Affinage

CYFIP2

Cytoplasmic FMR1-interacting protein 2 · UniProt Q96F07

Length
1278 aa
Mass
148.4 kDa
Annotated
2026-06-09
53 papers in source corpus 28 papers cited in narrative 28 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

CYFIP2 is an evolutionarily conserved component of the WAVE regulatory complex (WRC) that holds WAVE/SCAR-driven Arp2/3-dependent actin polymerization in a trans-inhibited state until relieved by Rac signaling, a function first established for its Dictyostelium ortholog PIR121, which binds Rac directly and acts as a SCAR inhibitor whose loss yields hyperactive SCAR (PMID:12956949). In neurons, CYFIP2 associates with transporting ribonucleoprotein particles and translocates into growth cones upon axon-axon contact to join the WRC at the periphery, where it controls actin remodeling and filopodial dynamics to drive contact-triggered fasciculation, repulsion, and topographic axon sorting in a WRC-binding-dependent manner (PMID:29518358, PMID:20537992). This WRC-coupled actin control shapes dendritic spine morphology, synaptic transmission, and circuit excitability: Cyfip2 haploinsufficiency increases filamentous actin, enlarges spines, and produces layer-5 prefrontal hyperexcitability and seizure susceptibility (PMID:32562430), and Cyfip2 sets the innate acoustic startle threshold through branched actin polymerization (PMID:29669291). Beyond actin, CYFIP2 functions as a translational regulator, controlling synaptic levels of APP and CaMKII protein independent of transcript (PMID:27524794) and suppressing eIF2α phosphorylation to modulate protein synthesis through WRC-dependent actin regulation (PMID:38981622), while interactome analysis places it with both WRC actin regulators and Argonaute-containing RNA-binding machinery and links it to stress granule dynamics (PMID:32560809). CYFIP2 is a direct p53 transcriptional target whose induction is sufficient to activate caspases and trigger apoptosis (PMID:17245118), and its protein abundance is tuned by ubiquitin-proteasome degradation and by extracellular-vesicle-dependent secretion (PMID:36251395, PMID:41153799). Disease-associated de novo missense variants cluster at the CYFIP2–WAVE1 interface—the Arg87 hotspot being prototypical—and predominantly act as gain-of-function alleles that weaken trans-inhibition and constitutively activate the WRC, whereas truncating variants are loss-of-function alleles that fail to incorporate into the complex (PMID:29534297, PMID:32486060); the R87C variant additionally destabilizes CYFIP2 via enhanced ubiquitination and recapitulates West syndrome in knock-in mice (PMID:36251395).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2003 High

    Established the founding biochemical logic of CYFIP2/PIR121 as a Rac-binding negative regulator of SCAR/WAVE, answering whether it activates or restrains actin nucleation.

    Evidence Gene disruption and pirA-/scar- double-mutant epistasis with actin assays in Dictyostelium

    PMID:12956949

    Open questions at the time
    • Did not resolve mammalian WRC architecture or the structural basis of trans-inhibition
    • Mechanism of Rac-triggered relief not defined at this stage
  2. 2004 Medium

    Connected CYFIP2 to integrin-based adhesion through the Rac1/WAVE1 pathway, extending its actin-regulatory role to a defined cellular behavior in T cells.

    Evidence Adenoviral overexpression and antisense knockdown with fibronectin adhesion assays plus Rac1 inhibition in Jurkat and primary CD4+ T cells

    PMID:15048733

    Open questions at the time
    • Direct biochemical demonstration of CYFIP2 in the T-cell WRC not shown
    • Single lab
  3. 2007 Medium

    Revealed a transcriptional/pro-apoptotic identity distinct from actin regulation by showing CYFIP2 is a direct p53 target sufficient to trigger caspase-dependent apoptosis.

    Evidence p53 promoter binding and reporter assays, inducible overexpression with caspase/apoptosis readouts, leptomycin-B localization analysis

    PMID:17245118

    Open questions at the time
    • Molecular effectors linking CYFIP2 to caspase activation not identified
    • Relationship between nucleocytoplasmic shuttling and WRC function unresolved
  4. 2010 High

    Demonstrated cell-autonomous and non-autonomous in vivo developmental roles, establishing CYFIP2 as required for retinal ganglion cell axon sorting and lamination, and showed CYFIP-complex coupling of Arf1/Rac1 signaling at the TGN.

