Affinage

CFL1

Cofilin-1 · UniProt P23528

Length
166 aa
Mass
18.5 kDa
Annotated
2026-06-09
42 papers in source corpus 15 papers cited in narrative 15 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

CFL1 (non-muscle cofilin-1) is an actin-binding protein that severs and depolymerizes F-actin to drive cytoskeletal remodeling underlying cell migration, tissue morphogenesis, and synaptic function (PMID:8800436, PMID:41684538). Its activity is gated by reversible phosphorylation: LIMK1 directly phosphorylates and inactivates CFL1, blocking its F-actin/G-actin remodeling activity (PMID:29156719), while the phosphatase SSH1 dephosphorylates and reactivates it (PMID:33044112). This kinase-phosphatase switch sits downstream of RHOA/CDC42 signaling, where upstream regulators such as Hhex (via RHOGDIA sequestration of RHOA/CDC42) and HUNK (via GEF-H1/RhoA activation) tune the RHOA/CDC42-LIMK1-pCFL1 cascade to control filopodium/lamellipodium formation, EMT, and metastasis (PMID:34321041, PMID:37193711). Mechanical forces transmitted through vinculin recruit SSH1 and cofilin to remodel F-actin during cardiomyocyte myofilament maturation, embedding CFL1 in mechanotransduction (PMID:31495694). CFL1-dependent actin depolymerization is genetically essential for connective tissue mast cell formation and systemic anaphylaxis (PMID:41684538) and, together with ADF, for microglial process motility, migration, and learning-related behavior [PMID:bio_10.1101_2024.09.27.615114]. Beyond its cytoskeletal role, CFL1 acts as a transcriptional driver: c-Myc binds E-boxes in the CFL1 promoter to upregulate cofilin-1 and induce oncogene-induced senescence with nuclear G-actin accumulation (PMID:41888102), and CFL1 promotes PHGDH transcription to enhance serine synthesis and antioxidant output, conferring sorafenib resistance in hepatocellular carcinoma (PMID:37203277).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1996 High

    Establishing the molecular identity and chromosomal locus of human non-muscle cofilin distinguished CFL1 from its muscle paralog and framed it as an actin-binding protein capable of nuclear translocation.

    Evidence PCR in somatic cell hybrids, FISH, and radiation hybrid mapping

    PMID:8800436

    Open questions at the time
    • Did not define the biochemical regulation of severing activity
    • Functional consequences of cytoplasm-to-nucleus translocation left unresolved
  2. 2017 Medium

    Identifying LIMK1 as a direct upstream kinase that phosphorylates and inactivates CFL1 connected cofilin regulation to cancer cell motility.

    Evidence LIMK1 knockdown with pCFL1/CFL1 Western blot and migration/invasion assays in TNBC cells

    PMID:29156719

    Open questions at the time
    • No in vitro kinase reconstitution
    • Single cell-line context
  3. 2019 High

    Linking CFL1 to mechanotransduction showed that vinculin recruits the SSH1 phosphatase to activate cofilin for F-actin rearrangement during cardiomyocyte myofilament maturation.

    Evidence Interactome profiling, Co-IP, genetic loss-of-function and epistasis with live imaging in zebrafish cardiomyocytes

    PMID:31495694

    Open questions at the time
    • Direct binding stoichiometry of the VCL-SSH1-CFL axis not resolved
    • Mammalian generalization not tested in this study
  4. 2020 High

    Demonstrating that SSH1 dephosphorylates p62/SQSTM1 independently of cofilin established that the cofilin phosphatase has CFL-independent substrates, refining how SSH1 activity relates to CFL1.

    Evidence RNAi, overexpression of defined mutants, fluorescent reporters in cell lines and primary neurons

    PMID:33044112

    Open questions at the time
    • Does not directly address CFL1 catalytic mechanism
    • Relative flux through CFL-dependent vs independent SSH1 actions in vivo unknown
  5. 2021 Medium

    Placing CFL1 downstream of RHOA/CDC42-LIMK1 and under Hhex/RHOGDIA control clarified how upstream small-GTPase regulation tunes cofilin-mediated severing and migration.

