Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT80M3BV)

• DOT Name: Serine/threonine-protein kinase PAK 3 (PAK3)
• Synonyms: EC 2.7.11.1; Beta-PAK; Oligophrenin-3; p21-activated kinase 3; PAK-3
• Gene Name: PAK3
• Related Disease:
  Intellectual disability, X-linked 30
  Partington syndrome
  Scleroderma
  Systemic sclerosis
  X-linked syndromic intellectual disability
  Advanced cancer
  Alzheimer disease
  Borjeson-Forssman-Lehmann syndrome
  Carcinoid tumor
  Cerebral palsy
  Classic Hodgkin lymphoma
  Congenital contractural arachnodactyly
  Corpus callosum, agenesis of
  Epilepsy
  Epithelial ovarian cancer
  Ewing sarcoma
  Hepatitis C virus infection
  Hydrocephalus
  Hydrocephalus, nonsyndromic, autosomal recessive 1
  Intellectual disability
  Intellectual disability, X-linked 1
  Keratoconjunctivitis
  Leukemia
  Leukopenia
  Megalencephaly
  Neoplasm
  Neuroendocrine neoplasm
  Obesity
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Prostate cancer
  Prostate carcinoma
  Psychotic disorder
  Rheumatoid arthritis
  Schizophrenia
  Systemic lupus erythematosus
  X-linked intellectual disability
  Chronic hepatitis B virus infection
  High blood pressure
  Non-syndromic X-linked intellectual disability
  Cognitive impairment
  Fetal growth restriction
  Stroke
• UniProt ID: PAK3_HUMAN
• PDB ID: 6FD3
• EC Number: 2.7.11.1
• Pfam ID: PF00786 ; PF00069
• Sequence:
  MSDGLDNEEKPPAPPLRMNSNNRDSSALNHSSKPLPMAPEEKNKKARLRSIFPGGGDKTN
  KKKEKERPEISLPSDFEHTIHVGFDAVTGEFTPDLYGSQMCPGKLPEGIPEQWARLLQTS
  NITKLEQKKNPQAVLDVLKFYDSKETVNNQKYMSFTSGDKSAHGYIAAHPSSTKTASEPP
  LAPPVSEEEDEEEEEEEDENEPPPVIAPRPEHTKSIYTRSVVESIASPAVPNKEVTPPSA
  ENANSSTLYRNTDRQRKKSKMTDEEILEKLRSIVSVGDPKKKYTRFEKIGQGASGTVYTA
  LDIATGQEVAIKQMNLQQQPKKELIINEILVMRENKNPNIVNYLDSYLVGDELWVVMEYL
  AGGSLTDVVTETCMDEGQIAAVCRECLQALDFLHSNQVIHRDIKSDNILLGMDGSVKLTD
  FGFCAQITPEQSKRSTMVGTPYWMAPEVVTRKAYGPKVDIWSLGIMAIEMVEGEPPYLNE
  NPLRALYLIATNGTPELQNPERLSAVFRDFLNRCLEMDVDRRGSAKELLQHPFLKLAKPL
  SSLTPLIIAAKEAIKNSSR
• Function: Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, or cell cycle regulation. Plays a role in dendrite spine morphogenesis as well as synapse formation and plasticity. Acts as a downstream effector of the small GTPases CDC42 and RAC1. Activation by the binding of active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates MAPK4 and MAPK6 and activates the downstream target MAPKAPK5, a regulator of F-actin polymerization and cell migration. Additionally, phosphorylates TNNI3/troponin I to modulate calcium sensitivity and relaxation kinetics of thin myofilaments. May also be involved in early neuronal development. In hippocampal neurons, necessary for the formation of dendritic spines and excitatory synapses; this function is dependent on kinase activity and may be exerted by the regulation of actomyosin contractility through the phosphorylation of myosin II regulatory light chain (MLC).
• Tissue Specificity: Restricted to the nervous system. Highly expressed in postmitotic neurons of the developing and postnatal cerebral cortex and hippocampus.
