Affinage

SYNE2

Nesprin-2 · UniProt Q8WXH0

Length
6885 aa
Mass
796.4 kDa
Annotated
2026-04-28
66 papers in source corpus 34 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SYNE2 (Nesprin-2) is a giant spectrin-repeat scaffolding protein that mechanically couples the actin cytoskeleton to the nuclear interior and transduces force across the nuclear envelope through the LINC complex. Its N-terminal calponin-homology actin-binding domain engages F-actin via a catch-bond mechanism and recruits FHOD formins for actin bundling, while its C-terminal KASH domain anchors to SUN1/SUN2 in the perinuclear space; spectrin-repeat domains unfold and refold at piconewton forces, enabling the protein to function as a molecular force absorber over micrometer-scale displacements (PMID:12118075, PMID:16079285, PMID:41576090, PMID:40340251). Through a LEWD motif and adjacent spectrin repeats, Nesprin-2 simultaneously recruits BicD2/dynein/dynactin and kinesin-1 to drive nuclear positioning during neuronal migration, retinal photoreceptor development, and interkinetic nuclear migration, while its interactions with lamin A/C and emerin maintain nuclear envelope integrity and mechanotransduction in cardiomyocytes and fibroblasts (PMID:32619477, PMID:31770881, PMID:21177258, PMID:15843432, PMID:24586179). Smaller nuclear isoforms lacking the KASH domain scaffold ERK1/2 at PML nuclear bodies to regulate DNA damage signaling fidelity, interact with α/β-catenin to modulate Wnt/TCF-LEF transcription, and promote apoptosis by facilitating Bak activation and mitochondrial outer membrane permeabilization (PMID:19861416, PMID:25744025, PMID:20801886, PMID:38225256). A SYNE2 risk variant associated with atrial fibrillation reduces expression of a short isoform, altering nuclear mechanics and cardiomyocyte electrophysiology (PMID:39355904).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2002 High

    The fundamental question of how the actin cytoskeleton physically connects to the nuclear envelope was answered by identifying Nesprin-2 as a novel protein with an N-terminal actin-binding domain that binds F-actin and a C-terminal transmembrane domain targeting the outer nuclear membrane.

    Evidence F-actin co-sedimentation, GFP-fusion live imaging, and domain truncation in mammalian cells

    PMID:12118075

    Open questions at the time
    • Binding partner at the inner nuclear membrane unknown
    • In vivo functional consequences not yet tested
    • Full-length protein not characterized
  2. 2005 High

    The mechanism by which Nesprin-2 is retained at the nuclear envelope was established: its KASH domain binds SUN1 in the perinuclear space, while its inner face interacts directly with lamin A/C and emerin, forming a tripartite anchoring system whose disruption phenocopies laminopathies.

    Evidence Co-IP, GST pull-down, dominant-negative constructs, siRNA, and lamin A/C knockout fibroblasts

    PMID:15671068 PMID:15843432 PMID:16079285

    Open questions at the time
    • Structural basis of SUN–KASH interaction not resolved
    • Whether SUN1 and SUN2 are redundant or distinct partners unclear
    • Force transmission across this linkage not measured
  3. 2007 High

    The physiological necessity of Nesprin-mediated nuclear anchoring was demonstrated: double knockout of Syne-1 and Syne-2 KASH domains caused lethal myonuclear positioning defects and respiratory failure at birth, establishing the LINC complex as essential for skeletal muscle function.

    Evidence Single and double KASH-domain knockout mice with histology and motor nerve analysis

    PMID:17267447

    Open questions at the time
    • Relative contribution of Syne-2 versus Syne-1 not fully dissected
    • Molecular motors involved in myonuclear positioning not identified
    • Whether non-KASH isoforms compensate unknown
  4. 2008 High

    The actin-binding domain was shown to be required not just for cytoskeletal linkage but for maintaining nuclear envelope architecture itself: ABD deletion caused misshapen nuclei and emerin redistribution resembling laminopathies.

    Evidence Nesprin-2 ABD-deletion mouse model with nuclear morphology quantification

    PMID:18477613

    Open questions at the time
    • Whether the phenotype reflects loss of actin force or loss of ABD protein interactions unclear
    • Chromatin organization consequences not examined
  5. 2009 High

    Two unexpected functional dimensions were uncovered: Nesprin-2 participates in ciliogenesis through interaction with the ciliopathy protein meckelin, and nuclear isoforms scaffold ERK1/2 at PML nuclear bodies to restrain ERK signaling and smooth muscle cell proliferation.

    Evidence Co-IP with meckelin plus siRNA ciliogenesis phenotype; GST pull-down of ERK1/2 plus transcriptional reporter assays

    PMID:19596800 PMID:19861416

    Open questions at the time
    • How meckelin–nesprin-2 interaction regulates RhoA and centrosome migration mechanistically unclear
    • ERK scaffolding mechanism at PML bodies not structurally resolved
    • Whether ERK and ciliogenesis roles are linked unknown
  6. 2010 High

    Nesprin-2 was placed in two additional signaling and transport pathways: it forms a complex with α/β-catenin and emerin at the nuclear envelope to positively regulate Wnt/TCF-LEF transcription, and it connects to dynein/kinesin motors via SUN proteins for interkinetic nuclear migration in the retina.