    Evidence Zebrafish forward genetics with mosaic rescue and axon tracing; co-IP, synthetic membrane reconstitution and imaging at the TGN

    PMID:20228810 PMID:20537992

    Open questions at the time
    • Molecular distinction between CYFIP2 actin and translational outputs not yet separated
    • TGN study used CYFIP/PIR121 complexes broadly rather than CYFIP2 specifically
  5. 2016 High

    Defined CYFIP2 as a synaptic translational regulator by showing haploinsufficiency raises APP, BACE1 and CaMKII protein without mRNA change, linking it to spine maturation and memory.

    Evidence Cyfip2 heterozygous mice with immunoblot, Aβ42 ELISA, spine morphology, and Morris water maze

    PMID:27524794

    Open questions at the time
    • Direct mechanism of CYFIP2 control over specific transcript translation not defined
    • Whether this acts via WRC or RNP machinery unresolved
  6. 2018 High

    Resolved how CYFIP2 toggles between RNP and WRC functions in neurons and showed axon sorting depends on WRC binding rather than translational regulation, while genetic work defined an FMRP-independent circuit role.

    Evidence Xenopus RGC knockdown, live imaging, fractionation, co-IP, FRAP and dominant-negative WRC-binding rescue; zebrafish forward genetics with conditional rescue and circuit calcium imaging

    PMID:29518358 PMID:29669291

    Open questions at the time
    • Signal that triggers RNP-to-WRC translocation not molecularly identified
    • Cargo mRNAs of CYFIP2-RNP particles not enumerated
  7. 2018 Medium

    Provided the first mechanistic basis for disease variants, showing Arg87 substitutions disrupt the CYFIP2–WAVE1/VCA interface to cause gain-of-function WRC activation.

    Evidence Structural modeling, transfection with actin/CYFIP2 immunofluorescence, and co-IP of mutant versus WT with VCA domain

    PMID:29534297

    Open questions at the time
    • Quantitative WRC activation in physiological context not measured
    • Generalizability beyond Arg87 not tested here
  8. 2019 Low

    Mapped the spatial clustering of de novo variants at WRC interfaces (WAVE1, NCKAP1) and identified a splice variant predicting a truncated protein.

    Evidence Trio exome/genome sequencing, 3D structural modeling, RT-PCR of exon skipping

    PMID:30664714

    Open questions at the time
    • Structural prediction without in vitro functional validation
    • NMD escape and truncated protein behavior inferred not demonstrated
  9. 2020 High

    Systematically distinguished gain-of-function from loss-of-function disease mechanisms, showing most variants activate the WRC by impairing trans-inhibition while truncating variants fail to incorporate, and confirmed WRC dysfunction in patient cells.

    Evidence CRISPR/Cas9 reconstitution in B16-F1 cells with WRC activation assays and co-IP; patient fibroblast actin polymerization assays with structural modeling

    PMID:32486060 PMID:33149277

    Open questions at the time
    • In vivo consequences of constitutive WRC activation in neurons not addressed in cell models
    • One variant near the Rac A-site implies a second activation mechanism not fully dissected
  10. 2020 High

    Defined CYFIP2's brain interactome and circuit-level synaptic functions, linking it to WRC and Argonaute/RNA-binding proteins, prefrontal layer-5 hyperexcitability, presynaptic plasticity, and mitochondrial associations.

    Evidence Cyfip2-3xFlag knock-in IP/MS interactome with stress granule and Argonaute imaging; Cyfip2+/- electrophysiology, EM, F-actin staining, viral knockdown, RNA-seq, and mitochondrial fractionation

    PMID:32560809 PMID:32562430 PMID:32917241

    Open questions at the time
    • Direct role of CYFIP2 at mitochondria versus indirect association unresolved
    • Causal link between Argonaute co-clustering and translational output not established
  11. 2022 High

    Established CYFIP2 protein homeostasis as a disease mechanism and clarified the divergence from its paralog, showing R87C destabilizes CYFIP2 via ubiquitin-proteasome degradation to model West syndrome, while CYFIP1 and CYFIP2 form largely non-overlapping interactomes and do not associate.

    Evidence Cyfip2+/R87C knock-in mice with ubiquitination and proteasome-inhibitor assays and behavior; reciprocal co-IP knock-in mice with mass spectrometry, SEC, IHC and PLA

    PMID:35567753 PMID:36251395

    Open questions at the time
    • E3 ligase mediating CYFIP2 ubiquitination not identified
    • How reduced abundance reconciles with gain-of-function WRC activation for R87C not fully integrated
  12. 2024 Medium

    Linked CYFIP2 to translational control of the integrated stress response, showing it suppresses eIF2α phosphorylation through WRC-dependent actin regulation and influences membraneless organelle proteomes.