• KEGG Pathway:
  ErbB sig.ling pathway (hsa04012)
  Ras sig.ling pathway (hsa04014)
  Axon guidance (hsa04360)
  Focal adhesion (hsa04510)
  T cell receptor sig.ling pathway (hsa04660)
  Regulation of actin cytoskeleton (hsa04810)
  Pathogenic Escherichia coli infection (hsa05130)
  Salmonella infection (hsa05132)
  Human immunodeficiency virus 1 infection (hsa05170)
  Re.l cell carcinoma (hsa05211)
• Reactome Pathway:
  CD28 dependent Vav1 pathway (R-HSA-389359)
  Ephrin signaling (R-HSA-3928664)
  Sema3A PAK dependent Axon repulsion (R-HSA-399954)
  Activation of RAC1 (R-HSA-428540)
  VEGFR2 mediated vascular permeability (R-HSA-5218920)
  CD209 (DC-SIGN) signaling (R-HSA-5621575)
  RHO GTPases activate PAKs (R-HSA-5627123)
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RHOJ GTPase cycle (R-HSA-9013409)
  RHOU GTPase cycle (R-HSA-9013420)
  Generation of second messenger molecules (R-HSA-202433)

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, X-linked 30	DISOEQO6	Definitive	X-linked	[1]
Partington syndrome	DIS3H205	Definitive	Biomarker	[2]
Scleroderma	DISVQ342	Definitive	Genetic Variation	[3]
Systemic sclerosis	DISF44L6	Definitive	Genetic Variation	[3]
X-linked syndromic intellectual disability	DISG1YOH	Definitive	X-linked	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[6]
Borjeson-Forssman-Lehmann syndrome	DISJ5QNF	Strong	Biomarker	[7]
Carcinoid tumor	DISMNRDC	Strong	Altered Expression	[8]
Cerebral palsy	DIS82ODL	Strong	Genetic Variation	[9]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[10]
Congenital contractural arachnodactyly	DISOM1K7	Strong	Genetic Variation	[11]
Corpus callosum, agenesis of	DISO9P40	Strong	Genetic Variation	[11]
Epilepsy	DISBB28L	Strong	Genetic Variation	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[12]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[13]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[14]
Hydrocephalus	DISIZUF7	Strong	Genetic Variation	[11]
Hydrocephalus, nonsyndromic, autosomal recessive 1	DISCYZI4	Strong	Genetic Variation	[11]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[11]
Intellectual disability, X-linked 1	DISET38E	Strong	GermlineCausalMutation	[15]
Keratoconjunctivitis	DISOYCQC	Strong	Biomarker	[16]
Leukemia	DISNAKFL	Strong	Biomarker	[17]
Leukopenia	DISJMBMM	Strong	Biomarker	[18]
Megalencephaly	DISYW5SV	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Neuroendocrine neoplasm	DISNPLOO	Strong	Altered Expression	[8]
Obesity	DIS47Y1K	Strong	Biomarker	[19]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[12]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[12]
Pancreatic cancer	DISJC981	Strong	Biomarker	[5]
Prostate cancer	DISF190Y	Strong	Biomarker	[20]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[20]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[21]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[22]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[23]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[24]
X-linked intellectual disability	DISYJBY3	Strong	Genetic Variation	[15]
Chronic hepatitis B virus infection	DISHL4NT	moderate	Altered Expression	[25]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[26]
Non-syndromic X-linked intellectual disability	DIS71AI3	Supportive	X-linked	[15]
Cognitive impairment	DISH2ERD	Limited	Biomarker	[27]
Fetal growth restriction	DIS5WEJ5	Limited	Biomarker	[28]
Stroke	DISX6UHX	Limited	Biomarker	[29]

7 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 Serine/threonine-protein kinase PAK 3 (PAK3).	[30]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Serine/threonine-protein kinase PAK 3 (PAK3).	[31]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Serine/threonine-protein kinase PAK 3 (PAK3).	[32]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Serine/threonine-protein kinase PAK 3 (PAK3).	[33]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Serine/threonine-protein kinase PAK 3 (PAK3).	[34]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Serine/threonine-protein kinase PAK 3 (PAK3).	[35]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Serine/threonine-protein kinase PAK 3 (PAK3).	[30]

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 Serine/threonine-protein kinase PAK 3 (PAK3).	[36]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Serine/threonine-protein kinase PAK 3 (PAK3).	[37]

References

• [1] Gene for nonspecific X-linked mental retardation (MRX 47) is located in Xq22.3-q24. Am J Med Genet. 1997 Oct 31;72(3):324-8. doi: 10.1002/(sici)1096-8628(19971031)72:3<324::aid-ajmg14>3.0.co;2-v.
