Affinage

ACTN4

Alpha-actinin-4 · UniProt O43707

Length
911 aa
Mass
104.9 kDa
Annotated
2026-06-09
96 papers in source corpus 31 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACTN4 (alpha-actinin-4) is a multifunctional actin crosslinking protein whose ability to bundle F-actin underlies cytoskeletal architecture in podocytes and motile cells (PMID:10700177, PMID:31664084). Autosomal dominant familial focal segmental glomerulosclerosis (FSGS) is caused by ACTN4 mutations (K255E, T259I, S262P, G195D, M240T, W59R) that increase F-actin binding affinity, producing a 'frozen' cytoskeleton, and that also reduce protein stability and disrupt nephrocyte function in genetic rescue models (PMID:10700177, PMID:31664084, PMID:26740551, PMID:36815115). Actin engagement is tunable: EGFR/TAM-family receptor signaling drives N-terminal tyrosine phosphorylation (Y4, Y31, Y11/13) that lowers actin affinity and protects ACTN4 from m-calpain cleavage, while TGF-β/high-glucose-driven Ser159 phosphorylation increases F-actin bundling and produces proteinuria and glomerulosclerosis in knock-in mice (PMID:26012634, PMID:29274473, PMID:32540856, PMID:33532643). Beyond the cytoskeleton, ACTN4 builds Arp2/3-dependent junctional actin at cadherin adherens junctions and concentrates in PI3K-dependent ruffle-edge lamellipodia to drive migration (PMID:22232703, PMID:39222868). In the nucleus it acts as a transcriptional co-activator, using a LXXLL motif to potentiate nuclear-receptor (ERα, GR) and RelA/p65 NF-κB signaling, a function abolished by FSGS mutants that are sequestered in the cytoplasm (PMID:21078666, PMID:22351778, PMID:23482348, PMID:27998979); HDAC5-mediated deacetylation at K417 licenses its nuclear translocation and modulation of YBX1 during wound reepithelialization (PMID:41442502). ACTN4 additionally scaffolds RIPK1-cIAP1 assembly to activate NF-κB in a feedforward loop (PMID:29706658) and is set quantitatively by competing E3 ligases (SOCS1, RNF38) and deubiquitinases (OTUD3, MINDY2) that govern its stability in cancer (PMID:34380780, PMID:40890444, PMID:37207150, PMID:35568845).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 High

    Established ACTN4 as a human disease gene and proposed a gain-of-function cytoskeletal mechanism, answering how an actin crosslinker could cause dominant glomerular disease.

    Evidence Disease-mutation identification in families plus in vitro F-actin binding assays comparing mutant versus wild-type protein

    PMID:10700177

    Open questions at the time
    • Did not resolve how increased actin affinity translates to podocyte loss in vivo
    • No nuclear or signaling functions addressed
  2. 2010 High

    Defined a nuclear, non-cytoskeletal role by showing ACTN4 is a LXXLL-dependent transcriptional co-activator, reframing it as a dual cytoplasmic/nuclear protein.

    Evidence Co-IP, ChIP, reporter assays and siRNA knockdown for ERα interaction; nuclear proteomics identifying RNA-binding protein associations

    PMID:20519146 PMID:21078666

    Open questions at the time
    • mRNA-metabolism role inferred from interactome only, no functional validation
    • Mechanism of nucleocytoplasmic shuttling unknown
  3. 2012 High

    Linked ACTN4 to active actin assembly at adherens junctions and connected FSGS mutations to the nuclear co-activator defect, unifying its junctional and transcriptional functions.

    Evidence Reconstituted actin assembly on cadherin membranes with knockdown and dominant-negative mutant; Co-IP and reporter assays in podocytes for nuclear-receptor loss

    PMID:22232703 PMID:22351778

    Open questions at the time
    • How a single mutation simultaneously hyperactivates actin binding and abolishes nuclear localization not mechanistically reconciled
    • Arp2/3 recruitment mechanism not detailed
  4. 2013 Medium

    Showed ACTN4 is a selective co-activator of RelA/p65, defining gene-specific NF-κB output and that actin-binding domains are dispensable for this nuclear function.

    Evidence Reporter assays, siRNA knockdown, nuclear localization assays and domain-deletion mutants

    PMID:23482348

    Open questions at the time
    • Single lab, not independently replicated
    • Basis for promoter selectivity unresolved
  5. 2015 High

    Identified growth-factor-driven N-terminal tyrosine phosphorylation (Y4/Y31) as a switch lowering actin affinity, explaining how ACTN4-actin engagement is dynamically regulated.

    Evidence In vitro actin binding with phosphomimetic mutagenesis, molecular dynamics, EGF stimulation and kinase inhibition in cells

    PMID:26012634

    Open questions at the time
    • In vivo relevance of phosphoswitch not established
    • Identity of physiological kinase not fully resolved beyond TAM family
  6. 2016 High

    Extended the nuclear co-activator role to liganded GR in podocytes and tied protein instability of a de novo mutant to FSGS, connecting transcription and degradation to disease.

    Evidence Co-IP, ChIP at endogenous GREs, reporter assays and LXXLL mutants in podocytes; quantitative proteomics of patient urinary cells mapping ubiquitylation

    PMID:26740551 PMID:27998979

    Open questions at the time
    • Degradation pathway for unstable mutant not identified at the E3-ligase level
    • Link between transcriptional loss and proteinuria not directly tested
  7. 2018 Medium

    Revealed a scaffolding function for RIPK1-cIAP1 assembly with domain-mapped binding, establishing a feedforward NF-κB loop driven by ACTN4.

