGSALEEDDEDDEED
  GEPPYEPESGCVEIPGLSEEEDPAPSRKIHFSTAPIQVFSTYSNEDYDRRNEDVDPMAAS
  AEYELEKRVERLELFPVELEKDSEGLGISIIGMGAGADMGLEKLGIFVKTVTEGGAAHRD
  GRIQVNDLLVEVDGTSLVGVTQSFAASVLRNTKGRVRFMIGRERPGEQSEVAQLIQQTLE
  QERWQREMMEQRYAQYGEDDEETGEYATDEDEELSPTFPGGEMAIEVFELAENEDALSPV
  DMEPEKLVHKFKELQIKHAVTEAEIQQLKRKLQSLEQEKGRWRVEKAQLEQSVEENKERM
  EKLEGYWGEAQSLCQAVDEHLRETQAQYQALERKYSKAKRLIKDYQQKEIEFLKKETAQR
  RVLEESELARKEEMDKLLDKISELEGNLQTLRNSNST
• Function: Seems to act as a scaffold protein in multiple signaling pathways. Modulates excitatory synaptic transmission and dendritic spine morphology. Binds to actin filaments (F-actin) and shows cross-linking activity. Binds along the sides of the F-actin. May play an important role in linking the actin cytoskeleton to the plasma membrane at the synaptic junction. Believed to target protein phosphatase 1/PP1 to dendritic spines, which are rich in F-actin, and regulates its specificity toward ion channels and other substrates, such as AMPA-type and NMDA-type glutamate receptors. Plays a role in regulation of G-protein coupled receptor signaling, including dopamine D2 receptors and alpha-adrenergic receptors. May establish a signaling complex for dopaminergic neurotransmission through D2 receptors by linking receptors downstream signaling molecules and the actin cytoskeleton. Binds to ADRA1B and RGS2 and mediates regulation of ADRA1B signaling. May confer to Rac signaling specificity by binding to both, RacGEFs and Rac effector proteins. Probably regulates p70 S6 kinase activity by forming a complex with TIAM1. Required for hepatocyte growth factor (HGF)-induced cell migration.

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioma	DIS5RPEH	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Colon adenocarcinoma	DISDRE0J	Strong	Altered Expression	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[4]
Craniosynostosis	DIS6J405	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[7]
Lung neoplasm	DISVARNB	Strong	Biomarker	[8]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[9]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[3]
Mood disorder	DISLVMWO	Strong	Biomarker	[9]
Obsessive compulsive disorder	DIS1ZMM2	Strong	Biomarker	[10]
Parkinson disease	DISQVHKL	Strong	Biomarker	[11]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[12]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[13]
High blood pressure	DISY2OHH	moderate	Biomarker	[14]
Neoplasm	DISZKGEW	moderate	Biomarker	[13]
Anxiety	DISIJDBA	Limited	Biomarker	[15]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[15]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[13]
Lung cancer	DISCM4YA	Limited	Biomarker	[8]
Lung carcinoma	DISTR26C	Limited	Biomarker	[8]
Sinusitis	DISX5NCF	Limited	Biomarker	[6]

3 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 Neurabin-2 (PPP1R9B).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Neurabin-2 (PPP1R9B).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Neurabin-2 (PPP1R9B).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Neurabin-2 (PPP1R9B).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Neurabin-2 (PPP1R9B).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Neurabin-2 (PPP1R9B).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Neurabin-2 (PPP1R9B).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Neurabin-2 (PPP1R9B).	[22]

References

• [1] Doublecortin induces mitotic microtubule catastrophe and inhibits glioma cell invasion.J Neurochem. 2009 Jan;108(1):231-45. doi: 10.1111/j.1471-4159.2008.05758.x.
• [2] Tyrosol Reduces Amyloid- Oligomer Neurotoxicity and Alleviates Synaptic, Oxidative, and Cognitive Disturbances in Alzheimer's Disease Model Mice.J Alzheimers Dis. 2019;70(3):937-952. doi: 10.3233/JAD-190098.
• [3] Low spinophilin expression enhances aggressive biological behavior of breast cancer.Oncotarget. 2015 May 10;6(13):11191-202. doi: 10.18632/oncotarget.3586.
• [4] Spinophilin expression determines cellular growth, cancer stemness and 5-flourouracil resistance in colorectal cancer.Oncotarget. 2014 Sep 30;5(18):8492-502. doi: 10.18632/oncotarget.2329.
• [5] Spinophilin loss correlates with poor patient prognosis in advanced stages of colon carcinoma.Clin Cancer Res. 2013 Jul 15;19(14):3925-35. doi: 10.1158/1078-0432.CCR-13-0057. Epub 2013 May 31.
• [6] Gene expression profiling of nasal polyps associated with chronic sinusitis and aspirin-sensitive asthma.Laryngoscope. 2008 May;118(5):881-9. doi: 10.1097/MLG.0b013e31816b4b6f.
• [7] Low expression of the putative tumour suppressor spinophilin is associated with higher proliferative activity and poor prognosis in patients with hepatocellular carcinoma.Br J Cancer. 2013 May 14;108(9):1830-7. doi: 10.1038/bjc.2013.165. Epub 2013 Apr 16.
• [8] Coordinated downregulation of Spinophilin and the catalytic subunits of PP1, PPP1CA/B/C, contributes to a worse prognosis in lung cancer.Oncotarget. 2017 Oct 26;8(62):105196-105210. doi: 10.18632/oncotarget.22111. eCollection 2017 Dec 1.
• [9] CAPON Is a Critical Protein in Synaptic Molecular Networks in the Prefrontal Cortex of Mood Disorder Patients and Contributes to Depression-Like Behavior in a Mouse Model.Cereb Cortex. 2019 Aug 14;29(9):3752-3765. doi: 10.1093/cercor/bhy254.
• [10] The association of spinophilin with disks large-associated protein 3 (SAPAP3) is regulated by metabotropic glutamate receptor (mGluR) 5.Mol Cell Neurosci. 2018 Jun 14;90:60-69. doi: 10.1016/j.mcn.2018.06.001. Online ahead of print.
• [11] Mechanisms Regulating the Association of Protein Phosphatase 1 with Spinophilin and Neurabin.ACS Chem Neurosci. 2018 Nov 21;9(11):2701-2712. doi: 10.1021/acschemneuro.8b00144. Epub 2018 Jun 1.
• [12] Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
• [13] Loss of the tumor suppressor spinophilin (PPP1R9B) increases the cancer stem cell population in breast tumors.Oncogene. 2016 May;35(21):2777-88. doi: 10.1038/onc.2015.341. Epub 2015 Sep 21.
• [14] Spinophilin Is Indispensable for the 2B Adrenergic Receptor-Elicited Hypertensive Response.PLoS One. 2015 Aug 5;10(8):e0135030. doi: 10.1371/journal.pone.0135030. eCollection 2015.
• [15] Age-dependent differential regulation of anxiety- and depression-related behaviors by neurabin and spinophilin.PLoS One. 2017 Jul 10;12(7):e0180638. doi: 10.1371/journal.pone.0180638. eCollection 2017.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [21] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] 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.