    Evidence Co-IP, scratch assays, confocal imaging, and pathway epistasis in NSCLC cells

    PMID:34321041

    Open questions at the time
    • Single lab and cell-type
    • Direct effect on CFL1 severing kinetics not measured
  6. 2023 Medium

    Identifying HUNK-GEF-H1-RhoA as an upstream input into the LIMK1/CFL1 axis extended the regulatory map of cofilin phosphorylation to suppression of EMT and metastasis.

    Evidence In vitro kinase assay on GEF-H1, phospho-CFL1 Western blot, and metastasis assays in colorectal cancer cells

    PMID:37193711

    Open questions at the time
    • CFL1 phosphorylation inferred from cascade, not directly reconstituted
    • Single lab
  7. 2023 Medium

    Revealing that CFL1 promotes PHGDH transcription assigned cofilin a non-cytoskeletal role in serine/antioxidant metabolism that drives chemoresistance.

    Evidence Transcriptome sequencing, siRNA knockdown, metabolic assays, and in vivo nanoparticle co-delivery in HCC

    PMID:37203277

    Open questions at the time
    • Mechanism by which CFL1 reaches/regulates the PHGDH promoter not defined
    • Whether this requires nuclear actin binding unknown
  8. 2024 High

    Genetic knock-in of non-functional Cfl1 in connective tissue mast cells proved that cofilin-dependent actin depolymerization is required for mast cell formation and anaphylaxis.

    Evidence Cell-type-specific knock-in (Mcpt5-Cre-nf-Cfl1), flow cytometry, passive systemic anaphylaxis

    PMID:41684538

    Open questions at the time
    • Developmental step at which CTMCs are lost not pinpointed
    • Upstream regulators of CFL1 in mast cells not identified
  9. 2024 Medium

    Conditional loss of ADF/Cfl1 in microglia established cofilin as required for F-actin/microtubule balance, process motility, and lesion-directed migration with cognitive consequences.

    Evidence Conditional KO, in vivo two-photon imaging, cytoskeletal staining, behavioral tests (preprint)

    PMID:bio_10.1101_2024.09.27.615114

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • ADF and Cfl1 contributions not separated
  10. 2024 Medium

    Linking CFL1 to chemokine signaling and to perineural invasion broadened its migratory roles to MSC homing (CCR1 axis) and tumor-nerve interactions.

    Evidence Lentiviral CFL1 overexpression with CCR1 inhibitor rescue and NOD model; conditional neuronal CFL1 KO with tumor-nerve co-culture and multiplex IHC

    PMID:38183912 PMID:38353363

    Open questions at the time
    • Mechanism connecting CFL1 to CCR1 transcription unclear
    • Cell-intrinsic vs microenvironmental contributions only partly dissected
  11. 2025 Medium

    Bidirectional manipulation of hippocampal Cfl1 demonstrated a role in regulating synaptic transmission and alcohol-seeking behavior, extending cofilin function to neural circuits.

    Evidence Viral overexpression/knockdown in dentate gyrus subregions, two-photon synaptic imaging, IntelliCage behavior, RNA-seq

    PMID:40931167

    Open questions at the time
    • Molecular link between cofilin activity and synaptic change not resolved
    • Single lab
  12. 2026 Medium

    Showing c-Myc directly transactivates CFL1 via promoter E-boxes positioned cofilin as a transcriptional effector driving oncogene-induced senescence and nuclear G-actin accumulation.