    Evidence Domain-mapped Co-IP, knockdown/overexpression with NF-κB readout and melanoma xenograft

    PMID:29706658

    Open questions at the time
    • Single lab, not independently replicated
    • Structural basis of the ternary complex unresolved
  8. 2019 High

    Demonstrated that the EGF tyrosine phosphoswitch can override FSGS mutant hyperactivity, offering a mechanistic handle on disease-causing actin overbinding.

    Evidence In vitro F-actin binding with phosphomimetic FSGS mutants plus aggregation and motility assays in multiple cell types

    PMID:31664084

    Open questions at the time
    • Therapeutic exploitation in vivo not tested
    • Endogenous phosphorylation levels in FSGS patient cells unknown
  9. 2020 High

    Identified Ser159 phosphorylation as a TGF-β/glucose-responsive activator of actin bundling sufficient to cause glomerular disease in vivo, linking metabolic signaling to podocyte injury.

    Evidence MS phosphomapping, crystallography, in vitro bundling and CRISPR knock-in mouse with renal phenotype

    PMID:32540856

    Open questions at the time
    • Kinase responsible for S159 phosphorylation not pinpointed
    • Relationship between S159 and tyrosine phosphoswitch not integrated
  10. 2021 Medium

    Established ubiquitin-driven proteostatic control of ACTN4 and a direct EGFR-binding interface, refining how its abundance and phosphorylation are gated.

    Evidence OTUD3 deubiquitinase substrate assays in HCC; Co-IP domain mapping of direct EGFR binding; nsp12 competition assays for SARS-CoV-2

    PMID:33532643 PMID:34380780 PMID:39289355

    Open questions at the time
    • Individual ligase/DUB findings each from single labs
    • Antiviral and oncogenic roles not mechanistically reconciled
  11. 2022 Medium

    Expanded the regulatory network of competing E3 ligases and revealed a DNA repair pathway-choice function, broadening ACTN4 beyond cytoskeletal roles.

    Evidence SOCS1 K63 ubiquitination at K66 and RNF38 degradation assays; CRISPR knockout with NHEJ/HR reporter and repair-protein foci assays; Drosophila nephrocyte rescue of FSGS mutants

    PMID:35568845 PMID:36476259 PMID:36815115 PMID:40890444

    Open questions at the time
    • Mechanism by which ACTN4 biases NHEJ versus HR not defined
    • Tissue specificity of ligase/DUB control unknown
  12. 2024 Medium

    Localized ACTN4 to PI3K-dependent lamellipodia and identified MINDY2 and CCT3 as new partners coupling its stability to migration and ferroptosis resistance.

    Evidence Live-cell imaging and CLEM with PI3K inhibition and knockdown; MINDY2 deubiquitination assays; CCT3 Co-IP with TFRC recycling readout

    PMID:37207150 PMID:39210442 PMID:39222868

    Open questions at the time
    • ACTN1 versus ACTN4 isoform selectivity at lamellipodia not mechanistically explained
    • Most partner findings single-lab
  13. 2025 High

    Defined an acetylation switch (HDAC5/K417) controlling nuclear entry during wound healing and connected ACTN4 to inactive integrin α5 anchoring, integrating its cytoskeletal and nuclear lives.

    Evidence LC-MS, K417 mutagenesis, conditional knockout mouse and ex vivo human skin; integrin activation-state interactome with ABD-deletion in zebrafish somites

    PMID:41072919 PMID:41442502

    Open questions at the time
    • Interplay between K417 acetylation and phosphorylation switches untested
    • Integrin-anchoring role shown only in zebrafish development

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct post-translational switches (Y4/Y31/Y11-13 phosphorylation, S159 phosphorylation, K417 acetylation, K66 ubiquitination) are coordinated to partition ACTN4 between actin bundling, junctional assembly, and nuclear transcription remains unresolved.
  • No unified model integrating the competing modification states
  • Cell-type-specific dominance of each function not established
  • Structural basis for mutually exclusive cytoplasmic versus nuclear partitioning unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 5 GO:0140110 transcription regulator activity 5 GO:0060090 molecular adaptor activity 2 GO:0005198 structural molecule activity 1
Localization
GO:0005634 nucleus 4 GO:0005856 cytoskeleton 3 GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-73894 DNA Repair 1
Partners
EGFRESR1GRHDAC5OTUD3RELARIPK1SOCS1
Complex memberships
RIPK1-cIAP1 complexcadherin adherens junctioncardiac Z-disc

