Affinage

RTN4

Reticulon-4 · UniProt Q9NQC3

Round 2 corrected
Length
1192 aa
Mass
129.9 kDa
Annotated
2026-04-28
130 papers in source corpus 31 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RTN4 (Nogo-A/Nogo-B) is a multifunctional reticulon-family ER membrane protein that inhibits axonal regeneration, shapes ER and nuclear envelope tubular morphology, and regulates synaptic plasticity. Its extracellular inhibitory activity is mediated by at least three discrete domains—Nogo-66, Nogo-A-Δ20, and an N-terminal region—that engage distinct receptor systems: NgR1 (shared with MAG) for Nogo-66 (PMID:11201742, PMID:12089450), S1PR2/G13/LARG with the co-receptor TSPAN3 for Nogo-A-Δ20 (PMID:24453941, PMID:26290381), and syndecan-3/4 heparan sulfate proteoglycans as S1PR2-independent Nogo-A-Δ20 receptors (PMID:28943240), all converging on RhoA activation and Rac1 suppression to collapse growth cones and restrict neurite outgrowth (PMID:12451136). Intracellularly, RTN4 cooperates with atlastin GTPases to generate ER tubules (PMID:19665976), regulates PDI distribution and ER stress responses relevant to ALS-model neuroprotection (PMID:19889996), controls sphingolipid-dependent AKT membrane localization in cancer cells (PMID:30078441), and through S1PR2-ROCK1-BECN1 signaling governs vascular autophagy and angiogenesis after stroke (PMID:35263212). At synapses, Nogo-A constrains dendritic spine dynamics, AMPA/NMDA receptor expression via NgR1-RhoA-mTOR signaling (PMID:21985178, PMID:26748478), and destabilizes inhibitory synaptic terminals by reducing scaffold proteins (PMID:17957480).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2000 High

    Identification of RTN4/Nogo-A as the long-sought myelin-associated neurite outgrowth inhibitor resolved a decades-old question about the molecular basis of CNS regeneration failure, attributing inhibitory activity to a 66-residue extracellular loop (Nogo-66) unique among reticulon family members.

    Evidence Molecular cloning, recombinant Nogo-66 protein in neurite outgrowth and growth cone collapse assays; three independent groups published concurrently

    PMID:10667796 PMID:10667797 PMID:10937871

    Open questions at the time
    • Topology of full-length Nogo-A at the oligodendrocyte surface was unresolved
    • Neuronal receptor for Nogo-66 was unknown
  2. 2001 High

    Discovery of NgR (Nogo-66 receptor) as a GPI-anchored neuronal receptor for Nogo-66 established the first ligand-receptor pair in myelin-mediated inhibition and explained why only neurons with surface NgR are sensitive to Nogo.

    Evidence Ligand-binding assay, GPI-cleavage ablation of sensitivity, gain-of-function expression in resistant neurons

    PMID:11201742

    Open questions at the time
    • Signal transduction mechanism downstream of GPI-anchored NgR was unknown
    • Whether Nogo-A regions outside Nogo-66 used NgR was untested
  3. 2002 High

    Mapping the intracellular signaling pathway to RhoA activation and Rac1 suppression downstream of both Nogo-66 and Amino-Nogo domains unified disparate inhibitory activities into a common cytoskeletal collapse mechanism, while demonstrating that NgR was not required for all Nogo-A-triggered RhoA activation.

    Evidence RhoA/Rac1 pull-down assays, C3 transferase and ROCK inhibitor rescue of neurite outgrowth and growth cone collapse

    PMID:12451136

    Open questions at the time
    • Identity of the receptor(s) mediating NgR-independent RhoA activation was unknown
    • Downstream transcriptional consequences of RhoA signaling in neurons were not explored
  4. 2002 High

    NgR was shown to be a shared receptor for both Nogo-66 and MAG, explaining convergent inhibitory signaling from multiple myelin ligands and providing a therapeutic rationale for NgR blockade—validated by in vivo corticospinal tract regeneration with the competitive antagonist NEP1-40.