    Evidence Cyfip2-knockout embryonic mouse proteomics, single-cell transcriptomics, MLO imaging, and eIF2α phosphorylation assay in knockdown cells

    PMID:38981622

    Open questions at the time
    • Mechanistic bridge from actin regulation to eIF2α kinase/phosphatase activity not defined
    • Specific transcripts whose synthesis is affected not identified
  13. 2025 Medium

    Extended CYFIP2 regulation to extracellular-vesicle secretion and RNA editing, and broadened its roles into cancer cell migration/immune evasion and adipocyte browning.

    Evidence EV blockade and glutamate stimulation with Fmr1 KO neurons and EV proteomics; ADAR-edited K320E isoform rescue in neurons; ELK3 promoter suppression with NK-killing assays; siRNA in 3T3-L1 adipocytes with mTORC1/GABA-BR dissection

    PMID:35233844 PMID:39930469 PMID:41153799 PMID:41203017

    Open questions at the time
    • Functional consequence of editing isoform balance in vivo unclear
    • How EV secretion integrates with proteasomal control of CYFIP2 abundance unresolved
  14. 2026 Medium

    Expanded CYFIP2 functions into peripheral nervous system development and non-neuronal disease, demonstrating roles in phrenic nerve/NMJ formation and a CYFIP2–p53 feedback loop driving renal fibrosis via Hippo/YAP.

    Evidence Cyfip2-null embryonic mouse NMJ morphometry; tubule-specific Cyfip2 KO hypertension model with CYFIP2-p53 co-IP, YAP imaging, senescence assays, and Nutlin-3a rescue

    PMID:42035098 PMID:42098400

    Open questions at the time
    • Whether peripheral NMJ phenotype is WRC-dependent not tested
    • Direct mode of CYFIP2-p53 physical interaction and its relation to actin function unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how CYFIP2 mechanistically partitions its three documented activities—WRC trans-inhibition, RNP-associated translational control, and p53-linked apoptotic/transcriptional signaling—and what molecular signals route the same protein between these distinct pools.
  • No structural model integrating WRC binding with RNP/translational roles
  • Signals governing RNP-to-WRC switching unidentified
  • E3 ligase and full regulatory logic of CYFIP2 abundance 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 3 GO:0003723 RNA binding 2 GO:0045182 translation regulator activity 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005856 cytoskeleton 3 GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0005739 mitochondrion 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-162582 Signal Transduction 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-5357801 Programmed Cell Death 2
Partners
AGOARF1NCKAP1NUAK2RAC1TP53WASF1
Complex memberships
WAVE regulatory complex (WRC)