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Mutations in ACTN4 (encoding alpha-actinin-4) cause autosomal dominant familial FSGS. In vitro F-actin binding assays showed that FSGS-associated mutant alpha-actinin-4 binds F-actin more strongly than wild-type protein, suggesting a 'frozen' cytoskeleton mechanism in podocytes. In vitro F-actin binding assays; identification of disease-causing mutations in human families Nature genetics High 10700177
2012 Alpha-actinin-4/FSGS1 is required for Arp2/3-dependent actin nucleation and assembly at cadherin-based adherens junctions. Reconstitution biochemistry identified ACTN4 as an essential factor; knockdown decreased junctional actin; the K255E FSGS mutant failed to support actin assembly and acted as a dominant negative at junctional complexes. In vitro actin assembly reconstitution assay on purified cadherin-enriched membranes; siRNA knockdown; dominant-negative mutant analysis; localization by immunofluorescence in MDCK cells The Journal of cell biology High 22232703
2010 ACTN4 contains a functional LXXLL nuclear receptor interaction motif, interacts with estrogen receptor α (ERα) in vitro and in mammalian cells, and potentiates ERα-mediated transcription. The CaM-like domain of ACTN4 is required for interaction with HDAC7, which opposes ACTN4 co-activator function. Knockdown of ACTN4 decreases ERα target gene expression and MCF-7 cell proliferation. Co-immunoprecipitation; transient transfection reporter assays; ChIP; siRNA knockdown; in vitro binding The Journal of biological chemistry High 21078666
2012 FSGS-linked ACTN4 mutants (K255E, T259I, S262P) mislocalize to the cytoplasm, lose ability to associate with nuclear receptors (RARα, PPARγ), and fail to potentiate transcriptional activation by nuclear hormone receptors in podocytes. Overexpression of FSGS mutants suppresses transcriptional activity of endogenous wild-type ACTN4 through cytoplasmic sequestration. Co-immunoprecipitation; transient transfection reporter assays; immunofluorescence localization; dominant-negative analysis in podocytes The Journal of biological chemistry High 22351778
2013 ACTN4 functions as a selective transcriptional co-activator of the RelA/p65 subunit of NF-κB, enhancing RelA/p65-dependent expression of c-fos, MMP-3, and MMP-1, but not TNC, ICAM1, or FN1. The actin-binding domains of ACTN4 are not critical for nuclear translocation or co-activation of RelA/p65-dependent transcription. Transient transfection reporter assays; siRNA knockdown; nuclear localization assays; domain deletion mutants Oncotarget Medium 23482348
2015 EGF stimulation triggers phosphorylation of ACTN4 at Tyr4 and Tyr31 within the intrinsically disordered N-terminal region, and a double phosphomimetic (Y4E/Y31E) reduces ACTN4 interaction with actin in vitro. m-Calpain cleavage removes the Tyr4 site. Phosphorylation at Tyr31 alone was sufficient to inhibit actin binding in vitro. TAM family receptor tyrosine kinases (e.g., AXL) mediate EGF-stimulated ACTN4 phosphorylation. In vitro actin binding assays; phosphomimetic mutagenesis; molecular dynamics simulation; cell-based EGF stimulation assays; kinase inhibitor experiments Science signaling High 26012634
2016 ACTN4 interacts with the glucocorticoid receptor (GR) in the nucleus of human podocytes via its LXXLL motif, enhances GRE-driven transcription, and is recruited with GR to GREs of dexamethasone-transactivated genes (SERPINE1, ANGPTL4, CCL20, SAA1) and NF-κB binding sites on GR-transrepressed promoters. FSGS-linked ACTN4 mutants lose ability to bind liganded GR and support GRE-mediated transcription. Co-immunoprecipitation; ChIP; reporter assays; shRNA stable knockdown; LXXLL mutant analysis; actin-binding domain isoform comparison in human podocytes The Journal of biological chemistry High 27998979
2017 Tyro3 receptor tyrosine kinase-mediated phosphorylation of ACTN4 at tyrosines 11 and 13 requires FAK activation at Y397 and the EGF receptor cascade. This phosphorylation renders ACTN4 resistant to m-calpain cleavage between Y13 and G14, a cleavage that normally prevents growth-factor regulation of ACTN4-actin interaction. ACTN4 Y11/13E phosphomimetic promotes a mesenchymal-to-amoeboidal transition and increases invasiveness in melanoma cells. PCR-based mutagenesis; siRNA knockdown; kinase inhibitor experiments; in vitro calpain cleavage assay; cell migration and invasion assays The international journal of biochemistry & cell biology Medium 29274473
2019 FSGS-associated ACTN4 mutants (K255E, T259I, S262P) show elevated actin binding that can be downregulated by EGF-mediated tandem phosphorylation at Y4 and Y31. The double phosphomimetic Y4/31E significantly reduced actin binding of FSGS mutants and prevented their aggregation and inhibition of motility in podocytes, fibroblasts, and melanoma cells. A novel phosphomimetic Y265E showed even greater actin binding than FSGS mutants. In vitro F-actin binding assays; phosphomimetic mutagenesis; cell imaging for aggregate formation; motility assays Scientific reports High 31664084
2012 MTBP (MDM2 binding protein) co-immunoprecipitates with ACTN4 (identified by mass spectrometry) and co-localizes with endogenous ACTN4. MTBP overexpression inhibits ACTN4-mediated cell migration and filopodia formation. MTBP also inhibits ACTN4-mediated F-actin bundling in vitro. Nuclear localization of MTBP is dispensable for these cytoplasmic inhibitory functions. Co-immunoprecipitation; mass spectrometry; in vitro F-actin bundling assay; cell migration assays; siRNA co-depletion epistasis Oncogene Medium 22370640