    Evidence Direct binding assays for MAG-NgR, dominant-negative NgR, in vivo NEP1-40 intrathecal delivery after rat spinal cord hemisection with axon tracing and behavioral recovery

    PMID:12037567 PMID:12089450

    Open questions at the time
    • Long-term functional recovery and specificity of NEP1-40 were not established
    • Co-receptor complex for NgR signal transduction (later identified as p75NTR/LINGO-1) was not yet known
  5. 2003 High

    Systematic domain mapping revealed three discrete inhibitory regions in Nogo-A and established that Nogo-A adopts at least two membrane topologies—surface-exposed and ER-retained—resolving how a reticulon protein can function both as an extracellular ligand and an intracellular ER-shaping molecule.

    Evidence Recombinant fragment assays, cell-surface biotinylation of living oligodendrocytes, selective permeabilization immunofluorescence

    PMID:12577319 PMID:12843238

    Open questions at the time
    • Regulation of topology switching was unknown
    • Whether intraneuronal Nogo-A has cell-autonomous signaling functions was unclear
  6. 2005 High

    Identification of a second, high-affinity NgR-binding site within the Amino-Nogo region demonstrated that Nogo-A engages NgR bivalently, converting a partial antagonist into a full agonist and explaining the potency of full-length Nogo-A relative to Nogo-66 alone.

    Evidence SPR and radioligand binding of 24-aa domain, bivalent fusion construct converts antagonist peptide to agonist in neurite outgrowth and spreading assays

    PMID:15930377

    Open questions at the time
    • Structural basis of bivalent NgR engagement was lacking
    • Whether this second site is accessible in native myelin topology was unconfirmed
  7. 2009 High

    RTN4 was established as an essential structural component of the tubular ER network through its physical interaction with atlastin GTPases, extending its function beyond neurite inhibition to a fundamental role in organelle morphogenesis shared across eukaryotes.

    Evidence Co-IP of RTN4 with atlastins, siRNA/dominant-negative disruption of ER tubules, genetic validation in yeast (Sey1p/Yop1p), electron microscopy

    PMID:19665976

    Open questions at the time
    • Whether ER-shaping and neurite-inhibitory functions are coupled or independent was unresolved
    • Stoichiometry and structure of reticulon-atlastin complexes were unknown
  8. 2009 Medium

    RTN4's intracellular role was extended to ER proteostasis: Nogo-A regulates PDI distribution, and genetic deletion of Nogo-A/B accelerates disease in SOD1(G93A) ALS mice, implicating RTN4 in neuroprotection through ER chaperone function.

    Evidence PDI redistribution by immunofluorescence upon overexpression/knockdown, Nogo-A/B knockout crossed to SOD1(G93A) mice with survival and behavioral analysis

    PMID:19889996

    Open questions at the time
    • Direct biochemical interaction between RTN4 and PDI was not demonstrated
    • Whether PDI redistribution is cause or consequence of Nogo-A loss was unresolved
  9. 2010 High

    The discovery that Nogo-A-Δ20 is internalized via Pincher/Rac-dependent macroendocytosis and retrogradely transported as signalosomes carrying active RhoA to the soma—reducing phospho-CREB—revealed a long-range signaling mechanism analogous to neurotrophin retrograde transport.

    Evidence Dominant-negative Pincher/Rac1/dynamin, compartmentalized DRG chambers, live imaging of retrograde NogoDelta20 transport, phospho-CREB Western blot

    PMID:20083601

    Open questions at the time
    • In vivo relevance of retrograde Nogo-A signaling was not established
    • Nuclear targets downstream of CREB suppression were unidentified
  10. 2014 High

    Identification of S1PR2 as the receptor for the Nogo-A-Δ20 domain—signaling through G13/LARG/RhoA at a site distinct from the S1P pocket—resolved the long-standing question of how Nogo-A inhibits neurite outgrowth independently of NgR and established S1PR2 as a regulator of hippocampal LTP.