    Evidence ChIP-qPCR, cofilin-1 knockdown, c-Myc mutants, Co-IP, F-actin/G-actin assays in lung cancer cells

    PMID:41888102

    Open questions at the time
    • Functional significance of the c-Myc-cofilin physical interaction unclear
    • How nuclear G-actin accumulation enforces senescence not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the phosphorylation switch, nuclear actin shuttling, and transcriptional/metabolic functions of CFL1 are coordinated within a single cell remains unresolved.
  • No structural model integrating regulatory inputs
  • Direct vs indirect mechanism of CFL1 transcriptional effects unknown
  • Tissue-specific regulators upstream of LIMK/SSH1 not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 2 GO:0005856 cytoskeleton 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2
Partners

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 Mechanical forces from cardiac contractility regulate cardiomyocyte myofilament maturation through the VCL-SSH1-CFL axis: vinculin (VCL) recruits the phosphatase SSH1 and its effector cofilin (CFL) to regulate F-actin rearrangement and promote myofilament maturation in zebrafish cardiomyocytes. Interactome profiling (contracting vs. non-contracting cardiomyocytes), Co-IP, genetic loss-of-function, live imaging, epistasis analysis Developmental cell High 31495694
2017 LIMK1 directly phosphorylates and inactivates CFL1; inhibition of LIMK1 reduces CFL1 expression and phosphorylation, thereby impairing CFL1-dependent F-actin/G-actin remodeling and suppressing breast cancer cell migration and invasion. Western blot for pCFL1/CFL1 following LIMK1 knockdown, migration/invasion assays, miRNA mimic transfection in TNBC cells Oncotarget Medium 29156719
2020 SSH1, the canonical CFL (cofilin) phosphatase, dephosphorylates phospho-Ser403-SQSTM1/p62, impairing autophagic cargo clearance; this action is separable from SSH1-mediated CFL activation, demonstrating that SSH1 has a CFL-independent substrate. RNAi knockdown, overexpression with defined mutant constructs, genetically encoded fluorescent reporters, cell lines and primary neurons Autophagy High 33044112
2021 Hhex enhances the interaction of RHOGDIA with RHOA/CDC42, maintaining them in inactive forms, which blocks the RHOA/CDC42–LIMK1–pCFL1 signaling cascade, preserving CFL1 F-actin-severing activity and suppressing filopodium/lamellipodium formation and cell migration in lung cancer cells. Western blot, co-immunoprecipitation, wound-healing scratch assay, laser confocal imaging, overexpression/knockdown in NSCLC cells Cell communication and signaling : CCS Medium 34321041
2023 HUNK kinase directly phosphorylates GEF-H1 at serine 645, which activates RhoA and triggers a cascade of LIMK-1/CFL-1 phosphorylation that stabilizes F-actin and inhibits EMT and metastasis in colorectal cancer cells. In vitro kinase assay (direct phosphorylation), Western blot for phospho-CFL-1, overexpression/knockdown, metastasis assays Cell death & disease Medium 37193711
2023 CFL1 promotes phosphoglycerate dehydrogenase (PHGDH) transcription to enhance serine synthesis and metabolism, increasing antioxidant production that scavenges sorafenib-induced ROS, thereby impairing sorafenib sensitivity in hepatocellular carcinoma. Transcriptome sequencing of sorafenib-sensitive vs. insensitive HCC patients, siRNA knockdown, metabolic assays, nanoparticle co-delivery experiments in vivo Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 37203277
2022 Estradiol (E2) dose-dependently increases total CFL1 and phosphorylated CFL1 (pCFL1) expression in PBMCs and endocervical mucosa, and this induction is abrogated by LIMK1/2 inhibitor LIMKi3; CFL1 knockdown partially restores HIV-1 infection suppressed by E2, linking E2-mediated CFL1 phosphorylation to inhibition of HIV-1BaL infection. LIMK inhibitor treatment, CFL1 siRNA knockdown, protein expression by Western blot, HIV-1 infectivity assay in PBMCs and endocervical explants Scientific reports Medium 35418661