2020 ACTN4 is phosphorylated at serine 159 in human podocytes (identified by mass spectrometry). Phosphomimetic ACTN4-S159 shows increased F-actin binding and bundling in vitro and increased spatial correlation of F-actin alignment in podocytes. Phosphomimetic Actn4 knock-in mice develop proteinuria and glomerulosclerosis after subtotal nephrectomy. High extracellular glucose and TGF-β stimulate S159 phosphorylation in podocytes. Mass spectrometry phosphorylation mapping; X-ray crystallography; F-actin binding and bundling assays; CRISPR/Cas9 knock-in mouse model; organ-on-a-chip detachment assay; immunofluorescence Journal of the American Society of Nephrology : JASN High 32540856
2016 A novel ACTN4 mutation (p.G195D, de novo) causes decreased protein stability associated with increased ubiquitylation near the mutation site, as revealed by quantitative proteomics of patient-derived urinary epithelial cells. The ACTN4 interactome is predominantly composed of cytoskeletal modulators and LIM-domain proteins, which are globally decreased in patient cells along with ACTN4, suggesting proteome perturbation through ACTN4 instability. Quantitative mass spectrometry proteomics; ubiquitylation site mapping; next-generation sequencing; interactome profiling Human molecular genetics Medium 26740551
2021 ACTN4 binds to SARS-CoV-2 nsp12 (RNA-dependent RNA polymerase) and competes with viral RNA for binding to the RdRp complex, thereby impeding viral replication. Reduction of m6A modification on ACTN4 mRNA by SARS-CoV-2 infection decreases mRNA stability and translation efficiency, reducing ACTN4 expression. Co-immunoprecipitation/binding assays; high-throughput sequencing; m6A modification analysis; antiviral drug assays in cell lines and K18-hACE2 transgenic mice Signal transduction and targeted therapy Medium 39289355
2018 ACTN4 acts as a scaffold for stabilization of RIPK1 by facilitating its physical association with cIAP1. ACTN4 binds RIPK1 through its N-terminal actin-binding domain and cIAP1 through its C-terminal CaM-like domain. This complex stabilizes RIPK1, which in turn activates NF-κB. NF-κB transcriptionally activates ACTN4, forming a feedforward loop. Co-immunoprecipitation; domain mapping mutants; siRNA knockdown; overexpression studies; melanoma xenograft model Oncogene Medium 29706658
2021 The deubiquitinase OTUD3 directly binds ACTN4, deubiquitinates it to stabilize its protein levels, and thereby promotes HCC proliferation and metastasis. ACTN4 was identified as an OTUD3 substrate by mass spectrometry and co-immunoprecipitation. Mass spectrometry; co-immunoprecipitation; ubiquitination assays; gain/loss-of-function in vitro and in vivo xenograft Aging Medium 34380780
2022 SOCS1, an E3 ubiquitin ligase, binds ACTN4 via its SH2 domain interacting with the N-terminal region of ACTN4, promotes K63-linked ubiquitination of ACTN4 at Lys66, and drives its proteasomal degradation. Loss of SOCS1 stabilizes ACTN4 and promotes osteosarcoma stemness and cisplatin resistance. Immunoprecipitation-mass spectrometry; co-immunoprecipitation; ubiquitination assays; site-directed mutagenesis (K66); domain mapping; in vitro and in vivo models Acta pharmacologica Sinica Medium 40890444
2023 The deubiquitinase MINDY2 interacts with ACTN4 (identified by mass spectrometry), stabilizes ACTN4 protein by deubiquitination, and thereby activates the PI3K/AKT/mTOR signaling pathway to promote pancreatic cancer proliferation and metastasis. Mass spectrometry interactome; co-immunoprecipitation; ubiquitination assays; gain/loss-of-function in vitro and in vivo Frontiers in oncology Medium 37207150
2022 RNF38, a RING finger E3 ubiquitin ligase, interacts with ACTN4, induces its ubiquitination and degradation, and thereby inactivates NF-κB and ERK1/2 signaling pathways in nasopharyngeal carcinoma. Co-immunoprecipitation; mass spectrometry; CHX chase assay; ubiquitination assay; gain/loss-of-function in vitro and in vivo BMC cancer Medium 35568845
2019 TRIP13 interacts with ACTN4 and positively regulates its expression, thereby activating the AKT/mTOR pathway to promote HCC cell migration, invasion, EMT, and metastasis. Co-immunoprecipitation; gain/loss-of-function assays; western blot; in vitro and in vivo tumor models Journal of experimental & clinical cancer research : CR Low 31533816
2019 ACTN4 knockdown in trophoblast cells reduced AKT membrane translocation and inhibited cell proliferation. E-cadherin regulated ACTN4 and β-catenin co-localization on trophoblast podosomes, and ACTN4 downregulation suppressed E-cadherin-induced cell invasion increase via depolymerization of actin filaments. siRNA knockdown; actin polymerization assays; co-localization by immunofluorescence; cell invasion assays FASEB journal Low 30776251
2017 ACTN4 directly interacts with β-catenin; interruption of the ACTN4/β-catenin interaction results in activation of β-catenin proteasomal degradation in breast cancer stem cells. Co-immunoprecipitation; ubiquitination assays; DARTS (drug affinity responsive target stability) identifying ACTN4 as direct target of ellagic acid; cancer stem cell functional assays Journal of experimental & clinical cancer research : CR Low 29197410
2010 Nuclear ACTN4 associates with a large number of RNA-binding proteins and ribonucleoproteins involved in mRNA processing and transport, identified by 2D gel electrophoresis and MALDI-TOF mass spectrometry, suggesting a role in mRNA metabolism. 2D gel electrophoresis; MALDI-TOF mass spectrometry; nuclear fractionation Biochemical and biophysical research communications Low 20519146
