| 1998 |
LIM-kinase 1 (LIMK1) directly phosphorylates cofilin (CFL1) at Serine 3, both in vitro and in vivo. This phosphorylation abolishes cofilin's actin-depolymerizing activity. LIMK1 expression induces actin stress fiber formation, while an inactive LIMK1 suppresses Rac-induced lamellipodium formation. Rac and insulin activate LIMK1, placing LIMK1-mediated cofilin phosphorylation downstream of Rac in actin cytoskeletal reorganization. |
In vitro kinase assay, site-directed mutagenesis (Ser3), overexpression and dominant-negative LIMK1 in cultured cells, actin depolymerization assay |
Nature |
High |
9655398
|
| 1999 |
The Rho-associated kinase ROCK phosphorylates and activates LIM-kinase, which in turn phosphorylates cofilin (CFL1) to inactivate its actin-depolymerizing activity. This ROCK→LIMK→cofilin cascade mediates Rho-induced actin cytoskeletal reorganization (stress fiber formation) and neurite retraction. ROCK does not phosphorylate cofilin directly; the Y-27632 ROCK inhibitor blocks cofilin phosphorylation in cells. |
Pharmacological inhibition (Y-27632), overexpression of LIMK1 in HeLa cells, in vivo phosphorylation assays in neuroblastoma cells, epistasis with dominant-negative constructs |
Science |
High |
10436159
|
| 2002 |
The Slingshot (SSH) family of phosphatases dephosphorylate phospho-cofilin (p-CFL1) to reactivate its actin-depolymerizing function. SSH binds F-actin and dephosphorylates P-cofilin both in cultured cells and in cell-free assays. Loss of SSH in Drosophila dramatically increases F-actin levels and phospho-cofilin, disrupting epidermal cell morphogenesis. Human SSH homologs (hSSH1) suppress LIMK1-induced actin reorganization by reactivating cofilin. |
Drosophila loss-of-function genetics, cell-free phosphatase assays, overexpression of hSSH in mammalian cells, F-actin binding assays |
Cell |
High |
11832213
|
| 1996 |
Human non-muscle cofilin (CFL1) was cloned from a promyelocytic cDNA library and mapped to chromosome 11q13 by PCR in somatic cell hybrids and FISH. Muscle-type cofilin (CFL2) was mapped to chromosome 14. CFL1 encodes an actin-binding protein involved in translocation of the actin-cofilin complex from cytoplasm to nucleus. |
cDNA cloning, PCR mapping in rodent-human somatic cell hybrids, FISH with genomic cosmid clones, irradiation hybrid panel mapping |
Annals of human genetics |
High |
8800436
|
| 2007 |
Genetic variants (SNPs) in the human CFL1 gene are associated with increased spina bifida risk, consistent with the essential role of CFL1 in actin depolymerization during neural tube closure. Cfl1 knockout mice fail to close the neural tube at E10.5 and die in utero, establishing CFL1 as essential for neural tube development. |
Population-based case-control SNP association study, reference to Cfl1 knockout mouse phenotype |
BMC medical genetics |
Medium |
17352815
|
| 2017 |
miR-200b-3p and miR-429-5p directly target LIMK1, reducing LIMK1 expression and consequently decreasing phosphorylation (inactivation) of cofilin-1 (CFL1). Reduced LIMK1 activity allows CFL1 to remain active, altering F-actin/G-actin dynamics. This LIMK1/CFL1 pathway mediates the suppressive effects of these miRNAs on triple-negative breast cancer cell proliferation, migration, and invasion. |
Luciferase reporter assay for direct miRNA targeting of LIMK1, Western blotting for CFL1 and p-CFL1, migration/invasion assays, cell cycle analysis |
Oncotarget |
Medium |
29156719
|
| 2019 |
In contracting zebrafish cardiomyocytes, mechanical forces regulate vinculin (VCL) localization and activation. VCL recruits the phosphatase SSH1 and its effector cofilin (CFL) to regulate F-actin rearrangement and promote myofilament maturation. The VCL-SSH1-CFL axis is essential: loss of VCL or disruption of this pathway impairs myofilament maturation in response to cardiac contractility. |
Zebrafish genetic knockouts, interactome analysis (contracting vs. non-contracting cardiomyocytes by MS), co-immunoprecipitation, live imaging |
Developmental cell |
High |
31495694
|
| 2020 |
