Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT32WQGL)

• DOT Name: Serine/threonine-protein kinase PAK 5 (PAK5)
• Synonyms: EC 2.7.11.1; p21-activated kinase 5; PAK-5; p21-activated kinase 7; PAK-7
• Gene Name: PAK5
• Related Disease:
  Esophageal squamous cell carcinoma
  Bladder cancer
  Bone osteosarcoma
  Cervical cancer
  Cervical carcinoma
  Colon cancer
  Colon carcinoma
  Epithelial ovarian cancer
  Glioma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Psychotic disorder
  Urinary bladder cancer
  Urinary bladder neoplasm
  Breast cancer
  Breast carcinoma
  Gastric cancer
  Lupus nephritis
  Neuroblastoma
  Stomach cancer
  Advanced cancer
  Glaucoma/ocular hypertension
  Psoriasis
• UniProt ID: PAK5_HUMAN
• PDB ID: 2F57; 8C12
• EC Number: 2.7.11.1
• Pfam ID: PF00786 ; PF00069
• Sequence:
  MFGKKKKKIEISGPSNFEHRVHTGFDPQEQKFTGLPQQWHSLLADTANRPKPMVDPSCIT
  PIQLAPMKTIVRGNKPCKETSINGLLEDFDNISVTRSNSLRKESPPTPDQGASSHGPGHA
  EENGFITFSQYSSESDTTADYTTEKYREKSLYGDDLDPYYRGSHAAKQNGHVMKMKHGEA
  YYSEVKPLKSDFARFSADYHSHLDSLSKPSEYSDLKWEYQRASSSSPLDYSFQFTPSRTA
  GTSGCSKESLAYSESEWGPSLDDYDRRPKSSYLNQTSPQPTMRQRSRSGSGLQEPMMPFG
  ASAFKTHPQGHSYNSYTYPRLSEPTMCIPKVDYDRAQMVLSPPLSGSDTYPRGPAKLPQS
  QSKSGYSSSSHQYPSGYHKATLYHHPSLQSSSQYISTASYLSSLSLSSSTYPPPSWGSSS
  DQQPSRVSHEQFRAALQLVVSPGDPREYLANFIKIGEGSTGIVCIATEKHTGKQVAVKKM
  DLRKQQRRELLFNEVVIMRDYHHDNVVDMYSSYLVGDELWVVMEFLEGGALTDIVTHTRM
  NEEQIATVCLSVLRALSYLHNQGVIHRDIKSDSILLTSDGRIKLSDFGFCAQVSKEVPKR
  KSLVGTPYWMAPEVISRLPYGTEVDIWSLGIMVIEMIDGEPPYFNEPPLQAMRRIRDSLP
  PRVKDLHKVSSVLRGFLDLMLVREPSQRATAQELLGHPFLKLAGPPSCIVPLMRQYRHH
• Function: Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, proliferation or cell survival. Activation by various effectors including growth factor receptors or active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates the proto-oncogene RAF1 and stimulates its kinase activity. Promotes cell survival by phosphorylating the BCL2 antagonist of cell death BAD. Phosphorylates CTNND1, probably to regulate cytoskeletal organization and cell morphology. Keeps microtubules stable through MARK2 inhibition and destabilizes the F-actin network leading to the disappearance of stress fibers and focal adhesions.
• Tissue Specificity: Predominantly expressed in brain.
• 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)
  Human immunodeficiency virus 1 infection (hsa05170)
  Re.l cell carcinoma (hsa05211)
• Reactome Pathway:
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RHOD GTPase cycle (R-HSA-9013405)
  RHOH GTPase cycle (R-HSA-9013407)
  Activation of RAC1 (R-HSA-428540)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Esophageal squamous cell carcinoma	DIS5N2GV	Definitive	Altered Expression	[1]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[2]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[3]
Cervical cancer	DISFSHPF	Strong	Biomarker	[4]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Strong	Altered Expression	[5]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[6]
Glioma	DIS5RPEH	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[8]
Lung cancer	DISCM4YA	Strong	Biomarker	[9]
Lung carcinoma	DISTR26C	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[10]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[3]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[6]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[6]
Psychotic disorder	DIS4UQOT	Strong	Altered Expression	[11]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	moderate	Biomarker	[12]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[12]
Gastric cancer	DISXGOUK	moderate	Biomarker	[13]
Lupus nephritis	DISCVGPZ	moderate	Genetic Variation	[14]
Neuroblastoma	DISVZBI4	moderate	Altered Expression	[15]
Stomach cancer	DISKIJSX	moderate	Biomarker	[13]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[16]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Genetic Variation	[17]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[18]