2021 ACTN4 directly binds to EGFR via its N-terminal 32 amino acids. EGF stimulation triggers phosphorylation of ACTN4 within seconds through this direct EGFR interaction. A C-terminal truncation enhances ACTN4 binding to EGFR, and phosphomimetic Y4/31E shows reduced binding to EGFR. Co-immunoprecipitation; domain mapping with truncation mutants; phosphomimetic mutants; time-course EGF stimulation assays Heliyon Medium 33532643
2022 ACTN4 knockout in H1299 NSCLC cells (CRISPR/Cas9) enhanced NHEJ and suppressed HR efficiency for DNA double-strand break repair, increased resistance to topoisomerase II inhibitors (etoposide, doxorubicin), and accelerated assembly of 53BP1 foci with reduced phospho-BRCA1 foci after etoposide treatment, indicating ACTN4 influences the balance between NHEJ and HR repair pathways. CRISPR/Cas9 knockout; DNA comet assay; γH-2AX staining; NHEJ/HR reporter plasmid assays; immunostaining of repair proteins Biology direct Medium 36476259
2025 HDAC5, upon cytoplasmic localization during wound healing, interacts with ACTN4 and deacetylates it at K417. This deacetylation enables nuclear translocation of ACTN4 and subsequent modulation of YBX1 transcriptional activity, with cystatin A identified as a downstream effector promoting reepithelialization. LC-MS identification of HDAC5-ACTN4 interaction; site-directed mutagenesis (K417); immunofluorescence; luciferase assays; conditional knockout mouse model; ex vivo human skin Science translational medicine High 41442502
2020 SEPT14 interacts with ACTN4 in male germ cells (identified by co-IP and nano-LC-MS/MS). SEPT14 co-localizes with ACTN4 at perinuclear and manchette regions of the sperm head. Mutated SEPT14 disrupts the localization pattern of ACTN4, and clinical SEPT14 mutations cause mislocalized and fragmented ACTN4 signals, leading to sperm head defects. Co-immunoprecipitation; nano-LC-MS/MS; immunostaining; cell line and clinical sperm analysis Biomedicines Medium 33228246
2022 De novo ACTN4 mutation (p.M240T) leads to decreased alpha-actinin-4 protein stability, protein mislocalization, and actin cytoskeleton rearrangements. Transgenic expression of wild-type human ACTN4 in Drosophila nephrocytes rescued phenotypes from knockdown of endogenous actinin, whereas p.M240T, p.W59R, and p.K255E mutants failed to rescue, establishing pathogenicity. In vitro stability assays; immunofluorescence localization; Drosophila nephrocyte transgenic rescue experiments; in silico modeling Kidney international reports Medium 36815115
2024 ACTN4 localizes to ruffle-edge lamellipodia at cell leading edges in a PI3K-dependent manner, distinct from its localization in stress fibers and focal adhesions. Overexpression of ACTN4 (but not ACTN1) promotes lamellipodial formation. ACTN4 knockdown suppresses ruffle-edge lamellipodia formation and cell migration in wound healing assays. Live-cell imaging; CLEM (correlative light and electron microscopy); PI3K inhibition; EGFP-ACTN4 overexpression; ACTN4 knockdown Experimental cell research Medium 39222868
2025 ACTN4 associates preferentially with inactive (ligand-binding-deficient) Integrin α5 in zebrafish somites. The ACTN4 actin-binding domain (ABD) is required for co-localization with Itgα5, as ABD deletion causes cytoplasmic retention and loss of Itgα5 co-localization. This suggests ACTN4 links inactive integrin α5 to the actin cytoskeleton during somite boundary formation. Label-free mass spectrometry interactome of Itgα5 activation states; Parallel Reaction Monitoring validation; ACTN4 ABD deletion mutant; immunofluorescence co-localization in zebrafish somites Molecular & cellular proteomics : MCP Medium 41072919
2024 An alternative splicing isoform of ACTN4 enhanced cell migration in glioblastoma, as shown by functional assays demonstrating that the dysregulated AS isoform promotes migration compared to the canonical form. RNA-seq AS analysis; functional migration assays with splice isoform expression bioRxivpreprint Low
2024 ACTN4 is a component of the cardiac Z-disc in human heart and zebrafish, forming a heterodimeric complex with muscle-specific ACTN2 in cardiomyocytes. ACTN4 depletion from human iPSC-derived cardiomyocytes stabilizes sarcomere proteins and drives contractility-dependent cellular hypertrophy, while overexpression destabilizes sarcomeres. ACTN4 depletion in zebrafish embryos increases ventricular contractility causing atrial enlargement. Biochemical fractionation; immunofluorescence; AI structure modeling; human iPSC-cardiomyocyte genetic depletion/overexpression; zebrafish genetic depletion with cardiac phenotype readout bioRxivpreprint Medium
2025 WIPF1 interacts with ACTN4 to regulate podosome formation, matrix degradation, and actin polymerization in extravillous trophoblasts (EVTs), potentially mediated by the ARG54 site of WIPF1. WIPF1 knockdown impaired cell migration, and this interaction underlies EVT invasion during placental development. Co-immunoprecipitation; site-directed mutagenesis (ARG54); podosome/matrix degradation assays; knockdown experiments in hTSC-derived EVTs Genes & diseases Low 40821124
2024 CCT3 interacts with ACTN4 and hinders the recycling of transferrin receptor TFRC to the cell membrane, thereby obstructing iron endocytosis and inhibiting ferroptosis in HCC cells, contributing to sorafenib resistance. Co-immunoprecipitation; CRISPR/Cas9 KO library screening; ubiquitination analysis; xenograft mouse model Journal of experimental & clinical cancer research : CR Medium 39210442

