Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCNZAJ5)

DOT Name Alpha-actinin-4 (ACTN4)
Synonyms Non-muscle alpha-actinin 4
Gene Name ACTN4
Related Disease
Melanoma ( )
Pancreatic cancer ( )
Adult glioblastoma ( )
Bladder cancer ( )
Carcinoma ( )
Chronic renal failure ( )
Colorectal carcinoma ( )
End-stage renal disease ( )
Epithelial ovarian cancer ( )
Esophageal squamous cell carcinoma ( )
Focal segmental glomerulosclerosis ( )
Focal segmental glomerulosclerosis 1 ( )
Glioblastoma multiforme ( )
Hepatocellular carcinoma ( )
IgA nephropathy ( )
Kidney failure ( )
Lung carcinoma ( )
Membranous glomerulonephritis ( )
Nephronophthisis ( )
Nephropathy ( )
Nephrotic syndrome ( )
Ovarian cancer ( )
Ovarian neoplasm ( )
Small-cell lung cancer ( )
Squamous cell carcinoma ( )
Urinary bladder cancer ( )
Urinary bladder neoplasm ( )
Wilms tumor ( )
Breast cancer ( )
Breast carcinoma ( )
Glomerulosclerosis ( )
High blood pressure ( )
Lung adenocarcinoma ( )
Lung cancer ( )
Macular corneal dystrophy ( )
Familial idiopathic steroid-resistant nephrotic syndrome ( )
Cervical cancer ( )
Cervical carcinoma ( )
Gastric cancer ( )
Nephrotic syndrome, type 2 ( )
Non-small-cell lung cancer ( )
Stomach cancer ( )
Undifferentiated carcinoma ( )
UniProt ID
ACTN4_HUMAN
3D Structure
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2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
1WLX; 1YDI; 2R0O; 6O31; 6OA6
Pfam ID
PF00307 ; PF08726 ; PF00435
Sequence
MVDYHAANQSYQYGPSSAGNGAGGGGSMGDYMAQEDDWDRDLLLDPAWEKQQRKTFTAWC
NSHLRKAGTQIENIDEDFRDGLKLMLLLEVISGERLPKPERGKMRVHKINNVNKALDFIA
SKGVKLVSIGAEEIVDGNAKMTLGMIWTIILRFAIQDISVEETSAKEGLLLWCQRKTAPY
KNVNVQNFHISWKDGLAFNALIHRHRPELIEYDKLRKDDPVTNLNNAFEVAEKYLDIPKM
LDAEDIVNTARPDEKAIMTYVSSFYHAFSGAQKAETAANRICKVLAVNQENEHLMEDYEK
LASDLLEWIRRTIPWLEDRVPQKTIQEMQQKLEDFRDYRRVHKPPKVQEKCQLEINFNTL
QTKLRLSNRPAFMPSEGKMVSDINNGWQHLEQAEKGYEEWLLNEIRRLERLDHLAEKFRQ
KASIHEAWTDGKEAMLKHRDYETATLSDIKALIRKHEAFESDLAAHQDRVEQIAAIAQEL
NELDYYDSHNVNTRCQKICDQWDALGSLTHSRREALEKTEKQLEAIDQLHLEYAKRAAPF
NNWMESAMEDLQDMFIVHTIEEIEGLISAHDQFKSTLPDADREREAILAIHKEAQRIAES
NHIKLSGSNPYTTVTPQIINSKWEKVQQLVPKRDHALLEEQSKQQSNEHLRRQFASQANV
VGPWIQTKMEEIGRISIEMNGTLEDQLSHLKQYERSIVDYKPNLDLLEQQHQLIQEALIF
DNKHTNYTMEHIRVGWEQLLTTIARTINEVENQILTRDAKGISQEQMQEFRASFNHFDKD
HGGALGPEEFKACLISLGYDVENDRQGEAEFNRIMSLVDPNHSGLVTFQAFIDFMSRETT
DTDTADQVIASFKVLAGDKNFITAEELRRELPPDQAEYCIARMAPYQGPDAVPGALDYKS
FSTALYGESDL
Function
F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein (Probable). Probably involved in vesicular trafficking via its association with the CART complex. The CART complex is necessary for efficient transferrin receptor recycling but not for EGFR degradation. Involved in tight junction assembly in epithelial cells probably through interaction with MICALL2. Links MICALL2 to the actin cytoskeleton and recruits it to the tight junctions. May also function as a transcriptional coactivator, stimulating transcription mediated by the nuclear hormone receptors PPARG and RARA.
Tissue Specificity Widely expressed.