    Evidence Binding assays, Co-IP, G-protein pathway dissection, S1PR2 blockade/knockout with neurite outgrowth and LTP electrophysiology in WT vs. Nogo-A−/− mice

    PMID:24453941

    Open questions at the time
    • Structural basis of Nogo-A-Δ20/S1PR2 interaction was lacking
    • Contribution of S1PR2 vs. NgR to in vivo regeneration was not quantified
  11. 2015 High

    TSPAN3 was identified as a modulatory co-receptor that clusters S1PR2 upon Nogo-A-Δ20 binding, undergoes co-internalization, and is required for efficient RhoA activation—adding a tetraspanin to the Nogo-A receptor complex.

    Evidence Single-molecule tracking of TSPAN3 membrane dynamics, Co-IP with S1PR2, siRNA knockdown reducing S1PR2 clustering and RhoA activation

    PMID:26290381

    Open questions at the time
    • Whether TSPAN3 directly contacts Nogo-A-Δ20 or only S1PR2 was unclear
    • Role of other tetraspanins in the complex was unexplored
  12. 2017 High

    Discovery that Nogo-A-Δ20 binds heparan sulfate GAGs and signals through syndecan-3 and syndecan-4 independently of S1PR2 revealed a parallel receptor system, explaining residual Nogo-A inhibitory activity in S1PR2-deficient conditions.

    Evidence Heparin-binding assay, syndecan-3/4 knockout/knockdown, RhoA activation, neurite outgrowth, and explant migration assays

    PMID:28943240

    Open questions at the time
    • Whether S1PR2 and syndecan pathways operate sequentially or in parallel at the same synapse was unknown
    • Structural details of Nogo-A-Δ20/HSPG interaction were lacking
  13. 2018 Medium

    RTN4 knockdown was shown to reduce sphingomyelin synthesis and impair AKT membrane localization and phosphorylation in cancer cells, revealing an intracellular lipid-metabolic function linking RTN4's ER role to oncogenic signaling.

    Evidence siRNA knockdown, sphingomyelin quantification, AKT membrane fractionation and phospho-Western blot, xenograft tumor growth

    PMID:30078441

    Open questions at the time
    • Mechanism by which RTN4 controls sphingomyelin synthesis was not identified
    • Generalizability beyond the cancer cell lines tested was unclear
  14. 2021 High

    NgR1-3 were revealed as high-affinity ligands for BAI adhesion-GPCRs, with a 1.65 Å crystal structure showing glycoconjugate-modified interfaces, reframing the Nogo receptor family as bidirectional signaling hubs that regulate dendritic arborization, axonal elongation, and synapse formation in human neurons.

    Evidence Unbiased interactome screen, quantitative binding, crystal structure of BAI-TSR/NgR complex, human neuron loss-of-function, network electrophysiology

    PMID:34758294

    Open questions at the time
    • Whether Nogo-A and BAI compete for NgR binding in vivo was untested
    • Downstream signaling from BAI-NgR in synaptogenesis was not fully characterized
  15. 2022 Medium

    RTN4 was linked to vascular autophagy control: Nogo-A acting through S1PR2-ROCK1 phosphorylates BECN1 at Thr119 to initiate autophagic flux and suppress angiogenesis after stroke, connecting RTN4's receptor signaling to a non-neuronal vascular remodeling process.

    Evidence siRNA/lentiviral manipulation of RTN4, S1PR2 pharmacology, p-BECN1 and autophagic flux assays, angiogenesis quantification in MCAO rat model and BMVECs