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 PIR121 (CYFIP2 ortholog in Dictyostelium) directly binds Rac and is required for proper SCAR/WAVE activity; genetic epistasis (pirA deletion in scar-null background) demonstrated that PIR121 acts primarily through SCAR in vivo. pirA-null cells show hyperactive SCAR phenotype consistent with PIR121 functioning as an inhibitor of SCAR in the absence of activating signals. Gene disruption, genetic epistasis (double mutant pirA-/scar-), actin polymerization assays, immunoblot for SCAR protein levels Current biology : CB High 12956949
2004 CYFIP2 overexpression increases fibronectin-mediated adhesion in Jurkat T cells, and CYFIP2 knockdown reduces fibronectin-mediated adhesion in Jurkat and primary CD4+ T cells; this adhesion function depends on the Rac-1/WAVE1 pathway, as inhibition of Rac-1 phenocopies CYFIP2 reduction. Adenoviral overexpression, antisense oligodeoxynucleotide knockdown, fibronectin adhesion assays, Rac-1 inhibition European journal of immunology Medium 15048733
2007 CYFIP2 is a direct transcriptional target of p53: the CYFIP2 promoter contains a p53-responsive element that confers p53 binding and transcriptional activation. Inducible CYFIP2 expression alone is sufficient to activate caspases and induce apoptosis. CYFIP2 protein subcellular localization is sensitive to leptomycin-B (CRM-1/exportin inhibitor), indicating nucleocytoplasmic shuttling. Promoter reporter assays, p53 binding assay, inducible overexpression with caspase activity and apoptosis readout, leptomycin-B treatment with localization analysis Cell cycle (Georgetown, Tex.) Medium 17245118
2010 CYFIP/PIR121-containing complexes coordinate Arf1 and Rac1 signaling at the TGN: Arf1 GTPase recruits clathrin-AP-1 coats and CYFIP-containing complexes to the TGN; Rac1 and its exchange factor β-PIX then activate these complexes to drive N-WASP- and Arp2/3-dependent actin polymerization, promoting tubule formation for clathrin-AP-1-coated carrier biogenesis. Co-immunoprecipitation, synthetic membrane reconstitution, siRNA knockdown, live imaging, biochemical fractionation Nature cell biology High 20228810
2010 CYFIP2 (encoded by the nevermind locus) is required cell-autonomously for dorso-ventral topographic sorting of dorsonasal retinal ganglion cell axons in the zebrafish optic tract, and is also required cell-nonautonomously for proper retinal lamination. Forward genetic screen, positional cloning, cell-autonomous rescue via mosaic analysis, axon tracing Developmental biology High 20537992
2011 CYFIP2 knockdown rescues IMP-1-knockdown-induced caspase-3- and PARP-mediated apoptosis in SW480 colon cancer cells, placing CYFIP2 downstream of IMP-1 in a K-Ras-linked pro-apoptotic pathway. CYFIP2 mRNA is upregulated upon IMP-1 loss, consistent with its role as a p53-inducible proapoptotic gene. RNA interference knockdown, RNA microarray, RT-PCR validation, caspase-3/PARP apoptosis assays, epistasis rescue experiment Cancer research Medium 21252116
2016 Reduced CYFIP2 expression in heterozygous null mice increases APP and BACE1 protein (but not mRNA) levels, elevates Aβ42 production, increases α-CaMKII protein expression leading to tau hyperphosphorylation at Ser-214, impairs dendritic spine maturity in CA1 pyramidal neurons, and prevents retention of spatial memory. This positions CYFIP2 as a translational regulator of APP and CaMKII at synapses. Cyfip2 heterozygous knockout mice, immunoblot, ELISA for Aβ42, immunohistochemistry, dendritic spine morphology analysis, Morris water maze Brain : a journal of neurology High 27524794
2018 De novo missense variants at CYFIP2 Arg87 (interface with WAVE1 in the WRC) disrupt hydrogen bonding between CYFIP2 and WAVE1, weaken CYFIP2–VCA domain interaction, and cause speckled ectopic accumulation of actin and CYFIP2 in transfected cells, consistent with gain-of-function WRC activation. Computational structural analysis, in vitro transfection, immunofluorescence of actin and CYFIP2 distribution, co-immunoprecipitation of mutant vs. WT CYFIP2 with VCA domain Annals of neurology Medium 29534297
2018 CYFIP2 mediates contact-triggered fasciculation and repulsion responses between dorsal and ventral retinal ganglion cell axons and is specifically required for optic tract topographic sorting. CYFIP2 associates with transporting ribonucleoprotein particles and, upon axon-axon contact, translocates into growth cones to join the WAVE regulatory complex in the periphery, regulating actin remodeling and filopodial dynamics. The function in axon sorting is mediated by WRC binding, not translational regulation. In vivo knockdown/knockout in Xenopus RGCs, live imaging, fractionation, co-immunoprecipitation, FRAP, dominant-negative WRC binding mutant rescue Neuron High 29518358
2018 Cyfip2 establishes the innate acoustic startle threshold by reducing neural activity in a defined set of excitatory hindbrain interneurons, acting independently of FMRP. Reactivation of cyfip2 after phenotype onset restores the baseline startle threshold. Forward genetic screen, whole-genome sequencing, conditional transgenic rescue, neural circuit calcium imaging, genetic epistasis with fmrp mutants Cell reports High 29669291