    Evidence Co-IP and TCF/LEF reporter in epithelial cells; conditional Syne-2 KO mice with ERG electrophysiology

    PMID:20801886 PMID:21177258

    Open questions at the time
    • Direct motor-binding sites on nesprin-2 not mapped
    • Whether Wnt regulation is force-dependent or purely scaffolding unknown
    • Retinal versus neuronal migration mechanisms not compared
  7. 2012 Medium

    Nesprin-2 Giant was found to associate with heterochromatic and centromeric DNA regions, and its loss impaired keratinocyte migration and wound healing, extending its role to chromatin organization and tissue repair.

    Evidence ChIP-seq and Nesprin-2 Giant knockout mouse wound healing model

    PMID:22198684

    Open questions at the time
    • Whether chromatin binding is direct or mediated by other factors unknown
    • Specific transcriptional targets affected not identified
    • Single study without independent replication
  8. 2013 High

    The lamin A–Nesprin-2 binding interface was mapped to precise residues, and laminopathic LMNA mutations in this region were shown to modulate the interaction, providing a molecular explanation for how laminopathies disrupt the LINC complex.

    Evidence GST pull-down, yeast two-hybrid domain mapping, patient cell analysis with multiple LMNA mutations

    PMID:23977161

    Open questions at the time
    • Structural basis of the interaction not solved at atomic resolution
    • Whether all laminopathy phenotypes trace to nesprin-2 disruption unclear
  9. 2014 High

    Nesprin-1/2 were established as essential mechanotransducers in the heart: double knockout in cardiomyocytes caused early-onset cardiomyopathy with altered nuclear positioning and chromatin, and impaired gene expression responses to biomechanical load.

    Evidence Cardiomyocyte-specific conditional double KO mice, echocardiography, gene expression under mechanical stimulation

    PMID:24586179

    Open questions at the time
    • Individual contribution of Nesprin-2 versus Nesprin-1 in cardiac mechanotransduction not dissected
    • Downstream mechanosensitive transcription factors not identified
    • Whether force-dependent SR unfolding is relevant in cardiomyocytes unknown
  10. 2015 High

    The ERK-scaffolding function was linked to the DNA damage response: Nesprin-2 at PML bodies is required for ATM-to-Chk2 signal relay, and its loss causes genomic instability independently of lamin A/C.

    Evidence siRNA KD with γ-H2AX foci, Chk2 phosphorylation, and comet assay in vascular smooth muscle cells

    PMID:25744025

    Open questions at the time
    • Structural mechanism of ERK/ATM/Chk2 scaffolding unknown
    • Whether this DDR role operates in cell types beyond VSMCs not tested
  11. 2020 High

    Two key advances in neuronal migration and nuclear mechanics: Nesprin-2 accumulates at the nuclear front during confined migration in an ABD- and actomyosin-dependent manner, and its LEWD motif recruits BicD2 to link dynein for neuronal migration in vivo, with kinesin-1 providing an opposing force.

    Evidence Endogenous GFP-tagged nesprin-2G live imaging with laser ablation; in utero electroporation with LEWD motif mutagenesis and motor inhibition

    PMID:32419336 PMID:32619477

    Open questions at the time
    • How opposing dynein and kinesin forces are coordinated unknown
    • Whether catch-bond mechanism operates during neuronal migration not tested
  12. 2023 High

    Competition between Nesprin-2 and RanBP2 for BICD2 binding was revealed as a molecular switch: RanBP2–BICD2 governs radial glial progenitor INM while Nesprin-2–BICD2 governs post-mitotic neuronal migration, and their balance controls brain development.

    Evidence In vitro competition binding assay, in utero electroporation with BICD2 mutants

    PMID:36930595

    Open questions at the time
    • Regulation of the competition (post-translational modifications, expression timing) not defined
    • Whether RanBP2–nesprin-2 switching occurs in non-neural tissues unknown
  13. 2024 Medium

    Nesprin-2 was established as a pro-apoptotic factor that redistributes from the nuclear envelope to mitochondria during apoptosis, promoting Bak activation and mitochondrial outer membrane permeabilization; separately, it was identified as a sarcomeric scaffold binding telethonin and FHL-2 at the Z-disc, with disease mutations impairing these interactions.

    Evidence siRNA KD with Bax/Bak activation and cytochrome c release assays; endogenous GFP live imaging of mitochondrial redistribution; yeast two-hybrid/GST pull-down for sarcomeric partners in neonatal cardiomyocytes

    PMID:38225256 PMID:38569934 PMID:39402980

    Open questions at the time
    • Mechanism of nesprin-2 release from the nuclear envelope during apoptosis unknown
    • Whether BH3-like motifs directly engage Bcl-2 family proteins not structurally confirmed
    • In vivo relevance of sarcomeric scaffold role not tested in knockout models
  14. 2024 Medium

    A SYNE2 risk variant for atrial fibrillation was causally linked to reduced expression of a short isoform (SYNE2α1), which when overexpressed or when SYNE2 is knocked down increases nuclear area, decreases nuclear stiffness, and alters cardiomyocyte electrophysiology.