    PMID:35263212

    Open questions at the time
    • Whether ROCK1-BECN1 axis operates in non-ischemic vasculature was unknown
    • Contribution of syndecan vs. S1PR2 pathways to vascular autophagy was not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the structural basis of Nogo-A-Δ20 binding to S1PR2 and syndecans, the mechanism governing RTN4 topology switching between ER-retained and surface-exposed states, whether intracellular ER-shaping and extracellular inhibitory functions are coordinated, and how neuronal versus glial RTN4 isoforms are differentially regulated during development and after injury.
  • No high-resolution structure of Nogo-A-Δ20 bound to S1PR2
  • Mechanism of RTN4 topology regulation remains unknown
  • In vivo dissection of RTN4 isoform-specific functions (Nogo-A vs. Nogo-B vs. Nogo-C) is incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0098772 molecular function regulator activity 4 GO:0005198 structural molecule activity 2 GO:0008289 lipid binding 2
Localization
GO:0005783 endoplasmic reticulum 6 GO:0005886 plasma membrane 3 GO:0005634 nucleus 1 GO:0005635 nuclear envelope 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-112316 Neuronal System 4 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 2
Partners
ATL1GPR50RTN3RTN4RS1PR2SDC3SDC4TSPAN3
Complex memberships
NgR1/p75NTR/LINGO-1 receptor complex (as ligand)S1PR2/TSPAN3/G13 signaling complex (as ligand)