Source papers

Stage 0 corpus · 96 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nature genetics 977 10700177
2021 Circular RNA ACTN4 promotes intrahepatic cholangiocarcinoma progression by recruiting YBX1 to initiate FZD7 transcription. Journal of hepatology 185 34509526
2012 α-Actinin-4/FSGS1 is required for Arp2/3-dependent actin assembly at the adherens junction. The Journal of cell biology 124 22232703
2015 The biological role of actinin-4 (ACTN4) in malignant phenotypes of cancer. Cell & bioscience 84 26288717
2010 The actin-binding protein, actinin alpha 4 (ACTN4), is a nuclear receptor coactivator that promotes proliferation of MCF-7 breast cancer cells. The Journal of biological chemistry 78 21078666
2019 Role of ACTN4 in Tumorigenesis, Metastasis, and EMT. Cells 67 31766144
2019 Elevated TRIP13 drives the AKT/mTOR pathway to induce the progression of hepatocellular carcinoma via interacting with ACTN4. Journal of experimental & clinical cancer research : CR 63 31533816
2005 Analysis of NPHS1, NPHS2, ACTN4, and WT1 in Japanese patients with congenital nephrotic syndrome. Kidney international 63 15780077
2000 The human non-muscle alpha-actinin protein encoded by the ACTN4 gene suppresses tumorigenicity of human neuroblastoma cells. Oncogene 63 10656685
2019 Long Noncoding RNA SChLAP1 Forms a Growth-Promoting Complex with HNRNPL in Human Glioblastoma through Stabilization of ACTN4 and Activation of NF-κB Signaling. Clinical cancer research : an official journal of the American Association for Cancer Research 60 31492748
2017 Direct inhibition of ACTN4 by ellagic acid limits breast cancer metastasis via regulation of β-catenin stabilization in cancer stem cells. Journal of experimental & clinical cancer research : CR 55 29197410
2012 MTBP suppresses cell migration and filopodia formation by inhibiting ACTN4. Oncogene 47 22370640
2009 Patients with ACTN4 mutations demonstrate distinctive features of glomerular injury. Journal of the American Society of Nephrology : JASN 46 19357256
2013 Actin-binding protein alpha-actinin 4 (ACTN4) is a transcriptional co-activator of RelA/p65 sub-unit of NF-kB. Oncotarget 40 23482348
2013 Distinct outcome of stage I lung adenocarcinoma with ACTN4 cell motility gene amplification. Annals of oncology : official journal of the European Society for Medical Oncology 39 23899839
2009 Functional analysis of promoter mutations in the ACTN4 and SYNPO genes in focal segmental glomerulosclerosis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 39 19666657
2008 Familial focal segmental glomerulosclerosis associated with an ACTN4 mutation and paternal germline mosaicism. American journal of kidney diseases : the official journal of the National Kidney Foundation 39 18436095
2020 The role of actinin-4 (ACTN4) in exosomes as a potential novel therapeutic target in castration-resistant prostate cancer. Biochemical and biophysical research communications 38 31941606
2012 Familial focal segmental glomerulosclerosis (FSGS)-linked α-actinin 4 (ACTN4) protein mutants lose ability to activate transcription by nuclear hormone receptors. The Journal of biological chemistry 35 22351778
2016 Three-layered proteomic characterization of a novel ACTN4 mutation unravels its pathogenic potential in FSGS. Human molecular genetics 34 26740551
2012 ACTN4 gene amplification and actinin-4 protein overexpression drive tumour development and histological progression in a high-grade subset of ovarian clear-cell adenocarcinomas. Histopathology 34 22348389
2016 α Actinin 4 (ACTN4) Regulates Glucocorticoid Receptor-mediated Transactivation and Transrepression in Podocytes. The Journal of biological chemistry 32 27998979
2015 ACTN4 and the pathways associated with cell motility and adhesion contribute to the process of lung cancer metastasis to the brain. BMC cancer 30 25885339
2011 Identification of an FHL1 protein complex containing ACTN1, ACTN4, and PDLIM1 using affinity purifications and MS-based protein-protein interaction analysis. Molecular bioSystems 27 21246116
2021 The deubiquitinase OTUD3 stabilizes ACTN4 to drive growth and metastasis of hepatocellular carcinoma. Aging 26 34380780
2015 ACTN4 copy number increase as a predictive biomarker for chemoradiotherapy of locally advanced pancreatic cancer. British journal of cancer 26 25602965
2015 Tandem phosphorylation within an intrinsically disordered region regulates ACTN4 function. Science signaling 26 26012634
2020 Phosphorylation of ACTN4 Leads to Podocyte Vulnerability and Proteinuric Glomerulosclerosis. Journal of the American Society of Nephrology : JASN 25 32540856
2024 CCT3/ACTN4/TFRC axis protects hepatocellular carcinoma cells from ferroptosis by inhibiting iron endocytosis. Journal of experimental & clinical cancer research : CR 24 39210442
2009 Analysis of recessive CD2AP and ACTN4 mutations in steroid-resistant nephrotic syndrome. Pediatric nephrology (Berlin, Germany) 24 19956976
2004 Molecular analysis of NPHS2 and ACTN4 genes in a series of 33 Italian patients affected by adult-onset nonfamilial focal segmental glomerulosclerosis. Nephron. Clinical practice 24 15627790
2016 Efficacy of adjuvant chemotherapy for non-small cell lung cancer assessed by metastatic potential associated with ACTN4. Oncotarget 21 27121206
2019 Dysregulated expression of ACTN4 contributes to endothelial cell injury via the activation of the p38-MAPK/p53 apoptosis pathway in preeclampsia. Journal of physiology and biochemistry 20 31399951