SSH1, the canonical cofilin (CFL1) phosphatase, also dephosphorylates phospho-Ser403-SQSTM1/p62, thereby impairing autophagic cargo clearance. This action of SSH1 on SQSTM1 is separable from SSH1-mediated CFL1 activation and independent of CFL1, revealing a bifurcated SSH1 function. SSH1-mediated inhibition of SQSTM1 impairs clearance of phospho-MAPT/tau. |
RNAi knockdown, overexpression, defined phospho-mutant constructs, fluorescent autophagy reporters, experiments in cell lines, primary neurons, and mouse brains |
Autophagy |
High |
33044112
|
| 2021 |
Hhex (hematopoietically expressed homeobox) inhibits CFL1 phosphorylation, keeping CFL1 in its active F-actin-severing form, thereby suppressing cell migration and protrusion formation in lung cancer cells. Mechanistically, Hhex enhances the interaction of RHOGDIA with RHOA/CDC42, maintaining these GTPases in their inactive state and blocking the RHOA/CDC42→p-CFL1 signaling cascade. This prevents filopodium and lamellipodium formation. |
Western blot, co-immunoprecipitation, wound-healing scratch assay, laser confocal microscopy, overexpression/knockdown in NSCLC and HEK293FT cells |
Cell communication and signaling |
Medium |
34321041
|
| 2021 |
E2F4-induced lncRNA AGAP2-AS1 acts as a competing endogenous RNA (ceRNA) to sponge miR-182-5p, thereby upregulating CFL1 expression. CFL1 restoration counteracts the suppression of CRC cell growth, migration, invasion, and EMT caused by AGAP2-AS1 depletion, placing CFL1 as a downstream effector of this AGAP2-AS1/miR-182-5p axis in colorectal cancer progression. |
RT-qPCR, Western blot, luciferase reporter assays, rescue experiments in vitro and in vivo (xenograft) |
Digestive and liver disease |
Medium |
34838479
|
| 2022 |
Computational analysis of nonsynonymous SNPs in CFL1 identifies L84P and L99A as the most damaging variants. Molecular docking shows these variants reduce cofilin-1 binding affinity for actin, and molecular dynamics simulations confirm protein structure destabilization. The actin-binding regions of cofilin-1 are highly conserved and critical for function. |
In silico prediction tools (SIFT, PolyPhen-2, DynaMut/DUET), molecular docking, molecular dynamics simulation |
Gene |
Low |
35092861
|
| 2022 |
Estradiol (E2) inhibits HIV-1 infection in PBMCs and endocervical tissue and simultaneously increases total CFL1 and phosphorylated CFL1 (p-CFL1) protein expression, raising the p-CFL1/CFL1 ratio. LIM kinase inhibitor (LIMKi3) abrogates both the anti-HIV effect and E2-induced CFL1/p-CFL1 upregulation, and CFL1 knockdown partially restores HIV infection, indicating that LIMK-mediated CFL1 phosphorylation is part of the mechanism by which E2 restricts HIV-1 entry/spread. |
HIV infection assay, siRNA knockdown of CFL1, pharmacological LIMK inhibition (LIMKi3), Western blotting for total and p-CFL1, dose-response experiments |
Scientific reports |
Medium |
35418661
|
| 2023 |
CFL1 promotes transcription of phosphoglycerate dehydrogenase (PHGDH), enhancing serine synthesis and metabolism to increase antioxidant production, thereby scavenging ROS induced by sorafenib and reducing sorafenib sensitivity in hepatocellular carcinoma. siRNA-mediated CFL1 silencing re-sensitizes HCC cells to sorafenib. |
Transcriptome sequencing comparison of sorafenib-sensitive vs. insensitive patients, CFL1 siRNA knockdown via nanoparticles, PHGDH promoter assays, ROS measurement, in vivo tumor growth assays |
Advanced science |
Medium |
37203277
|
| 2023 |
HUNK kinase directly phosphorylates GEF-H1 at Serine 645, which activates RhoA and triggers a phosphorylation cascade of LIMK-1 and CFL-1, thereby stabilizing F-actin and inhibiting EMT and metastasis in colorectal cancer cells. This places CFL-1 phosphorylation as a downstream effector of the HUNK→GEF-H1→RhoA→LIMK-1 cascade. |
In vitro kinase assay (HUNK phosphorylating GEF-H1), site-directed mutagenesis (S645), Western blotting for LIMK-1/p-CFL-1, migration/invasion assays, clinical tissue analysis |
Cell death & disease |
High |
37193711
|
| 2024 |
CFL1 overexpression in pSS bone marrow mesenchymal stem cells rescues their impaired migration and proliferation. RNA-seq identifies CCR1 as a downstream target gene of CFL1, and inhibition of CCR1 with BX431 suppresses the CFL1-induced increase in migration/proliferation, establishing that CFL1 promotes BM-MSC motility via upregulation of the CCL5/CCR1 axis. |