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 RTN4/Nogo-A was identified as a member of the Reticulon family (Reticulon 4-A), expressed by oligodendrocytes but not Schwann cells, and primarily associates with the endoplasmic reticulum. A 66-residue lumenal/extracellular domain (Nogo-66) inhibits axonal extension and collapses dorsal root ganglion growth cones, while the corresponding domains from Reticulon 1, 2 and 3 do not inhibit axonal regeneration. Molecular cloning, recombinant protein functional assays (neurite outgrowth inhibition, growth cone collapse), immunostaining of oligodendrocytes Nature High 10667796 10667797 10937871
2000 Nogo-A (NI-220/250) is a potent inhibitor of neurite outgrowth from dorsal root ganglia and fibroblast spreading; it is recognized by monoclonal antibody IN-1, is expressed by oligodendrocytes in CNS myelin, and its inhibitory activity is IN-1-sensitive. cDNA cloning, recombinant protein assays (neurite outgrowth on CNS myelin substrates, fibroblast spreading assay), immunostaining with IN-1 antibody Nature High 10667796
2001 A brain-specific, leucine-rich-repeat GPI-anchored protein (Nogo-66 receptor, NgR) binds soluble Nogo-66 with high affinity. Cleavage of NgR from axonal surfaces renders neurons insensitive to Nogo-66, and NgR expression is sufficient to confer Nogo-66-mediated axonal inhibition on otherwise unresponsive neurons. Ligand-binding assay, GPI-cleavage (PI-PLC), expression in non-responsive neurons, neurite outgrowth assay Nature High 11201742
2002 Nogo-A inhibitory domains (NiG and Nogo-66) mediate growth inhibition via antagonistic regulation of the small GTPases RhoA (activated) and Rac1 (suppressed). Inactivating RhoA with C3 transferase or blocking its downstream effector ROCK abolished inhibitory effects of both Nogo-A fragments and MAG on neurite outgrowth and growth cone collapse. NgR was shown not to be required for NiG- or MAG-induced RhoA activation. RhoA/Rac1 activity assays (pull-down), pharmacological inhibition (C3 transferase, Y-27632 ROCK inhibitor), neurite outgrowth and growth cone collapse assays The Journal of Neuroscience High 12451136
2002 Nogo-66 antagonist peptide NEP1-40 (Nogo-66(1-40)) competitively blocks NgR-mediated axonal outgrowth inhibition by Nogo-66 and CNS myelin in vitro; intrathecal NEP1-40 promotes corticospinal tract axon growth and functional recovery after spinal cord hemisection in rats. Competitive receptor binding assay, neurite outgrowth inhibition assay, in vivo rat spinal cord hemisection with anterograde tracing and behavioral assessment Nature High 12037567
2002 MAG binds directly and with high affinity to the Nogo-66 receptor (NgR). GPI-cleavage from axons protects growth cones from MAG-induced collapse; dominant-negative NgR eliminates MAG inhibition; NgR expression confers MAG sensitivity to resistant embryonic neurons, establishing NgR as a shared receptor for both Nogo-66 and MAG. Direct binding assay, GPI-cleavage, dominant-negative NgR expression, neurite outgrowth inhibition assay Science High 12089450
2003 Nogo-A contains at least three discrete inhibitory regions: (1) an N-terminal region inhibiting fibroblast spreading, (2) a Nogo-A-specific exon region restricting neurite outgrowth and inducing growth cone collapse, and (3) Nogo-66. Cell-surface Nogo-A is accessible on living oligodendrocytes and exhibits two topological variants (surface-exposed and ER-associated), with the ER-associated form having cytoplasmic exposure of the same epitopes. Structure-function analysis with recombinant fragments, cell-surface biotin labeling of living cells, selective permeabilization immunofluorescence, growth cone collapse assay, fibroblast spreading assay The Journal of Neuroscience High 12843238
2003 Intraneuronal Nogo-A is distributed at polyribosomes and rough ER in the perikaryon, beneath/on the plasma membrane, and within the nucleus (at chromatins), as demonstrated by immunogold electron microscopy and subcellular fractionation in rat CNS tissue and COS-7 cells transfected with nogo-A. Immunogold electron microscopy, subcellular fractionation with Western blot, confocal immunofluorescence, cell transfection The Journal of Comparative Neurology Medium 12577319
2005 A novel 24-amino-acid domain within the Amino-Nogo-A region binds NgR with nanomolar affinity. Fusion of this second NgR-binding site with Nogo-66 creates a bivalent ligand with substantially enhanced NgR affinity and converts an NgR antagonist peptide into an agonist, demonstrating that Nogo-A activates NgR via multiple interaction sites. Binding assays (surface plasmon resonance, radioligand), domain deletion and fusion constructs, neurite outgrowth and cell-spreading assays The Journal of Neuroscience High 15930377
2007 Reticulon 4a (Nogo-A) localizes to regions of high membrane curvature in the ER and at junctions between cytoplasmic membranes and the outer nuclear membrane in Xenopus oocytes. During NE assembly, Rtn4a localizes to edges of flattening membranes on chromatin, and antibody inhibition of Rtn4a causes ER to form vesicles instead of tubules and prevents nuclear envelope growth, implicating Rtn4a in NE assembly. Immunoelectron microscopy (immuno-EM), Xenopus egg extract NE assembly assay, antibody inhibition, immunofluorescence Journal of Structural Biology Medium 17889556