    Evidence CRISPR-Cas9 variant editing, AFM, calcium imaging, and optical mapping in iPSC-derived cardiomyocytes

    PMID:39355904

    Open questions at the time
    • Mechanism by which nuclear stiffness change alters electrophysiology unclear
    • Whether this isoform-specific effect operates through LINC complex disruption or independently unknown
    • Single study without replication cohort
  15. 2025 High

    The biophysical mechanism underlying nesprin-2's force transmission was resolved: spectrin repeats unfold/refold at piconewton forces enabling micrometer-scale displacement buffering, and a catch-bond mechanism between the ABD and actin strengthens the nuclear–cytoskeletal link under load; BicD2 binding was structurally modeled showing simultaneous dynein and kinesin engagement.

    Evidence Magnetic tweezers single-molecule manipulation, catch-bond mutagenesis, AlphaFold modeling with mutagenesis validation, dynein/dynactin motility reconstitution

    PMID:40340251 PMID:41576090 PMID:41770881

    Open questions at the time
    • Full-length nesprin-2 structure not solved experimentally
    • How SR unfolding modulates specific protein-protein interactions in cells not demonstrated
    • In vivo validation of catch-bond function in migration not performed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how nesprin-2 isoform expression is regulated across tissues, the structural basis of its multi-partner scaffolding at PML bodies and sarcomeres, whether the force-sensing spectrin-repeat unfolding mechanism regulates specific signaling outputs in vivo, and the full extent of its role in human disease beyond cardiomyopathy and atrial fibrillation.
  • No atomic-resolution structure of full-length nesprin-2 or major domain complexes
  • Isoform-specific functions in most tissues not systematically dissected
  • In vivo validation of catch-bond and SR-unfolding mechanotransduction lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0005198 structural molecule activity 4 GO:0008092 cytoskeletal protein binding 4
Localization
GO:0005635 nuclear envelope 7 GO:0005856 cytoskeleton 4 GO:0005634 nucleus 3 GO:0005739 mitochondrion 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 1
Partners
BICD2CTNNA1CTNNB1EMDLMNASUN1SUN2TCAP
Complex memberships
BicD2/dynein/dynactin transport complexLINC complex (SUN-KASH)Nesprin-2/α-catenin/β-catenin/emerin complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 NUANCE (Nesprin-2) was identified as a novel protein with an N-terminal alpha-actinin-like actin-binding domain (ABD) that binds F-actin in vitro and colocalizes with the actin cytoskeleton in vivo, and a C-terminal transmembrane domain responsible for targeting to the outer nuclear membrane, thus linking the microfilament system with the nucleus. F-actin co-sedimentation assay (in vitro), GFP-fusion live imaging, domain truncation analysis, subcellular fractionation Journal of cell science High 12118075
2005 Nesprin-2 is anchored to the nuclear envelope through a direct interaction between its conserved C-terminal PPPX motif and the inner nuclear membrane protein SUN1; SUN1 knockdown or dominant-negative SUN1 mislocalizes Nesprin-2 from the nuclear envelope. Co-immunoprecipitation, dominant-negative constructs, siRNA knockdown, immunofluorescence Journal of cell science High 16079285
2005 Nesprin-2 directly binds emerin and the C-terminal region of lamin A/C; lamin A/C is required for nuclear envelope localization of Nesprin-2, as shown in lamin A/C knockout fibroblasts and by redistribution upon dominant-negative lamin B expression. Nesprin-2 is in turn required for proper localization of emerin at the nuclear envelope. GST pull-down, biochemical binding assays, lamin A/C knockout fibroblasts, dominant-negative constructs, siRNA knockdown, immunofluorescence Molecular biology of the cell High 15843432
2005 Smaller isoforms of Nesprin-2 co-localize with and directly bind lamin A and emerin at the inner nuclear envelope; loss of lamin A/C in SW-13 cells mislocalizes nesprin-2 and emerin to the ER. Larger Nesprin-2 isoforms localize to heterochromatin, outer NE, mitochondria, sarcomeric Z-lines and sarcoplasmic reticulum in skeletal muscle, forming a subcellular linking network. Co-immunoprecipitation, immunogold electron microscopy, confocal immunolocalization, SW-13 lamin A/C-null cells, C2C12 myoblast differentiation Journal of cell science High 15671068
2007 In skeletal muscle, the KASH domain of Syne-1 is required for synaptic nuclear clustering, while Syne-1 and Syne-2 together are required for proper non-synaptic myonuclear anchorage; double knockout of both leads to respiratory failure at birth due to defective myonuclear positioning critical for motor neuron innervation. Single and double KASH-domain knockout mice, histology, immunofluorescence, motor nerve branching analysis Development (Cambridge, England) High 17267447