2024 CFL1 overexpression in pSS bone marrow MSCs restores their migratory capacity by upregulating CCR1 expression; pharmacological inhibition of CCR1 suppresses the CFL1-induced migration and proliferation, placing CFL1 upstream of the CCL5/CCR1 axis. Lentivirus-mediated CFL1 overexpression, RNA-seq, Transwell migration assay, wound healing assay, CCR1 inhibitor rescue experiment, NOD mouse model International immunopharmacology Medium 38183912
2024 Expression of a non-functional form of Cfl1 (nf-Cfl1) in connective tissue mast cells (CTMCs) via Mcpt5-Cre results in complete absence of CTMCs, demonstrating that Cfl1-dependent actin depolymerization is essential for CTMC formation; CTMCs lacking Cfl1 activity show impaired systemic anaphylaxis. Conditional knock-in of non-functional Cfl1 in CTMCs (Mcpt5-Cre-nf-Cfl1fl/fl), flow cytometry, passive systemic anaphylaxis model Frontiers in immunology High 41684538
2025 Overexpression of Cfl1 in the polymorphic layer of the hippocampal dentate gyrus (PoDG) inhibits ML-DG synapses, increases motivation to seek alcohol, impairs extinction of alcohol-seeking, and decreases reward consumption during relapse; reducing Cfl1 levels has opposite effects, establishing hippocampal Cfl1 as a regulator of synaptic transmission and AUD-relevant behavior. Local viral overexpression/knockdown of Cfl in hippocampal DG subregions, in vivo two-photon imaging of synaptic activity, automated IntelliCage behavioral testing, RNA sequencing Molecular psychiatry Medium 40931167
2026 c-Myc transcriptionally activates CFL1 by binding E-boxes in the CFL1 promoter (confirmed by ChIP-qPCR); cofilin-1 upregulation mediates c-Myc-induced oncogene-induced senescence (OIS) and F-actin/nuclear G-actin accumulation in lung cancer cells; knockdown of cofilin-1 suppresses cMIS, and a physical interaction between c-Myc and cofilin-1 was detected by co-immunoprecipitation. ChIP-qPCR, cofilin-1 knockdown, c-Myc overexpression/truncation mutants, Co-IP, F-actin/G-actin assays, conditioned medium bystander assays Cell death discovery Medium 41888102
2024 Conditional knockout of ADF and Cfl1 in microglia (ADF/Cfl1-KO) causes increased accumulation of stabilized F-actin and altered microtubule dynamics, reduces microglial fine process motility, and impairs migration toward laser-induced lesions in vivo; microglial ADF/Cfl1-deficiency also decreases learning and memory in mice. Conditional KO mouse model, in vivo two-photon imaging, F-actin staining, microtubule dynamics assays, behavioral memory tests bioRxivpreprint Medium bio_10.1101_2024.09.27.615114
1996 Human non-muscle cofilin (CFL1) was mapped to chromosome 11q13 by PCR in somatic cell hybrid panels and confirmed by FISH, while muscle-type cofilin (CFL2) was mapped to chromosome 14; CFL1 was identified as an actin-binding protein involved in actin-cofilin complex translocation from cytoplasm to nucleus. PCR in rodent-human somatic cell hybrids, FISH of genomic cosmid clones, radiation hybrid mapping Annals of human genetics High 8800436
2024 CFL1 expression in nerves (rather than in tumor cells) within the head and neck squamous cell carcinoma (HNSCC) tumor microenvironment is associated with perineural invasion; HNSCC cells induce neuronal CFL1 expression, and conditional knockout of neuronal CFL1 impedes tumor-nerve interactions. Multiplex fluorescent immunohistochemistry, conditional neuronal CFL1 knockout, tumor-nerve co-culture models Molecular carcinogenesis Medium 38353363
2024 Imatinib therapy in CML upregulates CFL1 expression and activity (cofilin, P-cofilin) and increases F-actin (including branched F-actin), indicating that imatinib affects F-actin remodeling in CML cells by regulating CFL1. Western blot for CFL1 and P-cofilin in CML patient samples and cell lines pre/post imatinib, F-actin staining Journal of Cancer Low 38495482

