Affinage

FMN2

Formin-2 · UniProt Q9NZ56

Length
1722 aa
Mass
180.1 kDa
Annotated
2026-04-28
14 papers in source corpus 8 papers cited in narrative 7 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FMN2 is a formin-family protein that nucleates actin filaments to organize specialized cytoskeletal structures and additionally stabilizes the CDK inhibitor p21 to regulate cell-cycle arrest. FMN2 is transcriptionally induced downstream of p14ARF via NF-κB signaling, and its N-terminal domain prevents p21 degradation, thereby enforcing cell-cycle arrest independently of p53 (PMID:23375502). In migrating cells, FMN2 generates a perinuclear actin and focal adhesion network that protects the nuclear envelope from rupture and DNA damage during confined 3D migration, promoting cell survival and metastasis (PMID:27839864). In neurons, FMN2 maintains dendritic spine density (PMID:25480035) and functions as a molecular clutch in growth cones by coupling F-actin retrograde flow to point-contact adhesions to generate traction forces for translocation (PMID:33002558).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2010 Medium

    Establishing that FMN2 has transforming potential: overexpression of mouse Fmn2 induced anchorage-independent growth and disrupted the actin cytoskeleton, providing the first indication that FMN2 dysregulation could contribute to oncogenesis through cytoskeletal remodeling.

    Evidence Overexpression in cell lines with anchorage-independent growth assay and actin imaging

    PMID:21135260

    Open questions at the time
    • Mechanism by which FMN2 overexpression drives anchorage independence not defined
    • No loss-of-function complement
    • Relevance to endogenous expression levels unclear
  2. 2013 High

    Revealing an unexpected non-cytoskeletal function: FMN2 was identified as a p14ARF/NF-κB transcriptional target that stabilizes the CDK inhibitor p21 via its N-terminal domain, establishing a formin as a direct cell-cycle regulator independent of p53.

    Evidence SILAC proteomics, siRNA knockdown, ChIP for RelA/E2F1 at FMN2 promoter, domain deletion analysis, western blotting for p21 levels

    PMID:23375502 PMID:23839046

    Open questions at the time
    • Biochemical mechanism of p21 stabilization (ubiquitin ligase interference, direct binding) not resolved
    • Whether actin nucleation and p21 stabilization functions are separable in vivo is unknown
  3. 2014 High

    Linking FMN2 to neuronal morphogenesis: FMN2 localizes to dendritic punctae and its genetic loss reduces dendritic spine density in mice, connecting its actin-nucleating function to synapse maintenance and cognition.

    Evidence Immunofluorescence in neurons, Fmn2 knockout mice with spine density quantification, patient iPSC-derived neural cells

    PMID:25480035

    Open questions at the time
    • Specific actin structure organized by FMN2 at spines not characterized
    • Whether spine loss is cell-autonomous not formally demonstrated
  4. 2016 High

    Defining a nuclear protection mechanism: FMN2 was shown to generate a perinuclear actin/focal adhesion system that shields the nucleus during confined migration, preventing nuclear envelope rupture and DNA damage and thereby promoting metastasis.

    Evidence Live imaging, FMN2 knockout, confined migration assays, comet assay, in vivo melanoma metastasis model

    PMID:27839864

    Open questions at the time
    • Upstream signals activating FMN2 in confined environments not identified
    • Whether the perinuclear actin network and the p21-stabilization function coordinately regulate cell fate during migration is unknown
  5. 2017 Medium

    Placing FMN2 downstream of a microRNA regulatory axis: miR-144 was shown to directly target the FMN2 3′UTR, and FMN2 re-expression rescued miR-144-mediated cell-cycle arrest in leukemia cells, extending FMN2's cell-cycle role to a hematopoietic malignancy context.

    Evidence Dual-luciferase reporter assay for direct targeting, epistasis rescue with FMN2 overexpression, xenograft model

    PMID:27556228

    Open questions at the time
    • Whether miR-144–FMN2 axis operates through p21 stabilization or an independent pathway not tested
    • Endogenous regulation in primary leukemia cells not confirmed
  6. 2020 High

    Elucidating FMN2 as a molecular clutch in growth cones: FMN2 couples F-actin retrograde flow to point-contact adhesions, generating the traction forces required for growth cone advance, thus defining how a formin directly transduces cytoskeletal dynamics into motile force in neurons.

    Evidence Fmn2 knockdown in primary neurons, F-actin retrograde flow live imaging, traction force microscopy, adhesion complex analysis

    PMID:33002558

    Open questions at the time
    • Identity of the adhesion receptor(s) engaged by FMN2 is not resolved
    • Whether the clutch mechanism operates at dendritic spines as well is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Open question: the biochemical mechanism by which FMN2's N-terminal domain stabilizes p21, and whether its actin-nucleation and p21-stabilization activities are functionally separable in physiological contexts, remain unresolved.
  • No structural data for FMN2–p21 interaction
  • Separation-of-function mutants distinguishing actin nucleation from p21 stabilization have not been generated
  • Whether FMN2's perinuclear actin network and p21 stabilization act in the same or distinct cell-protective pathways during confined migration is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005856 cytoskeleton 3 GO:0005634 nucleus 1
Pathway
R-HSA-112316 Neuronal System 2 R-HSA-1640170 Cell Cycle 2 R-HSA-73894 DNA Repair 1
Partners
CDKN1AE2F1RELA