2018 ACTN4 regulates the stability of RIPK1 in melanoma. Oncogene 20 29706658
2019 Focal segmental glomerulosclerosis ACTN4 mutants binding to actin: regulation by phosphomimetic mutations. Scientific reports 19 31664084
2021 TRIP13 exerts a cancer-promoting role in cervical cancer by enhancing Wnt/β-catenin signaling via ACTN4. Environmental toxicology 17 34061428
2020 CTCF-induced upregulation of HOXA11-AS facilitates cell proliferation and migration by targeting miR-518b/ACTN4 axis in prostate cancer. The Prostate 17 31971633
2019 Trophoblastic proliferation and invasion regulated by ACTN4 is impaired in early onset preeclampsia. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17 30776251
2018 Co-expression of RelA/p65 and ACTN4 induces apoptosis in non-small lung carcinoma cells. Cell cycle (Georgetown, Tex.) 17 29251177
2017 Tyro3-mediated phosphorylation of ACTN4 at tyrosines is FAK-dependent and decreases susceptibility to cleavage by m-Calpain. The international journal of biochemistry & cell biology 17 29274473
2013 Screening of ACTN4 and TRPC6 mutations in a Chinese cohort of patients with adult-onset familial focal segmental glomerulosclerosis. Contributions to nephrology 17 23689571
2019 ACTN4 Promotes the Proliferation, Migration, Metastasis of Osteosarcoma and Enhances its Invasive Ability through the NF-κB Pathway. Pathology oncology research : POR 16 30879239
2009 ACTN4 gene mutations and single nucleotide polymorphisms in idiopathic focal segmental glomerulosclerosis. Nephron. Clinical practice 16 19142020
2010 Proteomic analysis of ACTN4-interacting proteins reveals it's a putative involvement in mRNA metabolism. Biochemical and biophysical research communications 15 20519146
2022 MicroRNAs Promote the Progression of Sepsis-Induced Cardiomyopathy and Neurovascular Dysfunction Through Upregulation of NF-kappaB Signaling Pathway-Associated HDAC7/ACTN4. Frontiers in neurology 14 35756932
2023 The deubiquitinating enzyme MINDY2 promotes pancreatic cancer proliferation and metastasis by stabilizing ACTN4 expression and activating the PI3K/AKT/mTOR signaling pathway. Frontiers in oncology 13 37207150
2022 H3K27ac-activated EGFR-AS1 promotes cell growth in cervical cancer through ACTN4-mediated WNT pathway. Biology direct 13 34998421
2023 PHF23 promotes NSCLC proliferation, metastasis, and chemoresistance via stabilization of ACTN4 and activation of the ERK pathway. Cell death & disease 12 37626047
2022 Modeling of ACTN4-Based Podocytopathy Using Drosophila Nephrocytes. Kidney international reports 12 36815115
2020 circPHIP promotes oral squamous cell carcinoma progression by sponging miR-142-5p and regulating PHIP and ACTN4 expression. Molecular therapy. Nucleic acids 12 33376626
2014 Ubiquitin C-terminal hydrolase L1 deletion ameliorates glomerular injury in mice with ACTN4-associated focal segmental glomerulosclerosis. Biochimica et biophysica acta 12 24662305
2022 Angiopoietin-like protein 4 promotes hyperlipidemia-induced renal injury by down-regulating the expression of ACTN4. Biochemical and biophysical research communications 11 35101665
2022 ANGPTL4 promotes nephrotic syndrome by downregulating podocyte expression of ACTN4 and podocin. Biochemical and biophysical research communications 11 36495766
2020 ACTN4 Mediates SEPT14 Mutation-Induced Sperm Head Defects. Biomedicines 11 33228246
2022 Hsa_circ_0097922 promotes tamoxifen resistance and cell malignant behaviour of breast cancer cells by regulating ACTN4 expression via miR-876-3p. Clinical and experimental pharmacology & physiology 9 35856314
2022 RNF38 suppress growth and metastasis via ubiquitination of ACTN4 in nasopharyngeal carcinoma. BMC cancer 8 35568845
2019 Identification of a Novel ACTN4 Gene Mutation Which Is Resistant to Primary Nephrotic Syndrome Therapy. BioMed research international 8 31930129
2024 Terpene extract from the stem of Celastrus orbiculatus inhibits actin cytoskeleton remodelling in gastric cancer cells by regulating the protein interaction between PTBP1 and ACTN4. Journal of pharmaceutical analysis 7 39263353
2024 Characterization of ACTN4 as a novel antiviral target against SARS-CoV-2. Signal transduction and targeted therapy 7 39289355
2021 Binding of alpha-ACTN4 to EGF receptor enables its rapid phosphorylation. Heliyon 7 33532643
2024 Discovery of Novel TULP4/ACTN4/EWSR1/ACTB::MYB and ESRRG::DNM3 Fusions Expands Molecular Landscape of Adenoid Cystic Carcinoma Beyond Fusions Between MYB/MYBL1 and NFIB Genes. The American journal of surgical pathology 6 39235305
2022 Alpha-actnin-4 (ACTN4) selectively affects the DNA double-strand breaks repair in non-small lung carcinoma cells. Biology direct 6 36476259
2015 Rapid progression to end-stage renal disease in a child with a sporadic ACTN4 mutation. Clinical nephrology. Case studies 6 29043128
2013 Mutational analysis of ACTN4, encoding α-actinin 4, in patients with focal segmental glomerulosclerosis using HRM method. Folia biologica 6 23890478
2022 ANGPTL3 is involved in kidney injury in high-fat diet-fed mice by suppressing ACTN4 expression. Lipids in health and disease 5 36123608
2020 Combined Detection of ACTN4 and SCC-Ag is a Promising Serological Biomarker for Cervical Intraepithelial Neoplasia 3 or Worse: A Case-Control Study. Risk management and healthcare policy 5 33244281