Source papers

Stage 0 corpus · 42 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 The microRNAs miR-200b-3p and miR-429-5p target the LIMK1/CFL1 pathway to inhibit growth and motility of breast cancer cells. Oncotarget 78 29156719
2010 The expression of CFL1 and N-WASP in esophageal squamous cell carcinoma and its correlation with clinicopathological features. Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus 59 20095995
2000 Candida albicans CFL1 encodes a functional ferric reductase activity that can rescue a Saccharomyces cerevisiae fre1 mutant. Microbiology (Reading, England) 56 10784045
2019 Mechanical Forces Regulate Cardiomyocyte Myofilament Maturation via the VCL-SSH1-CFL Axis. Developmental cell 44 31495694
2013 A low membrane lipid phase transition temperature is associated with a high cryotolerance of Lactobacillus delbrueckii subspecies bulgaricus CFL1. Journal of dairy science 40 23810590
2023 Remodeling Serine Synthesis and Metabolism via Nanoparticles (NPs)-Mediated CFL1 Silencing to Enhance the Sensitivity of Hepatocellular Carcinoma to Sorafenib. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 33 37203277
1996 Mapping of human non-muscle type cofilin (CFL1) to chromosome 11q13 and muscle-type cofilin (CFL2) to chromosome 14. Annals of human genetics 33 8800436
2014 Novel role of the Candida albicans ferric reductase gene CFL1 in iron acquisition, oxidative stress tolerance, morphogenesis and virulence. Research in microbiology 32 24631590
2018 Identification of CRKII, CFL1, CNTN1, NME2, and TKT as Novel and Frequent T-Cell Targets in Human IDH-Mutant Glioma. Clinical cancer research : an official journal of the American Association for Cancer Research 26 29563135
2016 Plant lectins ConBr and CFL modulate expression toll-like receptors, pro-inflammatory cytokines and reduce the bacterial burden in macrophages infected with Salmonella enterica serovar Typhimurium. Phytomedicine : international journal of phytotherapy and phytopharmacology 24 28190471
2014 A novel role of the ferric reductase Cfl1 in cell wall integrity, mitochondrial function, and invasion to host cells in Candida albicans. FEMS yeast research 22 25130162
2021 Hhex inhibits cell migration via regulating RHOA/CDC42-CFL1 axis in human lung cancer cells. Cell communication and signaling : CCS 18 34321041
2020 SSH1 impedes SQSTM1/p62 flux and MAPT/Tau clearance independent of CFL (cofilin) activation. Autophagy 18 33044112
2007 Association between CFL1 gene polymorphisms and spina bifida risk in a California population. BMC medical genetics 18 17352815
2021 E2F4-induced AGAP2-AS1 up-regulation accelerates the progression of colorectal cancer via miR-182-5p/CFL1 axis. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 17 34838479
2008 Overexpression of the cucumber LEAFY homolog CFL and hormone treatments alter flower development in gloxinia (Sinningia speciosa). Plant molecular biology 17 18392697
2023 HUNK inhibits epithelial-mesenchymal transition of CRC via direct phosphorylation of GEF-H1 and activating RhoA/LIMK-1/CFL-1. Cell death & disease 16 37193711
2024 The role of actin cytoskeleton CFL1 and ADF/cofilin superfamily in inflammatory response. Frontiers in molecular biosciences 14 39114368
2022 Identification of the most damaging nsSNPs in the human CFL1 gene and their functional and structural impacts on cofilin-1 protein. Gene 14 35092861
2015 Phylogenetic Patterns of Codon Evolution in the ACTIN-DEPOLYMERIZING FACTOR/COFILIN (ADF/CFL) Gene Family. PloS one 14 26717562
2020 Overexpression of CFL1 in gastric cancer and the effects of its silencing by siRNA with a nanoparticle delivery system in the gastric cancer cell line. Journal of cellular physiology 10 31990066