2019 De novo CYFIP2 missense variants cluster spatially in the tertiary structure at interfaces with WAVE1 and NCKAP1 of the WRC, with structural modeling predicting weakened WRC interactions. A splice-donor variant causes exon skipping and a truncated protein that likely escapes NMD. Trio whole-exome/genome sequencing, 3D structural modeling, RT-PCR validation of exon skipping European journal of human genetics : EJHG Low 30664714
2020 Seven of eight intellectual-disability-causing CYFIP2 missense variants promote WRC activation in CRISPR/Cas9-engineered B16-F1 cells reconstituted with mutant CYFIP2. The majority of mutations occur in the WAVE-binding region required for WRC trans-inhibition; one mutation near the Rac-binding A-site eases Rac-mediated WRC activation. A truncating variant is a loss-of-function that fails to interact with WRC components. CRISPR/Cas9 cell line engineering, reconstitution with CYFIP2 variants, lamellipodia/WRC activation assays, co-immunoprecipitation Cells High 32486060
2020 Structural modeling of CYFIP2 missense variants predicts disruption of interactions within the WRC or impaired CYFIP2 stability; patient-derived fibroblasts from six CYFIP2 variant carriers show aberrant WRC-mediated actin polymerization, substantiating WRC dysfunction as a cellular pathomechanism. Structural modeling, actin polymerization assays in patient fibroblasts Genetics in medicine : official journal of the American College of Medical Genetics Medium 33149277
2020 CYFIP2 interactome in neonatal mouse forebrain (isolated via Cyfip2-3xFlag knock-in) contains 140 proteins including WRC actin regulators and 25 RNA-binding proteins including Argonaute proteins. Brain-disorder-associated CYFIP2 R87 variants (but not WT) inhibit stress granule formation and form intracellular clusters with Argonaute proteins under basal and stress conditions. Cyfip2-3xFlag knock-in mice, immunoprecipitation, mass spectrometry, overexpression of WT vs. mutant CYFIP2, immunofluorescence of stress granules and Argonaute Biochemical and biophysical research communications High 32560809
2020 Haploinsufficiency of Cyfip2 in mice increases filamentous actin, enlarges dendritic spines, and enhances excitatory synaptic transmission and intrinsic excitability specifically in layer 5 prefrontal cortex neurons. These layer-5-specific prefrontal defects are associated with increased seizure susceptibility and abnormal cortical auditory steady-state responses. Virus-mediated selective reduction of CYFIP2 in the PFC is sufficient to induce L5 hyperexcitability. Cyfip2+/- mice, electrophysiology (patch-clamp, EEG), electron microscopy of dendritic spines, F-actin staining, viral vector injection, RNA sequencing Annals of neurology High 32562430
2020 Cyfip2 heterozygous mice show enhanced presynaptic short-term plasticity upon high-frequency stimulation and a reduced number (but not volume or cristae density) of mitochondria in presynaptic boutons and axonal processes of mPFC layer 5. CYFIP2 is biochemically detected in a mitochondria-enriched fraction, and mitochondrial proteins were identified in the CYFIP2 interactome. Cyfip2+/- mice, patch-clamp electrophysiology, electron microscopy, biochemical fractionation, interactome cross-reference Molecular brain Medium 32917241
2021 NUAK2 directly binds CYFIP2 (demonstrated by co-immunoprecipitation), and NUAK2 silencing upregulates CYFIP2 expression; CYFIP2 knockdown reverses the anti-proliferative and anti-migratory effects of NUAK2 silencing in cervical cancer cells, placing CYFIP2 downstream of NUAK2. Co-immunoprecipitation, siRNA knockdown, proliferation/migration/invasion assays, western blotting Molecular medicine reports Medium 34558636
2022 The p.Arg87Cys variant enhances ubiquitination and proteasomal degradation of CYFIP2 protein, resulting in decreased CYFIP2 levels in Cyfip2+/R87C knock-in mouse brains. Cyfip2+/R87C mice recapitulate West syndrome phenotypes including spasm-like movements, microcephaly, impaired social communication, hippocampal cytoarchitectural disorganization, and gliosis. Cyfip2+/R87C knock-in mice, ubiquitination assay, proteasome inhibitor treatment, western blotting, behavioral and histological analyses Annals of neurology High 36251395
2022 CYFIP1 and CYFIP2 form largely non-overlapping interactomes in the mouse brain (only 8 common proteins out of 131 CYFIP1 and 140 CYFIP2 interactors). CYFIP1 and CYFIP2 do not significantly co-immunoprecipitate each other. CYFIP2 is detected only in neurons, while CYFIP1 is detected in both neurons and astrocytes, and CYFIP1 specifically associates with astrocytic focal adhesion proteins. Reciprocal co-IP using CYFIP1-2xMyc and CYFIP2-3xFlag knock-in mice, mass spectrometry, size-exclusion chromatography, immunohistochemistry, proximity ligation assay Journal of neurochemistry High 35567753