2008 The actin-binding domain (ABD) of Nesprin-2 Giant is required for maintaining nuclear envelope architecture and nuclear shape; loss of the ABD in mice causes misshapen nuclei in dermal fibroblasts and keratinocytes resembling laminopathies, and disrupts proper distribution of emerin along the nuclear envelope. Nesprin-2 ABD-deletion mouse model, immunofluorescence, nuclear morphology quantification Journal of cell science High 18477613
2009 Nesprin-2 actin-binding isoforms interact with the MKS ciliopathy protein meckelin; nesprin-2 (and nesprin-1) are required for centrosome migration and ciliogenesis, and loss of meckelin causes aberrant actin remodeling and mislocalization of nesprin-2 isoforms to stress fibers with RhoA activation. Co-immunoprecipitation, siRNA knockdown, immunofluorescence colocalization, RhoA activation assay, patient cell line analysis Journal of cell science High 19596800
2009 Nesprin-2 nuclear isoforms (lacking the KASH domain) tether active ERK1/2 at PML nuclear bodies, acting as an intranuclear ERK scaffold; disruption of nesprin-2 by siRNA or dominant-negative constructs augments ERK nuclear signaling (increased SP1 activity, ELK1 phosphorylation) and increases smooth muscle cell proliferation. GST pull-down, co-immunoprecipitation, siRNA knockdown, dominant-negative overexpression, immunofluorescence, transcriptional reporter assays The Journal of biological chemistry High 19861416
2010 Nesprin-2 interacts directly with α-N/E-catenins via their C-termini; the nesprin-2/α-catenin complex includes β-catenin and emerin at the nuclear envelope. Depletion of nesprin-2 reduces nuclear active β-catenin and TCF/LEF-dependent transcription, establishing nesprin-2 as a positive regulator of Wnt signaling at the nuclear envelope. Co-immunoprecipitation, siRNA knockdown, transcriptional reporter assay (TCF/LEF), immunofluorescence The Journal of biological chemistry High 20801886
2010 Syne-2/Nesprin-2 forms complexes with SUN1 or SUN2 at the nuclear envelope and connects to dynein/dynactin and kinesin motors to mediate interkinetic nuclear migration (INM) and photoreceptor cell migration in the mouse retina; deletion of Syne-2 or double deletion of Sun1/Sun2 causes severe reduction of outer nuclear layer thickness and profound electrophysiological retinal dysfunction. Co-immunoprecipitation, conditional knockout mice, ERG electrophysiology, immunofluorescence, histology Human molecular genetics High 21177258
2012 Nesprin-2 Giant associates with heterochromatic and centromeric DNA in ChIP-seq experiments, and its depletion alters transcription factor localization and actin cytoskeleton organization, impairing keratinocyte migration and myofibroblast differentiation during wound healing. ChIP-seq, Nesprin-2 Giant knockout mouse wound healing model, immunofluorescence, migration assays Nucleus (Austin, Tex.) Medium 22198684
2013 The lamin A–Nesprin-2 interaction was mapped to amino acids 403–425 in lamin A and amino acids 6146–6347 in Nesprin-2; laminopathic LMNA mutations in and around this region (R401C, G411D, G413C, V415I, R419C, L421P, R427G, Q432X) modulate the interaction, with Q432X causing LINC complex protein assembly changes and chromosomal/transcription factor rearrangements. GST pull-down, co-immunoprecipitation, yeast two-hybrid, domain mapping, immunofluorescence in patient cells PloS one High 23977161
2014 Ablation of both Nesprin-1 and Nesprin-2 (but neither alone) in cardiomyocytes causes early-onset cardiomyopathy with altered nuclear positioning, shape and chromatin positioning; loss of either nesprin impairs gene expression changes in response to biomechanical load, placing outer nuclear membrane nesprins in the mechanical signal transduction pathway from outer to inner nuclear membrane to nucleoskeleton. Cardiomyocyte-specific double knockout mice, echocardiography, nuclear morphology, chromatin positioning, gene expression analysis under biomechanical stimulation PLoS genetics High 24586179
2014 Nesprin-1 and Nesprin-2 depletion in endothelial cells increases cell spread area, stimulates stress fiber/F-actin assembly, increases nuclear area, reduces emerin localization to the nuclear envelope, and impairs cell migration and angiogenic loop formation. RNAi knockdown, immunofluorescence, migration assay (wound closure), in vitro angiogenesis assay, phalloidin F-actin staining Cytoskeleton (Hoboken, N.J.) Medium 24931616
2015 Nesprin-2/ERK compartmentalization at PML nuclear bodies is required for the DNA damage response: nesprin-2 depletion (but not lamin A/C depletion) ablates Chk2 activation downstream of ATM and induces genomic instability, establishing nesprin-2 as an essential component of the DDR signaling scaffold in vascular smooth muscle cells. siRNA knockdown of nesprin-2 and lamin A/C, immunofluorescence, γ-H2AX foci, Chk2 phosphorylation assay, DNA damage comet assay Cell death and differentiation High 25744025