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 FMN2 is induced at both mRNA and protein levels upon p14ARF induction via a NF-κB-dependent mechanism independent of p53; FMN2 prevents degradation of the cyclin-dependent kinase inhibitor p21, thereby promoting cell-cycle arrest. RelA and E2F1 bind the FMN2 promoter and repress its transcription under non-induced conditions, and the N-terminal domain of FMN2 is required for p21 stability. SILAC mass spectrometry, siRNA knockdown, overexpression, western blotting, promoter binding (ChIP), NF-κB inhibition, domain deletion analysis Molecular Cell High 23375502 23839046
2016 FMN2 associates with and generates a perinuclear actin/focal adhesion (FA) system distinct from previously characterized actin/FA structures, controls nuclear shape and positioning during 2D migration, and in confined 3D microenvironments limits nuclear envelope damage and DNA double-strand breaks to promote cell survival and metastasis. Fluorescence microscopy, live imaging, FMN2 knockdown/knockout, confined migration assays, comet assay for DNA damage, in vivo metastasis assay (mouse melanoma model), co-localization with FA markers Cell High 27839864
2014 FMN2 localizes to punctae along dendrites, and germline inactivation of mouse Fmn2 results in decreased dendritic spine density, linking FMN2's actin nucleation function to synaptic spine maintenance and fear-learning behavior. Immunofluorescence localization, Fmn2 knockout mice (spine density quantification), iPSC-derived neural cells from patients (synaptic density assay) American Journal of Human Genetics High 25480035
2020 Fmn2 regulates growth cone motility by mediating a molecular clutch: it stabilizes point contact adhesion complexes and couples F-actin retrograde flow to the growth substrate, thereby generating traction forces required for neuronal growth cone translocation. Fmn2 knockdown in neurons, F-actin retrograde flow analysis (live imaging), traction force microscopy, adhesion complex component analysis Neuroscience High 33002558
2010 Mouse Fmn2 overexpression induces anchorage-independent growth and causes disruption of the actin cytoskeleton with drastic modification in cell shape, consistent with an oncogenic role mediated through actin cytoskeleton dysregulation. Overexpression in cells, anchorage-independent growth assay, actin cytoskeleton imaging Blood Medium 21135260
2022 FMN2 missense variant (p.Arg656His) is associated with decreased FMN2 protein levels, decreased p21 protein, and increased H2AX (a marker of DNA double-strand breaks) in patient cells, linking FMN2 to DNA damage response and chromosomal stability in oocytes. Western blot, chromosomal breakage analysis, 3D structural modeling Journal of Ovarian Research Low 35227295
2017 miR-144 directly targets the 3′UTR of FMN2 mRNA (validated by dual-luciferase assay), suppressing FMN2 expression; FMN2 overexpression rescues the anti-proliferative and cell-cycle arrest effects of miR-144 in acute lymphoblastic leukemia cells, placing FMN2 downstream of miR-144 in cell-cycle regulation. Dual-luciferase reporter assay, lentiviral overexpression/knockdown, cell proliferation and cell-cycle assays, xenograft model The Journal of Gene Medicine Medium 27556228

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Biallelic truncating mutations in FMN2, encoding the actin-regulatory protein Formin 2, cause nonsyndromic autosomal-recessive intellectual disability. American journal of human genetics 52 25480035
2013 Identification and functional characterization of FMN2, a regulator of the cyclin-dependent kinase inhibitor p21. Molecular cell 45 23375502
2016 FMN2 Makes Perinuclear Actin to Protect Nuclei during Confined Migration and Promote Metastasis. Cell 38 27839864
2010 Gene profiling of Graffi murine leukemia virus-induced lymphoid leukemias: identification of leukemia markers and Fmn2 as a potential oncogene. Blood 24 21135260
2017 MicroRNA-144 regulates cancer cell proliferation and cell-cycle transition in acute lymphoblastic leukemia through the interaction of FMN2. The journal of gene medicine 20 27556228
2023 Exosomal Circ_FMN2 Derived from the Serum of Colorectal Cancer Patients Promotes Cancer Progression by miR-338-3p/MSI1 Axis. Applied biochemistry and biotechnology 19 36995659
2013 De novo deletion of FMN2 in a girl with mild non-syndromic intellectual disability. European journal of medical genetics 17 24161494
2005 Characterization and mutation analysis of the human formin-2 (FMN2) gene in women with unexplained infertility. Fertility and sterility 16 15866570
2013 FMN2 is a novel regulator of the cyclin-dependent kinase inhibitor p21. Cell cycle (Georgetown, Tex.) 12 23839046
2004 Characterization of FMN2 gene at human chromosome 1q43. International journal of molecular medicine 12 15289902
2020 Fmn2 Regulates Growth Cone Motility by Mediating a Molecular Clutch to Generate Traction Forces. Neuroscience 10 33002558
2020 A Novel Nonsense FMN2 Mutation in Nonsyndromic Autosomal Recessive Intellectual Disability Syndrome. Fetal and pediatric pathology 4 32162566
2022 Heterozygous FMN2 missense variant found in a family case of premature ovarian insufficiency. Journal of ovarian research 3 35227295
2025 Spontaneous ovarian hyperstimulation in a nonpregnant woman with PCOS: a rare case highlighting FMN2 missense mutation and androgen receptor gene deletion. Journal of ovarian research 0 41214804