2022 Loss of CYFIP2 in 3T3-L1 adipocytes induces browning of white adipocytes via activation of mTORC1 and suppression of GABA-BR signaling, independently promoting thermogenic gene expression (PGC-1α, PRDM16, UCP1) and mitochondrial biogenesis. siRNA knockdown in 3T3-L1 adipocytes, qRT-PCR, immunoblot, mTORC1 and GABA-BR pathway inhibitor experiments Journal of cellular biochemistry Medium 35233844
2024 CYFIP2 deficiency in embryonic mouse forebrains alters levels of 278 proteins, including WRC components and numerous membraneless organelle (MLO)-associated proteins (nucleolus, stress granules, processing bodies). CYFIP2 knockdown suppresses eIF2α phosphorylation levels, thereby enhancing protein synthesis, through a WRC-dependent actin regulation mechanism. Cyfip2-knockout embryonic mice, quantitative proteomics, single-cell transcriptomics, MLO morphology imaging, eIF2α phosphorylation assay in CYFIP2 knockdown cells Human molecular genetics Medium 38981622
2025 CYFIP2 RNA editing (A-to-I by ADAR enzymes) at codon 320 (K320E substitution) has distinct functional consequences: CYFIP2-KO neuroblastoma cells show actin disorganization and failure to differentiate; re-expression of the edited (E) isoform increases axon branch number, total axon length, and dendritic spine frequency more than the unedited (K) isoform in primary neurons with CYFIP2 knockdown. CRISPR-Cas9 CYFIP2 knockout, shRNA knockdown, overexpression of K vs. E isoforms, actin imaging, axon morphometry, dendritic spine quantification in primary neurons Neurochemistry international Medium 41203017
2025 ELK3 directly suppresses CYFIP2 transcription in triple-negative breast cancer cells; loss of CYFIP2 downstream of ELK3 promotes filopodia-mediated migration/adhesion and reduces sensitivity to NK cell-mediated killing by modulating actin accumulation at NK cell contact sites. RNA-sequencing, ChIP or promoter analysis for ELK3-CYFIP2 direct regulation, siRNA/overexpression, confocal imaging of actin at NK cell contacts, flow cytometry of NK killing Journal of experimental & clinical cancer research : CR Medium 39930469
2024 Cyfip2 controls the acoustic startle threshold through both Rac1 and FMRP pathways (but not FXR1 or FXR2). Cyfip2 acts acutely to maintain the startle threshold through branched actin polymerization and NMDARs. Loss of Cyfip2 alters cytoskeletal/ECM components, disrupts oxidative phosphorylation and GABA receptor signaling; pharmacological activation of GABAB receptors restores normal startle sensitivity in cyfip2 mutants. Conditional transgenic rescue, CRISPR/Cas9, drug screen, discovery proteomics, GABAB receptor agonist rescue bioRxivpreprint Medium 38187577
2025 Cyfip2 acts through Rac1-dependent actin polymerization (not FMRP-mediated translation) during a critical developmental window (30–50 hpf) to establish visual sensorimotor circuits in zebrafish. cyfip2 mutants show reduced spontaneous and stimulus-evoked neuronal activity in the optic tectum consistent with impaired RGC functional input. Conditional transgenic temporal rescue, CRISPR/Cas9, phospho-ERK immunostaining, pan-neuronal calcium imaging, behavioral assays (prey capture, flash response, OKR) bioRxivpreprint Medium 41509276
2025 Extracellular vesicle (EV)-dependent secretion controls intracellular CYFIP2 protein homeostasis in cortical neurons: pharmacological and genetic blockade of EV release elevates intracellular CYFIP2, glutamate-evoked EV release reduces CYFIP2 levels, and Fmr1 KO neurons secrete fewer EVs with concomitantly elevated CYFIP2. Evoking EV release in FXS neurons normalizes intracellular CYFIP2. EV pharmacological/genetic blockade, glutamate stimulation, proteomic analysis of EV cargo, Fmr1 KO mouse neurons, immunoblot Biomedicines Medium 41153799
2026 CYFIP2 is required for embryonic phrenic nerve axon development and diaphragm NMJ formation: Cyfip2-null embryos (E16.5) show reduced phrenic nerve axon length and branching, increased endplate bandwidth in sparse AChR regions, and reduced pre- and post-synaptic puncta density with decreased colocalization, demonstrating a peripheral nervous system role for CYFIP2. Cyfip2-null embryonic mice, immunofluorescence (synaptophysin, α-bungarotoxin), morphometric analysis of axon length/branching and NMJ organization Molecular brain Medium 42035098
2026 CYFIP2 and p53 form a positive feedback loop that promotes renal fibrosis by inhibiting the Hippo pathway and enhancing YAP nuclear translocation in tubular epithelial cells. Tubule-specific CYFIP2 deletion attenuates hypertension-induced cellular senescence (reduced SA-β-gal, p53/p21, SASP; increased Klotho) and mitigates renal dysfunction. The p53 agonist Nutlin-3a reverses protection from CYFIP2 KO. Tubule-specific Cyfip2 knockout mice (DOCA/salt hypertension model), co-immunoprecipitation/interaction assay for CYFIP2-p53, YAP nuclear translocation imaging, SA-β-gal assay, Nutlin-3a rescue, siRNA in HK-2 cells Acta pharmacologica Sinica Medium 42098400