• [2] Improvement of Self-Injury With Dopamine and Serotonin Replacement Therapy in a Patient With a Hemizygous PAK3 Mutation: A New Therapeutic Strategy for Neuropsychiatric Features of an Intellectual Disability Syndrome.J Child Neurol. 2018 Jan;33(1):106-113. doi: 10.1177/0883073817740443.
• [3] HLA antigens, autoantibodies and clinical subsets in scleroderma.Br J Rheumatol. 1984 Nov;23(4):267-71. doi: 10.1093/rheumatology/23.4.267.
• [4] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [5] p21-Activated kinase 3 promotes cancer stem cell phenotypes through activating the Akt-GSK3--catenin signaling pathway in pancreatic cancer cells.Cancer Lett. 2019 Aug 1;456:13-22. doi: 10.1016/j.canlet.2019.04.026. Epub 2019 Apr 30.
• [6] Synaptic actin stabilization protein loss in Down syndrome and Alzheimer disease.Brain Pathol. 2020 Mar;30(2):319-331. doi: 10.1111/bpa.12779. Epub 2019 Sep 8.
• [7] Characterization of ARHGEF6, a guanine nucleotide exchange factor for Rho GTPases and a candidate gene for X-linked mental retardation: mutation screening in Brjeson-Forssman-Lehmann syndrome and MRX27.Am J Med Genet. 2001 Apr 15;100(1):43-8. doi: 10.1002/ajmg.1189.
• [8] p21-activated kinase 3 is overexpressed in thymic neuroendocrine tumors (carcinoids) with ectopic ACTH syndrome and participates in cell migration.Endocrine. 2010 Aug;38(1):38-47. doi: 10.1007/s12020-010-9324-6. Epub 2010 May 4.
• [9] A de novo mutation in the X-linked PAK3 gene is the underlying cause of intellectual disability and macrocephaly in monozygotic twins.Eur J Med Genet. 2017 Apr;60(4):212-216. doi: 10.1016/j.ejmg.2017.01.004. Epub 2017 Jan 24.
• [10] Transfection of caspase-3 in the caspase-3-deficient Hodgkin's disease cell line, KMH2, results in enhanced sensitivity to CD95-, TRAIL-, and ARA-C-induced apoptosis.Exp Hematol. 2001 May;29(5):572-81. doi: 10.1016/s0301-472x(01)00627-0.
• [11] PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration.Neurobiol Dis. 2020 Mar;136:104709. doi: 10.1016/j.nbd.2019.104709. Epub 2019 Dec 14.
• [12] miR-193b-3p possesses anti-tumor activity in ovarian carcinoma cells by targeting p21-activated kinase 3.Biomed Pharmacother. 2017 Dec;96:1275-1282. doi: 10.1016/j.biopha.2017.11.086. Epub 2017 Nov 21.
• [13] Signature-based small molecule screening identifies cytosine arabinoside as an EWS/FLI modulator in Ewing sarcoma.PLoS Med. 2007 Apr;4(4):e122. doi: 10.1371/journal.pmed.0040122.
• [14] Efficacy and Pharmacokinetics of Glecaprevir and Pibrentasvir With Concurrent Use of Acid-Reducing Agents in Patients With Chronic HCV Infection.Clin Gastroenterol Hepatol. 2019 Feb;17(3):527-535.e6. doi: 10.1016/j.cgh.2018.07.003. Epub 2018 Sep 10.