2015 Nesprin-2 mediates Ca2+/Calmodulin-dependent nuclear transport of BRCA1 and NF-κB independently of the canonical RAN pathway; novel direct interactions between the ABD of Nesprin-2 and Calmodulin, and between BRCA1 NLS and Calmodulin were identified; Nesprin-2 displacement from the nuclear envelope increases cytoplasmic Ca2+ concentrations. shRNA knockdown, immunofluorescence localization of BRCA1/NF-κB, co-immunoprecipitation, Ca2+ imaging, patient-derived EDMD5 fibroblasts Nucleus (Austin, Tex.) Medium 26645154
2016 N-terminal nesprin-2 variants colocalize with β-catenin at cell-cell junctions; siRNA depletion of these variants causes loss of β-catenin from cell junctions, nuclear accumulation of active β-catenin and augmented β-catenin transcriptional activity, demonstrating nuclear-envelope-independent regulation of Wnt/β-catenin signaling by nesprin-2. siRNA knockdown, immunofluorescence, calcium switch assay, β-catenin transcriptional reporter assay, co-immunoprecipitation Experimental cell research Medium 27321956
2017 Nesprin-2 interacts with SMC2 and SMC4 (core condensin subunits) through a predicted SMC-like domain (aa 1436–1766) in its rod domain; this interaction occurs during all cell cycle phases but is strongest in S phase and persists in mitosis; Nesprin-2 knockdown causes significantly more chromatin bridges in anaphase. GST pull-down, co-immunoprecipitation, immunofluorescence, siRNA knockdown, chromatin bridge quantification International journal of cell biology Medium 29445399
2018 Nesprin-2 Giant interacts with actin filaments through its paired calponin homology (CH) domains, and also interacts with actin-bundling proteins FHOD1 and fascin; these interactions were quantified by actin co-sedimentation assay and GST pull-down. Actin co-sedimentation assay, GST pull-down Methods in molecular biology (Clifton, N.J.) Medium 30141036
2018 Pericentrin (Pcnt) is an interaction partner of Syne-2 in photoreceptors; CRISPR/Cas9 knockout of Syne-2 in cell culture causes overexpression and mislocalization of Pcnt and ciliogenesis defects, suggesting the Pcnt–Syne-2 complex is important for ciliogenesis and outer segment formation. Protein interaction screen, co-immunoprecipitation, CRISPR/Cas9 knockout, viral shRNA knockdown in vivo, immunofluorescence Journal of cell science Medium 30054381
2020 Nesprin-2 accumulates at the front of the nucleus during confined cell migration through narrow constrictions; this accumulation requires the actin-binding domain of nesprin-2, is actomyosin-dependent (pulling force from the cell front), and nesprins at the nuclear envelope dampen elastic recoil upon actin ablation, demonstrating a direct mechanical role for nesprin-2 in nuclear translocation. CRISPR/Cas9 endogenous GFP tagging of nesprin-2G, live imaging during confined migration, two-photon laser ablation, cytoskeletal drug treatment, artificial construct domain analysis EMBO reports High 32419336
2020 Nesprin-2 recruits the dynein/kinesin adaptor BicD2 to the nuclear envelope via its LEWD sequence motif; a ~100 kDa 'mini' Nesprin-2 containing this BicD2-binding region is sufficient for neuronal migration in vivo. Kinesin-1 inhibition accelerates neuronal migration suggesting opposing motor roles; the actin-binding domain is dispensable for neuronal migration. In utero electroporation, dominant-negative constructs, LEWD motif mutagenesis, co-immunoprecipitation, in vivo neuronal migration assay Current biology : CB High 32619477
2021 Silencing of Nesprin-2 in fibroblasts inhibits mechanical stretch-induced myofibroblast differentiation, blocking upregulation of lamin A/C, α-smooth muscle actin, TGF-β1, and collagen type I in response to cyclic stretch. siRNA knockdown, cyclic mechanical stretch model, Western blot, immunofluorescence International wound journal Medium 34558192
2021 In zebrafish, Syne2b (Nesprin-2 ortholog) is required for F-actin organization and epithelial integrity during epiboly; CRISPR/Cas9 deletion of the KASH domain causes aberrant F-actin clustering, abnormal cell shape changes and disintegration of the epithelial blastoderm, and defective yolk syncytial nuclear migration. CRISPR/Cas9 knockout (zebrafish), F-actin staining (phalloidin), live imaging, immunofluorescence Frontiers in cell and developmental biology Medium 34222245
2023 Nesprin-2 and RanBP2 compete for BICD2 binding at the nuclear envelope; RanBP2-BICD2 interaction governs INM in radial glial progenitors while Nesprin-2-BICD2 interaction governs post-mitotic neuronal migration; these are mutually exclusive interactions whose balance controls brain development. In vitro competition binding assay, in utero electroporation with BICD2 mutants, co-immunoprecipitation, brain developmental assay PLoS genetics High 36930595