2019 Correction to: Elevated TRIP13 drives the AKT/mTOR pathway to induce the progression of hepatocellular carcinoma via interacting with ACTN4. Journal of experimental & clinical cancer research : CR 5 31666112
2018 Measurement of copy number of ACTN4 to optimize the therapeutic strategy for locally advanced pancreatic cancer. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 5 29921500
2012 Relevance of the ACTN4 gene in African-Americans with non-diabetic end-stage renal disease. American journal of nephrology 5 22965004
2022 Case report and literature review: A de novo pathogenic missense variant in ACTN4 gene caused rapid progression to end-stage renal disease. Frontiers in pediatrics 4 36090564
2020 oxLDL promotes podocyte migration by regulating CXCL16, ADAM10 and ACTN4. Molecular medicine reports 4 32705248
2025 Cancer-associated fibroblast-derived COL17A1 promotes gemcitabine resistance and tumorigenesis in pancreatic cancer cells by interacting with ACTN4. Discover oncology 3 39907925
2025 KRAS/ACTN4/p65-NR2A axis mediates glutamine-glutamate metabolic coupling between schwann cells and pancreatic cancer promoting perineural invasion. Journal of advanced research 3 41135873
2022 Alpha-actinin-4 (ACTN4) gene amplification is a predictive biomarker for adjuvant chemotherapy with tegafur/uracil in stage I lung adenocarcinomas. Cancer science 3 34845792
2022 LncRNA TP73-AS1 Exacerbates the Non-Small-Cell Lung Cancer (NSCLC) Process via Regulating miR-125a-3p-Mediated ACTN4. Evidence-based complementary and alternative medicine : eCAM 3 36118078
2022 Benefits from Adjuvant Chemotherapy in Patients with Resected Non-Small Cell Lung Cancer: Possibility of Stratification by Gene Amplification of ACTN4 According to Evaluation of Metastatic Ability. Cancers 3 36139525
2025 A Novel Gastrodin Derivative with Neuroprotection Promotes NGF-Mimic Activity by Targeting INSR and ACTN4 to Activate PI3K/Akt Signaling Pathway in PC12 Cells. Antioxidants (Basel, Switzerland) 2 40227445
2025 Unraveling the role of the WIPF1/ACTN4 complex in podosome formation of human placental EVTs: Insights into recurrent spontaneous abortion. Genes & diseases 2 40821124
2025 Early use of renin-angiotensin-aldosterone system inhibitors and stable renal function in familial focal segmental glomerulosclerosis with ACTN4 mutation: a case report and literature review. BMC nephrology 2 41013435
2025 HDAC5 deacetylates cytosolic ACTN4 during skin reepithelialization and represents a therapeutic target for chronic wound healing. Science translational medicine 2 41442502
2024 ACTN4 is associated with the malignant potential of thymic epithelial tumors through the β-catenin/Slug pathway. Cancer science 2 39166351
2024 High MICAL-L2 promotes cancer progression and drug resistance in renal clear cell carcinoma cells through stabilization of ACTN4 following vimentin expression. Biochimica et biophysica acta. Molecular basis of disease 2 39689763
2025 DANCR knockdown alleviates neuroinflammation and functional recovery after spinal cord injury via regulating the ACTN4 / STAT3 axis. Archives of biochemistry and biophysics 1 39798643
2025 SOCS1 depletion drives osteosarcoma stemness and chemoresistance by suppressing ACTN4 degradation. Acta pharmacologica Sinica 1 40890444
2025 Novel WT1 and ACTN4 co-mutations in a patient with Denys-Drash syndrome and an atypical, potentially attenuated presentation of nephropathy: a case report. BMC nephrology 1 40890712
2025 Actn4 Links Inactive Integrin α5 With Actin in Zebrafish Somites. Molecular & cellular proteomics : MCP 1 41072919
2024 Live-cell imaging and CLEM reveal the existence of ACTN4-dependent ruffle-edge lamellipodia acting as a novel mode of cell migration. Experimental cell research 1 39222868
2021 [Molecular mechanism of miR-369-3p regulating hepatocellular carcinoma cell proliferation and apoptosis by targeting ACTN4]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 1 34794217
2018 Erratum: Actin-binding protein alpha-actinin 4 (ACTN4) is a transcriptional co-activator of RelA/p65 sub-unit of NF-kB. Oncotarget 1 30344954
2026 Endothelial PDLIM5 promotes tip cell filopodia formation and tumor angiogenesis by regulating ACTN1/ACTN4-dependent actin bundling. Nature communications 0 41605926
2026 The circular RNA Phc3 promotes the repair of damage to the intestinal mucosal barrier by regulating the miR-93/PHF6 and ACTN4 pathways. Burns : journal of the International Society for Burn Injuries 0 42155289
2025 A pediatric-onset case of chronic kidney disease caused by a novel sporadic ACTN4 variant and literature review. The Turkish journal of pediatrics 0 40925038
2024 Retracted: Identification of a Novel ACTN4 Gene Mutation Which Is Resistant to Primary Nephrotic Syndrome Therapy. BioMed research international 0 38550222
2024 Association of ACTN4 Gene Mutation with Primary Nephrotic Syndrome in Children in Guangxi Autonomous Region, China. Genetic testing and molecular biomarkers 0 38949978
2023 Analysis of the association of NPHS2 and ACTN4 genes polymorphism with nephrotic syndrome in Egyptian children. Molecular biology reports 0 37014572
2021 Retraction Notice to: circPHIP promotes oral squamous cell carcinoma progression by sponging miR-142-5p and regulating PHIP and ACTN4 expression. Molecular therapy. Nucleic acids 0 34938602

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