• [15] A novel splice mutation in PAK3 gene underlying mental retardation with neuropsychiatric features. Eur J Hum Genet. 2008 Nov;16(11):1358-63. doi: 10.1038/ejhg.2008.103. Epub 2008 Jun 4.
• [16] N-acetylcysteine supplementation reduces oxidative stress for cytosine arabinoside in rat model.Int Ophthalmol. 2017 Feb;37(1):209-214. doi: 10.1007/s10792-016-0259-7. Epub 2016 May 23.
• [17] An 1H NMR study of the cytarabine degradation in clinical conditions to avoid drug waste, decrease therapy costs and improve patient compliance in acute leukemia.Anticancer Drugs. 2020 Jan;31(1):67-72. doi: 10.1097/CAD.0000000000000850.
• [18] Intensive consolidation with G-CSF support: Tolerability, safety, reduced hospitalization, and efficacy in acute myeloid leukemia patients ?0 years.Am J Hematol. 2017 Oct;92(10):E567-E574. doi: 10.1002/ajh.24847. Epub 2017 Aug 17.
• [19] The Root of Atractylodes macrocephala Koidzumi Prevents Obesity and Glucose Intolerance and Increases Energy Metabolism in Mice.Int J Mol Sci. 2018 Jan 17;19(1):278. doi: 10.3390/ijms19010278.
• [20] Functional analysis of androgen receptor N-terminal and ligand binding domain interacting coregulators in prostate cancer.J Formos Med Assoc. 2000 Dec;99(12):885-94.
• [21] Sequence analysis of P21-activated kinase 3 (PAK3) in chronic schizophrenia with cognitive impairment.Schizophr Res. 2008 Dec;106(2-3):265-7. doi: 10.1016/j.schres.2008.08.021. Epub 2008 Sep 20.
• [22] Coexistent rheumatoid arthritis and gout: a case series and review of the literature.Clin Rheumatol. 2017 Dec;36(12):2835-2838. doi: 10.1007/s10067-017-3856-6. Epub 2017 Oct 12.
• [23] Functional analysis of rare variants found in schizophrenia implicates a critical role for GIT1-PAK3 signaling in neuroplasticity.Mol Psychiatry. 2017 Mar;22(3):417-429. doi: 10.1038/mp.2016.98. Epub 2016 Jul 26.
• [24] A family survey of lupus erythematosus. 1. Heritability.J Rheumatol. 1987 Oct;14(5):913-21.
• [25] Differential effect of ARA-AMP on serum DNA polymerase activity and serum HBV-DNA in chronic hepatitis B virus infection. A possible reason for lack of efficacy.J Hepatol. 1986;3 Suppl 2:S81-6. doi: 10.1016/s0168-8278(86)80104-0.
• [26] The role of a FADS1 polymorphism in the association of fatty acid blood levels, BMI and blood pressure in young children-Analyses based on path models.PLoS One. 2017 Jul 21;12(7):e0181485. doi: 10.1371/journal.pone.0181485. eCollection 2017.
• [27] The mental retardation protein PAK3 contributes to synapse formation and plasticity in hippocampus.J Neurosci. 2004 Dec 1;24(48):10816-25. doi: 10.1523/JNEUROSCI.2931-04.2004.
• [28] Effects of Arachidonic and Docosohexahenoic Acid Supplementation during Gestation in Rats. Implication of Placental Oxidative Stress.Int J Mol Sci. 2018 Dec 4;19(12):3863. doi: 10.3390/ijms19123863.
• [29] The Adult Assisting Hand Assessment Stroke: Psychometric Properties of an Observation-Based Bimanual Upper Limb Performance Measurement.Arch Phys Med Rehabil. 2018 Dec;99(12):2513-2522. doi: 10.1016/j.apmr.2018.04.025. Epub 2018 May 26.
• [30] 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.
• [31] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [32] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [33] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [34] 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.
• [35] Comparison of gene expression profiles in HepG2 cells exposed to arsenic, cadmium, nickel, and three model carcinogens for investigating the mechanisms of metal carcinogenesis. Environ Mol Mutagen. 2009 Jan;50(1):46-59.
• [36] 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.
• [37] 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.