Source papers

Stage 0 corpus · 53 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 PIR121 regulates pseudopod dynamics and SCAR activity in Dictyostelium. Current biology : CB 128 12956949
2011 IMP-1 displays cross-talk with K-Ras and modulates colon cancer cell survival through the novel proapoptotic protein CYFIP2. Cancer research 104 21252116
2010 Protein complexes containing CYFIP/Sra/PIR121 coordinate Arf1 and Rac1 signalling during clathrin-AP-1-coated carrier biogenesis at the TGN. Nature cell biology 87 20228810
2018 De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy. Annals of neurology 69 29534297
2019 Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures. European journal of human genetics : EJHG 56 30664714
2018 Axon-Axon Interactions Regulate Topographic Optic Tract Sorting via CYFIP2-Dependent WAVE Complex Function. Neuron 56 29518358
2016 Alzheimer-related decrease in CYFIP2 links amyloid production to tau hyperphosphorylation and memory loss. Brain : a journal of neurology 53 27524794
2018 A Cyfip2-Dependent Excitatory Interneuron Pathway Establishes the Innate Startle Threshold. Cell reports 50 29669291
2022 Analysis and Experimental Validation of Rheumatoid Arthritis Innate Immunity Gene CYFIP2 and Pan-Cancer. Frontiers in immunology 49 35898498
2020 New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics. Genetics in medicine : official journal of the American College of Medical Genetics 46 33149277
2007 CYFIP2, a direct p53 target, is leptomycin-B sensitive. Cell cycle (Georgetown, Tex.) 45 17245118
2004 CYFIP2 is highly abundant in CD4+ cells from multiple sclerosis patients and is involved in T cell adhesion. European journal of immunology 31 15048733
2019 Neuronal function and dysfunction of CYFIP2: from actin dynamics to early infantile epileptic encephalopathy. BMB reports 30 30982501
2019 Differential cell-type-expression of CYFIP1 and CYFIP2 in the adult mouse hippocampus. Animal cells and systems 26 31853374
2019 Hotspot DAXX, PTCH2 and CYFIP2 mutations in pancreatic neuroendocrine neoplasms. Endocrine-related cancer 24 30021865
2010 nev (cyfip2) is required for retinal lamination and axon guidance in the zebrafish retinotectal system. Developmental biology 23 20537992
2020 Epilepsy- and intellectual disability-associated CYFIP2 interacts with both actin regulators and RNA-binding proteins in the neonatal mouse forebrain. Biochemical and biophysical research communications 21 32560809
2021 NUAK2 silencing inhibits the proliferation, migration and epithelial‑to‑mesenchymal transition of cervical cancer cells via upregulating CYFIP2. Molecular medicine reports 19 34558636
2020 Molecular Dissection of Neurodevelopmental Disorder-Causing Mutations in CYFIP2. Cells 19 32486060
2019 Cyfip1 Haploinsufficiency Increases Compulsive-Like Behavior and Modulates Palatable Food Intake in Mice: Dependence on Cyfip2 Genetic Background, Parent-of Origin, and Sex. G3 (Bethesda, Md.) 19 31324746
2020 Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction. Annals of neurology 18 32562430
2017 Inhibition of CYFIP2 promotes gastric cancer cell proliferation and chemoresistance to 5-fluorouracil through activation of the Akt signaling pathway. Oncology letters 17 28454373
2020 Enhanced Prefrontal Neuronal Activity and Social Dominance Behavior in Postnatal Forebrain Excitatory Neuron-Specific Cyfip2 Knock-Out Mice. Frontiers in molecular neuroscience 16 33192297
2022 Deficiency of the neurodevelopmental disorder-associated gene Cyfip2 alters the retinal ganglion cell properties and visual acuity. Human molecular genetics 15 34508581
2022 CYFIP2 p.Arg87Cys Causes Neurological Defects and Degradation of CYFIP2. Annals of neurology 15 36251395
2020 Altered presynaptic function and number of mitochondria in the medial prefrontal cortex of adult Cyfip2 heterozygous mice. Molecular brain 11 32917241
2022 Loss of cytoplasmic FMR1-interacting protein 2 (CYFIP2) induces browning in 3T3-L1 adipocytes via repression of GABA-BR and activation of mTORC1. Journal of cellular biochemistry 9 35233844
2022 Protein interactome and cell-type expression analyses reveal that cytoplasmic FMR1-interacting protein 1 (CYFIP1), but not CYFIP2, associates with astrocytic focal adhesion. Journal of neurochemistry 9 35567753