4 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 Serine/threonine-protein kinase PAK 5 (PAK5).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Serine/threonine-protein kinase PAK 5 (PAK5).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Serine/threonine-protein kinase PAK 5 (PAK5).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Serine/threonine-protein kinase PAK 5 (PAK5).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Serine/threonine-protein kinase PAK 5 (PAK5).	[20]

References

• [1] Over expression of p21-activated kinase 7 associates with lymph node metastasis in esophageal squamous cell cancers.Cancer Biomark. 2016;16(2):203-9. doi: 10.3233/CBM-150557.
• [2] PAK5 mediates cell: cell adhesion integrity via interaction with E-cadherin in bladder cancer cells.Biochem J. 2017 Mar 24;474(8):1333-1346. doi: 10.1042/BCJ20160875.
• [3] PAK5 overexpression is associated with lung metastasis in osteosarcoma.Oncol Lett. 2018 Feb;15(2):2202-2210. doi: 10.3892/ol.2017.7545. Epub 2017 Dec 7.
• [4] PAK5 promotes the migration and invasion of cervical cancer cells by phosphorylating SATB1.Cell Death Differ. 2019 Jun;26(6):994-1006. doi: 10.1038/s41418-018-0178-4. Epub 2018 Aug 6.
• [5] PAK5-mediated E47 phosphorylation promotes epithelial-mesenchymal transition and metastasis of colon cancer.Oncogene. 2016 Apr 14;35(15):1943-54. doi: 10.1038/onc.2015.259. Epub 2015 Jul 27.
• [6] PAK5 Induces EMT and Promotes Cell Migration and Invasion by Activating the PI3K/AKT Pathway in Ovarian Cancer.Anal Cell Pathol (Amst). 2018 Sep 2;2018:8073124. doi: 10.1155/2018/8073124. eCollection 2018.
• [7] miR?89 promotes apoptosis and inhibits invasiveness of glioma cells by targeting PAK5/RAF1 signaling pathways.Oncol Rep. 2019 Dec;42(6):2390-2401. doi: 10.3892/or.2019.7381. Epub 2019 Oct 22.
• [8] MicroRNA-526a targets p21-activated kinase 7 to inhibit tumorigenesis in hepatocellular carcinoma.Mol Med Rep. 2017 Jul;16(1):837-844. doi: 10.3892/mmr.2017.6658. Epub 2017 May 31.
• [9] Targeted genetic dependency screen facilitates identification of actionable mutations in FGFR4, MAP3K9, and PAK5 in lung cancer.Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):12426-31. doi: 10.1073/pnas.1305207110. Epub 2013 Jul 8.
• [10] Correlation between chemotherapy resistance in osteosarcoma patients and PAK5 and Ezrin gene expression.Oncol Lett. 2018 Jan;15(1):879-884. doi: 10.3892/ol.2017.7355. Epub 2017 Nov 6.
• [11] An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis.Hum Mol Genet. 2014 Jun 15;23(12):3316-26. doi: 10.1093/hmg/ddu025. Epub 2014 Jan 28.
• [12] A PAK5-DNPEP-USP4 axis dictates breast cancer growth and metastasis.Int J Cancer. 2020 Feb 15;146(4):1139-1151. doi: 10.1002/ijc.32523. Epub 2019 Jun 20.
• [13] High expression of P21-activated kinase 5 protein is associated with poor survival in gastric cancer.Oncol Lett. 2017 Jul;14(1):404-410. doi: 10.3892/ol.2017.6115. Epub 2017 May 3.
• [14] Detecting Genetic Associations between ATG5 and Lupus Nephritis by trans-eQTL.J Immunol Res. 2015;2015:153132. doi: 10.1155/2015/153132. Epub 2015 Oct 5.
• [15] Nucleocytoplasmic shuttling of Pak5 regulates its antiapoptotic properties.Mol Cell Biol. 2006 Apr;26(8):3215-30. doi: 10.1128/MCB.26.8.3215-3230.2006.
• [16] Human p21-activated kinase 5 (PAK5) expression and potential mechanisms in relevant cancers: Basic and clinical perspectives for molecular cancer therapeutics.Life Sci. 2020 Jan 15;241:117113. doi: 10.1016/j.lfs.2019.117113. Epub 2019 Dec 2.
• [17] Copy number variations and primary open-angle glaucoma.Invest Ophthalmol Vis Sci. 2011 Sep 9;52(10):7122-33. doi: 10.1167/iovs.10-5606. Print 2011.
• [18] Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility.Nat Commun. 2015 Apr 23;6:6916. doi: 10.1038/ncomms7916.
• [19] 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.
• [20] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [21] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [22] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [23] 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.