KEGG Pathway
Focal adhesion (hsa04510 )
Adherens junction (hsa04520 )
Tight junction (hsa04530 )
Leukocyte transendothelial migration (hsa04670 )
Regulation of actin cytoskeleton (hsa04810 )
Shigellosis (hsa05131 )
Amoebiasis (hsa05146 )
Viral carcinogenesis (hsa05203 )
Systemic lupus erythematosus (hsa05322 )
Reactome Pathway
Nephrin family interactions (R-HSA-373753 )
Platelet degranulation (R-HSA-114608 )

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Melanoma DIS1RRCY Definitive Biomarker [1]
Pancreatic cancer DISJC981 Definitive Altered Expression [2]
Adult glioblastoma DISVP4LU Strong Biomarker [3]
Bladder cancer DISUHNM0 Strong Biomarker [4]
Carcinoma DISH9F1N Strong Altered Expression [5]
Chronic renal failure DISGG7K6 Strong Biomarker [6]
Colorectal carcinoma DIS5PYL0 Strong Biomarker [7]
End-stage renal disease DISXA7GG Strong Biomarker [6]
Epithelial ovarian cancer DIS56MH2 Strong Biomarker [8]
Esophageal squamous cell carcinoma DIS5N2GV Strong Altered Expression [9]
Focal segmental glomerulosclerosis DISJNHH0 Strong Genetic Variation [10]
Focal segmental glomerulosclerosis 1 DISJTXG4 Strong Autosomal dominant [11]
Glioblastoma multiforme DISK8246 Strong Biomarker [3]
Hepatocellular carcinoma DIS0J828 Strong Biomarker [12]
IgA nephropathy DISZ8MTK Strong Biomarker [13]
Kidney failure DISOVQ9P Strong Biomarker [14]
Lung carcinoma DISTR26C Strong Altered Expression [15]
Membranous glomerulonephritis DISFSUKQ Strong Biomarker [16]
Nephronophthisis DISXU4HY Strong Biomarker [17]
Nephropathy DISXWP4P Strong Biomarker [16]
Nephrotic syndrome DISSPSC2 Strong Biomarker [18]
Ovarian cancer DISZJHAP Strong Altered Expression [8]
Ovarian neoplasm DISEAFTY Strong Biomarker [8]
Small-cell lung cancer DISK3LZD Strong Genetic Variation [19]
Squamous cell carcinoma DISQVIFL Strong Biomarker [20]
Urinary bladder cancer DISDV4T7 Strong Biomarker [4]
Urinary bladder neoplasm DIS7HACE Strong Biomarker [4]
Wilms tumor DISB6T16 Strong Biomarker [21]
Breast cancer DIS7DPX1 moderate Altered Expression [5]
Breast carcinoma DIS2UE88 moderate Altered Expression [5]
Glomerulosclerosis DISJF20Z moderate Genetic Variation [22]
High blood pressure DISY2OHH moderate Biomarker [23]
Lung adenocarcinoma DISD51WR moderate Altered Expression [24]
Lung cancer DISCM4YA moderate Altered Expression [15]
Macular corneal dystrophy DISOLD0H moderate Biomarker [25]
Familial idiopathic steroid-resistant nephrotic syndrome DISQ53RS Supportive Autosomal dominant [11]
Cervical cancer DISFSHPF Limited Biomarker [26]
Cervical carcinoma DIST4S00 Limited Biomarker [26]
Gastric cancer DISXGOUK Limited Altered Expression [27]
Nephrotic syndrome, type 2 DISIRFO1 Limited Genetic Variation [28]
Non-small-cell lung cancer DIS5Y6R9 Limited Biomarker [29]
Stomach cancer DISKIJSX Limited Altered Expression [27]
Undifferentiated carcinoma DISIAZST Limited Biomarker [30]
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⏷ Show the Full List of 43 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
This DOT Affected the Drug Response of 1 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
4-hydroxy-2-nonenal DM2LJFZ Investigative Alpha-actinin-4 (ACTN4) affects the binding of 4-hydroxy-2-nonenal. [46]
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14 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 Alpha-actinin-4 (ACTN4). [31]
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of Alpha-actinin-4 (ACTN4). [32]
Doxorubicin DMVP5YE Approved Doxorubicin increases the expression of Alpha-actinin-4 (ACTN4). [33]
Estradiol DMUNTE3 Approved Estradiol increases the expression of Alpha-actinin-4 (ACTN4). [34]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Alpha-actinin-4 (ACTN4). [35]
Temozolomide DMKECZD Approved Temozolomide decreases the expression of Alpha-actinin-4 (ACTN4). [36]
Zoledronate DMIXC7G Approved Zoledronate decreases the expression of Alpha-actinin-4 (ACTN4). [37]
Selenium DM25CGV Approved Selenium increases the expression of Alpha-actinin-4 (ACTN4). [38]
Simvastatin DM30SGU Approved Simvastatin increases the expression of Alpha-actinin-4 (ACTN4). [39]
Tocopherol DMBIJZ6 Phase 2 Tocopherol increases the expression of Alpha-actinin-4 (ACTN4). [38]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 increases the expression of Alpha-actinin-4 (ACTN4). [40]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 decreases the expression of Alpha-actinin-4 (ACTN4). [41]
chloropicrin DMSGBQA Investigative chloropicrin increases the expression of Alpha-actinin-4 (ACTN4). [44]
QUERCITRIN DM1DH96 Investigative QUERCITRIN affects the expression of Alpha-actinin-4 (ACTN4). [45]
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⏷ Show the Full List of 14 Drug(s)
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 decreases the phosphorylation of Alpha-actinin-4 (ACTN4). [42]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the methylation of Alpha-actinin-4 (ACTN4). [43]
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References

1 ACTN4 regulates the stability of RIPK1 in melanoma.Oncogene. 2018 Jul;37(29):4033-4045. doi: 10.1038/s41388-018-0260-x. Epub 2018 Apr 30.