2023 Cell-autonomous reduction of CYFIP2 is insufficient to induce Alzheimer's disease-like pathologies in the hippocampal CA1 pyramidal neurons of aged mice. Animal cells and systems 7 36999135
2022 Molecular Dynamics of CYFIP2 Protein and Its R87C Variant Related to Early Infantile Epileptic Encephalopathy. International journal of molecular sciences 7 35955843
2024 Neurodevelopmental disorder-associated CYFIP2 regulates membraneless organelles and eIF2α phosphorylation via protein interactors and actin cytoskeleton. Human molecular genetics 5 38981622
2024 Recent advances in CYFIP2-associated neurodevelopmental disorders: From human genetics to molecular mechanisms and mouse models. Brain & development 4 39603202
2024 CYFIP2: potential pancreatic cancer biomarker and immunotherapeutic target. Discover oncology 4 39739214
2023 Different dysregulations of CYFIP1 and CYFIP2 in distinct types of dementia. Brain research bulletin 4 38128786
2025 Molecular basis of the CYFIP2 and NCKAP1 autism-linked variants in the WAVE regulatory complex. Protein science : a publication of the Protein Society 3 39660913
2025 ELK3-CYFIP2 axis-mediated actin remodeling modulates metastasis and natural killer cell responses in triple-negative breast cancer. Journal of experimental & clinical cancer research : CR 3 39930469
2024 The mutated cytoplasmic fragile X messenger ribonucleoprotein 1 (FMR1)-interacting protein 2 (CYFIP2 S968F) regulates cocaine-induced reward behaviour and plasticity in the nucleus accumbens. British journal of pharmacology 3 38751203
2024 Cell-autonomous reduction of CYFIP2 changes dendrite length, dendritic protrusion morphology, and inhibitory synapse density in the hippocampal CA1 pyramidal neurons of 17-month-old mice. Animal cells and systems 3 38832126
2023 Clinical Role of Codon 87 of the CYFIP2 Gene in Early Infantile Epileptic Encephalopathy: A Clinical Case Description. Cureus 3 36968925
2025 Functional impact of CYFIP2 RNA editing on actin regulation, axon growth, and spinogenesis. Neurochemistry international 2 41203017
2024 Cyfip2 controls the acoustic startle threshold through FMRP, actin polymerization, and GABAB receptor function. bioRxiv : the preprint server for biology 2 38187577
2023 Generation of an induced pluripotent stem cell line from a patient with epileptic encephalopathy caused by the CYFIP2 R87C variant. Human cell 2 37646972
2023 A novel variant in CYFIP2 in a girl with severe disabilities and bilateral perisylvian polymicrogyria. American journal of medical genetics. Part A 2 37975178
2025 Extracellular Vesicles-Dependent Secretion Regulates Intracellular CYFIP2 Protein Homeostasis in Cortical Neurons. Biomedicines 1 41153799
2024 Identification of CYFIP2 Arg87Cys Ligands via In Silico and In Vitro Approaches. Biomedicines 1 38540093
2024 Elucidating the role of CYFIP2 in conferring cisplatin resistance in esophageal squamous cell carcinoma. Scientific reports 1 39511293
2024 Epigallocatechin gallate ameliorates retinal pigment epithelial cell damage via the CYFIP2 /AKT pathway. Toxicology and applied pharmacology 1 39667565
2023 Cyfip2 allelic variation in C57BL/6J and C57BL/6NJ mice alters free-choice ethanol drinking but not binge-like drinking or wheel-running activity. Alcohol, clinical & experimental research 1 37356964
2026 Impact of the CYFIP2 R87C variant in a human neuronal model in vitro. Scientific reports 0 41851324
2026 Impaired phrenic nerve axon development and diaphragm neuromuscular junction formation in embryonic Cyfip2-null mice. Molecular brain 0 42035098
2026 CYFIP2 deficiency ameliorates renal interstitial fibrosis through attenuating tubular senescence in hypertensive nephropathy. Acta pharmacologica Sinica 0 42098400
2025 Novel CYFIP2 Frameshift Variant Linked to Dyskinetic Crises: Functional Studies Show Impaired Cell Motility. Clinical genetics 0 40425513
2025 Cyfip2 mediates sensorimotor integration of visual input through Rac1-dependent actin remodeling. bioRxiv : the preprint server for biology 0 41509276

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