2024 Nesprin-2 has pro-apoptotic activity: depletion of nesprin-2 inhibits Bax and Bak activation and cytochrome c release; nesprin-2 promotes Bak activation and regulates mitochondrial translocation/retrotranslocation of Bcl-2 family proteins in a Bcl-xL-dependent manner. siRNA knockdown, Bax/Bak activation assays (N-terminus exposure), cytochrome c release assay, immunofluorescence Cell death discovery Medium 38225256
2024 Nesprin-2 localizes to the Z-disc and I-band of the cardiomyocyte sarcomere; it directly binds telethonin (in a phosphorylation-dependent manner) and FHL-2; these interactions are impaired by EDMD/DCM/HCM mutations in nesprin-2, telethonin, and FHL-2, identifying nesprin-2 as a novel sarcomeric scaffold. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, GFP-tagged construct localization in neonatal rat cardiomyocytes, immunofluorescence The Journal of biological chemistry High 38569934
2024 During apoptosis, nesprin-2 Giant redistributes from the nuclear envelope to near mitochondria by two distinct modes (complete and partial); this redistribution precedes morphological apoptosis features and is associated with reduction in mitochondrial membrane potential and outer membrane permeabilization. Endogenous GFP-nesprin-2G live imaging, mitochondrial membrane potential assay, MOMP assay, kinetics quantification Nucleus (Austin, Tex.) Medium 39402980
2024 A SYNE2 risk variant (rs1152591) for atrial fibrillation reduces expression of a short SYNE2α1 isoform; SYNE2α1 overexpression or SYNE2 knockdown in iPSC-derived cardiomyocytes increases nuclear area and decreases nuclear stiffness, and alters electrophysiology (faster calcium reuptake, shortened action potential duration, decreased conduction velocity). CRISPR-Cas9 editing, reporter gene transfection, SYNE2 knockdown, SYNE2α1 overexpression, atomic force microscopy, RNAseq, Fura-2 calcium imaging, optical mapping Circulation. Genomic and precision medicine Medium 39355904
2025 The spectrin repeat (SR) domains of Nesprin-2 Giant undergo mechanical unfolding and refolding at pN-scale forces; the protein acts as a molecular force absorber maintaining nucleoskeleton-cytoskeleton linkage across displacement spans exceeding 1 μm; pN forces modulate nesprin-protein interactions through SR domain folding/unfolding dynamics. Magnetic tweezers single-molecule manipulation, molecular dynamics simulations, AlphaFold structural predictions Proceedings of the National Academy of Sciences of the United States of America High 41576090
2025 Nesprin-2 accumulation at the front of the nucleus during confined migration involves a catch-bond mechanism between the nesprin-2 ABD and actin (force-strengthening bond); SUN2 (but not SUN1) shows the same frontal accumulation as nesprin-2; a point mutation abrogating catch-bond behavior reduces frontal nesprin-2 accumulation as predicted by the model. Quantitative fluorescence imaging of endogenous nesprin-2 and SUN proteins, mininesprin-2 chimeric constructs, catch-bond point mutagenesis, physical modeling Biophysical journal Medium 40340251
2025 A structural model of the Nesprin-2/BicD2 complex was predicted by AlphaFold and experimentally validated: spectrin repeats of Nesprin-2 form an α-helical bundle with the cargo-binding domain of BicD2; a ~65-residue disordered linker separates the BicD2-binding site from the LEWD kinesin-1 recruitment motif, suggesting simultaneous binding of both motors. Nesprin-2 activates BicD2/dynein/dynactin for processive motility. AlphaFold structural prediction, mutagenesis, binding assays, single-molecule biophysical studies, dynein/dynactin motility reconstitution Biochemistry High 41770881
2025 FHOD formins interact with nesprin-2 of the LINC complex and this interaction activates FHOD actin bundling activity; FHOD-associated LINC complexes enhance mechanical resistance of nuclear-engaged actin cables in polarizing fibroblasts and sarcomeres in developing cardiomyocytes. Biochemical reconstitution of FHOD-nesprin-2 interaction, actin bundling assays, live imaging in fibroblasts and cardiomyocytes, mouse disease model (FHOD3 R637P knock-in) bioRxivpreprint Medium
2026 SV40 virus exploits Nesprin-2 at the outer nuclear membrane and its binding partner SUN1 to target the nuclear membrane; after targeting, SV40 engages the KPNA4 importin receptor for nuclear entry; the SUN domain of SUN1 is required for Nesprin-2-dependent recruitment of cytosolic SV40. siRNA knockdown, dominant-negative constructs, co-immunoprecipitation, immunofluorescence, viral infection assays bioRxivpreprint Medium 41959248
2026 Farnesylated prelamin A variants (including progerin) disrupt nesprin-2/SUN2 LINC complex function by reducing diffusional mobility of nesprin-2 and SUN2, inhibiting actin force transmission to the nucleus and impairing cell polarization; the farnesyl group is the critical element causing these defects. Live FRAP imaging of nesprin-2 and SUN2 mobility, cell polarization assays, farnesylation inhibitor treatment, expression of prelamin A tail fragments Journal of cell science Medium 42011117