2 Targeting Mechanoresponsive Proteins in Pancreatic Cancer: 4-Hydroxyacetophenone Blocks Dissemination and Invasion by Activating MYH14.Cancer Res. 2019 Sep 15;79(18):4665-4678. doi: 10.1158/0008-5472.CAN-18-3131. Epub 2019 Jul 29.
3 Long Noncoding RNA SChLAP1 Forms a Growth-Promoting Complex with HNRNPL in Human Glioblastoma through Stabilization of ACTN4 and Activation of NF-B Signaling.Clin Cancer Res. 2019 Nov 15;25(22):6868-6881. doi: 10.1158/1078-0432.CCR-19-0747. Epub 2019 Sep 6.
4 Increased expression of -actinin-4 is associated with unfavorable pathological features and invasiveness of bladder cancer.Oncol Rep. 2013 Sep;30(3):1073-80. doi: 10.3892/or.2013.2577. Epub 2013 Jul 1.
5 Actinin-4 as a Diagnostic Biomarker in Serum of Breast Cancer Patients.Med Sci Monit. 2019 May 4;25:3298-3302. doi: 10.12659/MSM.912404.
6 Functional Validation of an Alpha-Actinin-4 Mutation as a Potential Cause of an Aggressive Presentation of Adolescent Focal Segmental Glomerulosclerosis: Implications for Genetic Testing.PLoS One. 2016 Dec 15;11(12):e0167467. doi: 10.1371/journal.pone.0167467. eCollection 2016.
7 -Actinin-4 enhances colorectal cancer cell invasion by suppressing focal adhesion maturation.PLoS One. 2015 Apr 10;10(4):e0120616. doi: 10.1371/journal.pone.0120616. eCollection 2015.
8 Actinin-4 gene amplification in ovarian cancer: a candidate oncogene associated with poor patient prognosis and tumor chemoresistance.Mod Pathol. 2009 Apr;22(4):499-507. doi: 10.1038/modpathol.2008.234. Epub 2009 Jan 16.
9 Targeting TRIM3 deletion-induced tumor-associated lymphangiogenesis prohibits lymphatic metastasis in esophageal squamous cell carcinoma.Oncogene. 2019 Apr;38(15):2736-2749. doi: 10.1038/s41388-018-0621-5. Epub 2018 Dec 12.
10 Focal segmental glomerulosclerosis ACTN4 mutants binding to actin: regulation by phosphomimetic mutations.Sci Rep. 2019 Oct 29;9(1):15517. doi: 10.1038/s41598-019-51825-2.
11 Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet. 2000 Mar;24(3):251-6. doi: 10.1038/73456.
12 Elevated TRIP13 drives the AKT/mTOR pathway to induce the progression of hepatocellular carcinoma via interacting with ACTN4.J Exp Clin Cancer Res. 2019 Sep 18;38(1):409. doi: 10.1186/s13046-019-1401-y.
13 Kidney Transplantation Outcomes across GN Subtypes in the United States.J Am Soc Nephrol. 2017 Feb;28(2):632-644. doi: 10.1681/ASN.2016020126. Epub 2016 Jul 18.
14 Podocyte-Specific Deletion of Yes-Associated Protein Causes FSGS and Progressive Renal Failure.J Am Soc Nephrol. 2016 Jan;27(1):216-26. doi: 10.1681/ASN.2014090916. Epub 2015 May 26.