Lentivirus-mediated CFL1 overexpression, RNA-seq, Transwell migration assay, wound healing assay, CCR1 inhibitor rescue experiment (BX431), NOD mouse therapeutic model |
International immunopharmacology |
Medium |
38183912
|
| 2024 |
c-Myc directly transactivates the CFL1 promoter by binding to E-box elements (particularly middle and proximal E-boxes), inducing cofilin-1 expression. Cofilin-1 upregulation is required for c-Myc-induced oncogene-induced senescence (OIS): cofilin-1 knockdown suppresses cMIS. Physical interaction between c-Myc and cofilin-1 was detected, enhanced by H2O2. The conditioned medium from cMIS cells promotes migration and proliferation of other NSCLC cells, an effect abrogated by cofilin-1 silencing. |
ChIP-qPCR, luciferase reporter assay, siRNA knockdown, co-immunoprecipitation (c-Myc and cofilin-1), senescence assays, conditioned medium transfer experiments |
Cell death discovery |
High |
41888102
|
| 2024 |
Conditional knockout of neuronal CFL1 (cofilin-1) impedes tumor-nerve interactions in head and neck squamous cell carcinoma. HNSCC cells induce CFL1 expression in adjacent neurons, and it is neuronal (not tumoral) CFL1 that drives cancer-nerve crosstalk and perineural invasion, as demonstrated by multiplex fluorescent immunohistochemistry localizing CFL1 to nerves and by conditional KO experiments. |
Multiplex fluorescent immunohistochemistry, conditional neuronal CFL1 knockout, Gene Ontology/GSEA analysis |
Molecular carcinogenesis |
Medium |
38353363
|
| 2024 |
miR-342-5p targets CFL1 (cofilin-1) mRNA in HDACi-resistant HCC cells; overexpression of miR-342-5p decreases cofilin-1 protein expression and increases ROS-mediated apoptosis, sensitizing cells to HDACi treatment. This identifies the miR-342-5p/CFL1 axis as a mediator of HDACi resistance. |
miRNA microarray, qRT-PCR, gain/loss-of-function studies, Western blot, apoptosis assays (Bax, caspase-3, Bcl-2), ROS measurement |
Cancer cell international |
Medium |
39152428
|
| 2024 |
CFL1 (cofilin-1) is required for mast cell development: expression of a non-functional form of Cfl1 in connective tissue mast cells (CTMCs) using Mcpt5-Cre results in complete absence of CTMCs without affecting basophils. CTMCs lacking Cfl1 function show impaired systemic anaphylaxis but normal susceptibility to contact hypersensitivity and psoriasis-like dermatitis, demonstrating that cofilin-1-mediated actin dynamics are essential specifically for CTMC generation. |
Conditional knock-in mouse (Mcpt5-Cre-nf-Cfl1fl/fl), mast cell/basophil enumeration, anaphylaxis model, contact hypersensitivity model, imiquimod model, vaccinia virus infection |
Frontiers in immunology |
High |
41684538
|
| 2025 |
Overexpression of cofilin (Cfl1) in the polymorphic layer of the hippocampal dentate gyrus increases motivation to seek alcohol and sucrose rewards, impairs extinction of alcohol seeking, and inhibits ML-DG synapses; reducing Cfl1 has opposite effects. Three SNPs in human CFL1 (rs369270402, rs2376005, rs36124259) are associated with increased AUD risk, and CFL1 mRNA blood levels correlate with alcohol-related hospital admissions. AUD-prone mice show differential hippocampal Cfl expression linked to actin cytoskeleton and synaptic function genes. |
RNA sequencing, local viral vector Cfl overexpression/knockdown in DG, IntelliCage behavioral model, electrophysiology (ML-DG synapse recording), human genetic association study |
Molecular psychiatry |
High |
40931167
|
| 2024 |
Deficiency of ADF and Cofilin1 (Cfl1) in microglia causes profound morphological changes, reduces microglial fine process motility and migration toward laser-induced lesions in vivo, and increases stabilized F-actin with altered microtubule dynamics. Microglial ADF/Cfl1 deficiency also impairs learning and memory, linking microglial cytoskeletal dynamics to neuronal cognitive function. |
Conditional microglial ADF/Cfl1 knockout, in vivo two-photon imaging, F-actin immunostaining, microtubule dynamics assays, behavioral learning/memory tests |
bioRxiv (preprint)preprint |
Medium |
bio_10.1101_2024.09.27.615114
|