Source papers

Stage 0 corpus · 66 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 The inner nuclear membrane protein Sun1 mediates the anchorage of Nesprin-2 to the nuclear envelope. Journal of cell science 345 16079285
2002 NUANCE, a giant protein connecting the nucleus and actin cytoskeleton. Journal of cell science 245 12118075
2007 Syne-1 and Syne-2 play crucial roles in myonuclear anchorage and motor neuron innervation. Development (Cambridge, England) 223 17267447
2005 Nesprin-2 is a multi-isomeric protein that binds lamin and emerin at the nuclear envelope and forms a subcellular network in skeletal muscle. Journal of cell science 221 15671068
2005 Lamin A/C-dependent localization of Nesprin-2, a giant scaffolder at the nuclear envelope. Molecular biology of the cell 143 15843432
2010 KASH protein Syne-2/Nesprin-2 and SUN proteins SUN1/2 mediate nuclear migration during mammalian retinal development. Human molecular genetics 142 21177258
2008 Nesprin-2 Giant (NUANCE) maintains nuclear envelope architecture and composition in skin. Journal of cell science 122 18477613
2015 Global loss of a nuclear lamina component, lamin A/C, and LINC complex components SUN1, SUN2, and nesprin-2 in breast cancer. Cancer medicine 121 26175118
2014 Targeted ablation of nesprin 1 and nesprin 2 from murine myocardium results in cardiomyopathy, altered nuclear morphology and inhibition of the biomechanical gene response. PLoS genetics 117 24586179
2009 Nesprin-2 interacts with meckelin and mediates ciliogenesis via remodelling of the actin cytoskeleton. Journal of cell science 115 19596800
2012 Multiple novel nesprin-1 and nesprin-2 variants act as versatile tissue-specific intracellular scaffolds. PloS one 101 22768332
2009 Nuance in the double-helix and its role in protein-DNA recognition. Current opinion in structural biology 82 19362815
2018 Colloidal aggregation: from screening nuisance to formulation nuance. Nano today 79 30250495
2010 Nesprin-2 interacts with {alpha}-catenin and regulates Wnt signaling at the nuclear envelope. The Journal of biological chemistry 62 20801886
2007 Nesprin-2 giant safeguards nuclear envelope architecture in LMNA S143F progeria cells. Human molecular genetics 58 17881656
2014 Nesprin-1 and nesprin-2 regulate endothelial cell shape and migration. Cytoskeleton (Hoboken, N.J.) 57 24931616
2012 The nuclear envelope protein Nesprin-2 has roles in cell proliferation and differentiation during wound healing. Nucleus (Austin, Tex.) 55 22198684
2020 Nesprin-2 accumulates at the front of the nucleus during confined cell migration. EMBO reports 53 32419336
2012 Functional interaction between the Arabidopsis orthologs of spindle assembly checkpoint proteins MAD1 and MAD2 and the nucleoporin NUA. Plant molecular biology 50 22457071
2020 Nesprin-2 Recruitment of BicD2 to the Nuclear Envelope Controls Dynein/Kinesin-Mediated Neuronal Migration In Vivo. Current biology : CB 48 32619477
2009 Novel nuclear nesprin-2 variants tether active extracellular signal-regulated MAPK1 and MAPK2 at promyelocytic leukemia protein nuclear bodies and act to regulate smooth muscle cell proliferation. The Journal of biological chemistry 47 19861416
2015 Nesprin-2-dependent ERK1/2 compartmentalisation regulates the DNA damage response in vascular smooth muscle cell ageing. Cell death and differentiation 38 25744025
2013 Mutations in LMNA modulate the lamin A--Nesprin-2 interaction and cause LINC complex alterations. PloS one 35 23977161
2015 Nuance and behavioral cogency: How the Visible Burrow System inspired the Stress-Alternatives Model and conceptualization of the continuum of anxiety. Physiology & behavior 23 26066728
2016 EGFR and SYNE2 are associated with p21 expression and SYNE2 variants predict post-operative clinical outcomes in HBV-related hepatocellular carcinoma. Scientific reports 19 27502069
2022 Synonymous Variants: Necessary Nuance in Our Understanding of Cancer Drivers and Treatment Outcomes. Journal of the National Cancer Institute 18 35477782
2015 A Mutation in Syne2 Causes Early Retinal Defects in Photoreceptors, Secondary Neurons, and Müller Glia. Investigative ophthalmology & visual science 18 26066746
2024 LINC complex protein nesprin-2 has pro-apoptotic activity via Bcl-2 family proteins. Cell death discovery 16 38225256
2016 N-terminal nesprin-2 variants regulate β-catenin signalling. Experimental cell research 16 27321956
2023 Role of Nesprin-2 and RanBP2 in BICD2-associated brain developmental disorders. PLoS genetics 15 36930595
2016 Olfaction in context-sources of nuance in plant-pollinator communication. Current opinion in insect science 14 27436732
2015 Nesprin-2 mediated nuclear trafficking and its clinical implications. Nucleus (Austin, Tex.) 14 26645154
2007 NUA Activities at the Plant Nuclear Pore. Plant signaling & behavior 14 19704557