15 Co-expression of RelA/p65 and ACTN4 induces apoptosis in non-small lung carcinoma cells.Cell Cycle. 2018;17(5):616-626. doi: 10.1080/15384101.2017.1417709. Epub 2018 Jan 22.
16 Development of a novel cell-based assay to diagnose recurrent focal segmental glomerulosclerosis patients.Kidney Int. 2019 Mar;95(3):708-716. doi: 10.1016/j.kint.2018.10.030. Epub 2019 Jan 29.
17 Integration of Genetic Testing and Pathology for the Diagnosis of Adults with FSGS.Clin J Am Soc Nephrol. 2019 Feb 7;14(2):213-223. doi: 10.2215/CJN.08750718. Epub 2019 Jan 15.
18 Ofatumumab in post-transplantation recurrence of focal segmental glomerulosclerosis in a child.Pediatr Transplant. 2019 Jun;23(4):e13413. doi: 10.1111/petr.13413. Epub 2019 Apr 11.
19 The alternatively spliced actinin-4 variant as a prognostic marker for metastasis in small-cell lung cancer.Anticancer Res. 2015 Mar;35(3):1663-7.
20 Four PTEN-targeting co-expressed miRNAs and ACTN4- targeting miR-548b are independent prognostic biomarkers in human squamous cell carcinoma of the oral tongue.Int J Cancer. 2017 Dec 1;141(11):2318-2328. doi: 10.1002/ijc.30915. Epub 2017 Aug 18.
21 WT1 microdeletion and slowly progressing focal glomerulosclerosis in a patient with male pseudohermaphroditism, childhood leukemia, Wilms tumor and cerebellar angioblastoma.Clin Nephrol. 2013 May;79(5):414-8. doi: 10.5414/cn107276.
22 Mice with altered alpha-actinin-4 expression have distinct morphologic patterns of glomerular disease.Kidney Int. 2008 Mar;73(6):741-50. doi: 10.1038/sj.ki.5002751. Epub 2008 Jan 9.
23 Endothelial Epas1 Deficiency Is Sufficient To Promote Parietal Epithelial Cell Activation and FSGS in Experimental Hypertension.J Am Soc Nephrol. 2017 Dec;28(12):3563-3578. doi: 10.1681/ASN.2016090960. Epub 2017 Sep 19.
24 Actinin-4 protein overexpression as a predictive biomarker in adjuvant chemotherapy for resected lung adenocarcinoma.Biomark Med. 2017 Sep;11(9):721-731. doi: 10.2217/bmm-2017-0150. Epub 2017 Jun 29.
25 Minimal Change Disease.Clin J Am Soc Nephrol. 2017 Feb 7;12(2):332-345. doi: 10.2215/CJN.05000516. Epub 2016 Dec 9.
26 -Actinin-4 regulates cancer stem cell properties and chemoresistance in cervical cancer.Carcinogenesis. 2020 Jul 14;41(7):940-949. doi: 10.1093/carcin/bgz168.
27 -Actinin-4 promotes metastasis in gastric cancer.Lab Invest. 2017 Sep;97(9):1084-1094. doi: 10.1038/labinvest.2017.28. Epub 2017 Jun 5.
28 A locus for adolescent and adult onset familial focal segmental glomerulosclerosis on chromosome 1q25-31.J Am Soc Nephrol. 2000 Sep;11(9):1674-1680. doi: 10.1681/ASN.V1191674.
29 Efficacy of adjuvant chemotherapy for non-small cell lung cancer assessed by metastatic potential associated with ACTN4.Oncotarget. 2016 May 31;7(22):33165-78. doi: 10.18632/oncotarget.8890.
30 cDNA microarray profiling of rat mammary gland carcinomas induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 7,12-dimethylbenz[a]anthracene.Carcinogenesis. 2002 Oct;23(10):1561-8. doi: 10.1093/carcin/23.10.1561.
31 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.
32 Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
33 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.
34 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
35 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.
36 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.
37 Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
38 Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
39 Simvastatin maintains steady patterns of GFR and improves AER and expression of slit diaphragm proteins in type II diabetes. Kidney Int. 2006 Jul;70(1):177-86. doi: 10.1038/sj.ki.5001515. Epub 2006 May 17.
40 Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
41 Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
42 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.
43 DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
44 Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
45 Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
46 Site-specific protein adducts of 4-hydroxy-2(E)-nonenal in human THP-1 monocytic cells: protein carbonylation is diminished by ascorbic acid. Chem Res Toxicol. 2010 Jan;23(1):37-47. doi: 10.1021/tx9002462.