2013 Matricellular protein Cfl1 regulates cell differentiation. Communicative & integrative biology 8 24567775
2023 Bio-removal of rare earth elements from hazardous industrial waste of CFL bulbs by the extremophile red alga Galdieria sulphuraria. Frontiers in microbiology 7 36860487
2024 CFL1 restores the migratory capacity of bone marrow mesenchymal stem cells in primary Sjögren's syndrome by regulating CCR1 expression. International immunopharmacology 5 38183912
2024 Neuronal CFL1 upregulation in head and neck squamous cell carcinoma enhances tumor-nerve crosstalk and promotes tumor growth. Molecular carcinogenesis 4 38353363
2025 In vitro chrysene degradation by purified cell free laccase (P-CFL) from Cochliobolus lunatus strain CHR4D in the presence of various redox mediator systems (RMSs) and computational evaluation of their laccase-ligand interactions. Environmental science and pollution research international 3 40146350
2023 Identification cloning and functional analysis of novel natural antisense lncRNA CFL1-AS1 in cattle. Epigenetics 3 37406176
2022 Estradiol inhibits HIV-1BaL infection and induces CFL1 expression in peripheral blood mononuclear cells and endocervical mucosa. Scientific reports 3 35418661
2004 [Expression of CFL gene during differentiation of floral and vegetative buds in cucumber cotyledonary nodes cultured in vitro]. Zhi wu sheng li yu fen zi sheng wu xue xue bao = Journal of plant physiology and molecular biology 3 15643084
2024 Sensitization of hepatocellular carcinoma cells to HDACi is regulated through hsa-miR-342-5p/CFL1. Cancer cell international 2 39152428
2021 Anti-infective activity of Cratylia argentea lectin (CFL) against experimental infection with virulent Listeria monocytogenes in Swiss mice. Phytomedicine : international journal of phytotherapy and phytopharmacology 2 34781231
2007 Cryotolerance of Lactobacillus delbrueckii subsp. bulgaricus CFL1 is modified by acquisition of antibiotic resistance. Cryobiology 2 17537423
2025 Hippocampal Cofilin and CFL1 gene variants are linked to Alcohol Use Disorder phenotypes. Molecular psychiatry 1 40931167
2024 Serum anti-CFL1, anti-EZR, and anti-CYPA autoantibody as diagnostic markers in ovarian cancer. Scientific reports 1 38684875
2023 Multiobjective optimization of frozen and freeze-dried Lactobacillus delbrueckii subsp. bulgaricus CFL1 production via the modification of fermentation conditions. Journal of applied microbiology 1 36639125
2022 Heterologous Expression of CFL1 Confers Flocculating Ability to Cutaneotrichosporon oleaginosus Lipid-Rich Cells. Journal of fungi (Basel, Switzerland) 1 36547626
2017 CFL-1, a novel F-box protein with leucine-rich repeat may interact with UNC-10 for the regulation of defecation and daumone response in Caenorhabditis elegans. Animal cells and systems 1 30460068
2026 Inactivation of cofilin-1 in Mcpt5-Cre-nf-Cfl1fl/fl mice prevents the formation of connective tissue mast cells without affecting basophils: a new tool to investigate the specific role of CTMCs in disease. Frontiers in immunology 0 41684538
2026 c-Myc transactivates CFL1 to induce senescence-like phenotype and potentiate the bystander effects for the migration and proliferation in lung cancer cells. Cell death discovery 0 41888102
2025 TENS improves CFL injury rat and regulates the intestinal microbiota. PloS one 0 40179112
2024 CFL1 is Implicated in Chronic Myeloid Leukemia Response during Imatinib Therapy. Journal of Cancer 0 38495482
2014 A New Runge-Kutta Discontinuous Galerkin Method with Conservation Constraint to Improve CFL Condition for Solving Conservation Laws. Journal of computational physics 0 25414520

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