2023 NUA positively regulates plant immunity by coordination with ESD4 to deSUMOylate TPR1 in Arabidopsis. The New phytologist 10 37786257
2021 Silencing of Nesprin-2 inhibits the differentiation of myofibroblasts from fibroblasts induced by mechanical stretch. International wound journal 10 34558192
2021 Biallelic SYNE2 Missense Mutations Leading to Nesprin-2 Giant Hypo-Expression Are Associated with Intellectual Disability and Autism. Genes 9 34573277
2018 Functional analyses of Pericentrin and Syne-2 interaction in ciliogenesis. Journal of cell science 9 30054381
2018 Depletion of Nesprin-2 is associated with an embryonic lethal phenotype in mice. Nucleus (Austin, Tex.) 8 30220251
2013 Nonsteroidal anti-inflammatory drug sulindac sulfide suppresses structural protein Nesprin-2 expression in colorectal cancer cells. Biochimica et biophysica acta 8 24080406
2022 NUA and ESD4 negatively regulate ABA signaling during seed germination. Stress biology 6 37676575
2019 Lack of a Retinal Phenotype in a Syne-2/Nesprin-2 Knockout Mouse Model. Cells 6 31614616
2018 Analysis of Nesprin-2 Interaction with Its Binding Partners and Actin. Methods in molecular biology (Clifton, N.J.) 6 30141036
2016 Neurological Nuance: Hodgkin lymphoma presenting with Guillain-BarrÉ syndrome. Muscle & nerve 6 27756115
2011 Nesprin-2 epsilon: a novel nesprin isoform expressed in human ovary and Ntera-2 cells. Biochemical and biophysical research communications 6 21820406
2016 Detection of Diverse and High Molecular Weight Nesprin-1 and Nesprin-2 Isoforms Using Western Blotting. Methods in molecular biology (Clifton, N.J.) 5 27147045
2024 Nesprin-2 is a novel scaffold protein for telethonin and FHL-2 in the cardiomyocyte sarcomere. The Journal of biological chemistry 4 38569934
2024 Apoptosis-induced translocation of nesprin-2 from the nuclear envelope to mitochondria is associated with mitochondrial dysfunction. Nucleus (Austin, Tex.) 4 39402980
2021 Syne2b/Nesprin-2 Is Required for Actin Organization and Epithelial Integrity During Epiboly Movement in Zebrafish. Frontiers in cell and developmental biology 4 34222245
2020 A novel SYNE2 mutation identified by whole exome sequencing in a Korean family with Emery-Dreifuss muscular dystrophy. Clinica chimica acta; international journal of clinical chemistry 4 32184094
2022 The thematic role of extracellular loop of VraG in activation of the membrane sensor GraS in a cystic fibrosis MRSA strain differs in nuance from the CA-MRSA strain JE2. PloS one 3 35737676
2018 Evaluation of Hansen et al.: Nuance Is Crucial in Comparisons of Noise. Cell systems 3 30359620
2017 No shortcuts: new findings reinforce why nuance is the rule in genetic autoinflammatory syndromes. Current opinion in rheumatology 3 28604422
2017 Acute myeloid leukemia with t(14;21) involving RUNX1 and SYNE2: A novel favorable-risk translocation? Cancer genetics 3 29025598
2017 Nesprin-2 Interacts with Condensin Component SMC2. International journal of cell biology 3 29445399
2006 Receptors as microprocessors: pharmacological nuance on metabotropic glutamate receptors 1alpha. Science's STKE : signal transduction knowledge environment 3 16818798
2025 The mechanism of nesprin-2 accumulation at the nucleus front during confined cell migration. Biophysical journal 2 40340251
2021 Emotional Nuance Enhances Verbatim Retention of Written Materials. Frontiers in psychology 2 34194352
2025 Nesprin-2 contains BH3-like motifs that can promote cell death. Cell death discovery 1 40461467
2024 An Intronic Heterozygous SYNE2 Splice Site Mutation: A Rare Cause for Myalgia and hyperCKemia? Muscles (Basel, Switzerland) 1 40757551
2026 Force-dependent structural dynamics of the giant nesprin-2. Proceedings of the National Academy of Sciences of the United States of America 0 41576090
2026 Cargo Recognition of Nesprin-2 by the Dynein Adapter Bicaudal D2 for a Nuclear Positioning Pathway That Is Important for Brain Development. Biochemistry 0 41770881
2026 SV40 exploits the Nesprin-2-SUN1-KPNA4 axis for stepwise targeting and entry into the host nucleus to promote infection. bioRxiv : the preprint server for biology 0 41959248
2026 Farnesylated prelamin A induces fibroblast polarity defects in premature aging disorders by inhibiting nesprin-2-SUN2 LINC complex function. Journal of cell science 0 42011117
2025 Cargo recognition of Nesprin-2 by the dynein adapter Bicaudal D2 for a nuclear positioning pathway that is important for neuronal migration. bioRxiv : the preprint server for biology 0 40475460
2024 Common SYNE2 Genetic Variant Associated With Atrial Fibrillation Lowers Expression of Nesprin-2α1 With Downstream Effects on Nuclear and Electrophysiological Traits. Circulation. Genomic and precision medicine 0 39355904
2016 [Nitrogen Removal and the Characteristics of Denitrification Bacteria Using NUA-DAS Ecofilter]. Huan jing ke xue= Huanjing kexue 0 29964476