2009 Reticulon-4A (Nogo-A) is a novel regulator of the ER chaperone protein disulfide isomerase (PDI). Overexpression of reticulon induces punctate redistribution of PDI intracellularly in vitro and in vivo; reduction of endogenous Nogo-A causes more homogeneous PDI distribution. Deletion of one or both copies of the Nogo-A,B gene accelerates disease onset and progression in SOD1(G93A) ALS mice, implicating Nogo-A in PDI-dependent ER function and neuroprotection. Immunofluorescence (PDI redistribution), in vivo Nogo-A knockout mouse studies, survival/behavioral analysis in SOD1(G93A) mice The Journal of Neuroscience Medium 19889996
2010 The Nogo-A-specific fragment NogoDelta20 is internalized into neurons by a Pincher- and Rac-dependent, but clathrin- and dynamin-independent, macroendocytosis pathway. Internalization generates NogoDelta20-containing signalosomes that direct RhoA activation and growth cone collapse. In compartmentalized cultures, NogoDelta20 is retrogradely transported to cell bodies, triggering RhoA activation en route and decreasing phospho-CREB levels. Endocytosis assays (dominant-negative Pincher, Rac1, dynamin; clathrin inhibitors), live imaging, compartmentalized dorsal root ganglion chamber cultures, retrograde transport assay, RhoA activity assay, phospho-CREB Western blot The Journal of Cell Biology High 20083601
2001 RTN4/Nogo-B (also called ASY) induces apoptosis when ectopically expressed, particularly in cancer cells, and is suppressed in small cell lung cancer, identifying a novel apoptosis-inducing function for the RTN4/Nogo-B isoform. Ectopic expression, apoptosis assays (flow cytometry, morphology), quantitative RT-PCR in cancer cell lines Oncogene Medium 11494121
2003 Nogo-B/ASY (RTN4-B) physically associates with ASYIP (identical to RTN3) via both hydrophobic regions of RTN3. The two proteins co-localize in the ER of human cells, as shown by co-immunoprecipitation and immunofluorescence. Yeast two-hybrid, co-immunoprecipitation in mammalian cells, immunofluorescence co-localization, mutational analysis Journal of Cellular Physiology Medium 12811824
2006 Nogo-B/ASY overexpression induces apoptosis through ER stress, specifically via ER Ca2+ depletion and ER-specific apoptotic pathways. Stable overexpression also activates a protective ER stress response. Stable transfection, ER stress markers (Western blot), Ca2+ measurement, caspase assays, pharmacological ER stress inducers Experimental Cell Research Medium 16687140
2007 Neuronal Nogo-A is present in inhibitory presynaptic terminals of cerebellar Purkinje cells during Purkinje cell–Deep Cerebellar Nuclei synapse formation and is downregulated during maturation. Purkinje cell-specific overexpression of Nogo-A causes progressive disassembly and loss of inhibitory terminals, motor learning deficits, and downregulation of synaptic scaffold proteins spectrin, spectrin-E, and β-catenin in postsynaptic neurons. Transgenic mouse overexpression, immunofluorescence, confocal microscopy, Western blot (synaptic scaffold proteins), behavioral motor testing Brain Cell Biology Medium 17957480
2009 GPR50 (an orphan GPCR) physically interacts with neuronal Nogo-A in mammalian cells, confirmed by yeast two-hybrid and co-immunoprecipitation. Both GPR50 and Nogo-A are enriched at synapses. GPR50 overexpression (unlike Nogo-A overexpression) increases neurite length and filopodial/lamellipodial structures. Yeast two-hybrid, co-immunoprecipitation, synaptic fractionation, neurite outgrowth assay Molecular and Cellular Neurosciences Medium 19699797
2010 In the reperfused ischemic brain, Nogo-A promotes neuronal survival by maintaining RhoA activation and suppressing Rac1/RhoB, thereby keeping stress kinases p38/MAPK, SAPK/JNK1/2, and PTEN activity low. Nogo-A blockade leads to RhoA deactivation, Rac1/RhoB overactivation, p38/MAPK and SAPK/JNK1/2 activation via direct Rac1 interaction, PTEN stimulation, Akt/ERK1/2 inhibition, and p53-dependent cell death. Nogo-A knockout mice, neutralizing antibody (11C7) infusion, Rho GTPase activity assays, Western blot for kinase phosphorylation, focal cerebral ischemia model Journal of Cerebral Blood Flow and Metabolism Medium 20087369
2011 Neuronal Nogo-A signaling through NgR1 regulates glutamate receptor subunit expression via RhoA-ROCK and MEK-MAPK pathways and rapamycin-sensitive mTOR-dependent translation. Reducing Nogo-A or NgR1 increases PSD95, GluA1/GluA2 AMPA receptor, and GluN1/GluN2A/GluN2B NMDA receptor subunits; mTOR phosphorylation mediates this upregulation. siRNA knockdown of Nogo-A and NgR1, soluble NgR1 fragment treatment, ROCK/MEK/mTOR inhibitors, Western blot, primary hippocampal neuron cultures Journal of Neurochemistry Medium 21985178
2014 The G protein-coupled receptor S1PR2 is identified as a specific receptor for the Nogo-A-Δ20 domain. Nogo-A-Δ20 binds S1PR2 at sites distinct from the sphingosine 1-phosphate binding pocket and signals through G13, LARG (RhoGEF), and RhoA. Deletion or blockade of S1PR2 counteracts Nogo-A-Δ20- and myelin-mediated inhibition of neurite outgrowth. S1PR2 blockade strongly enhances LTP in hippocampus of wild-type but not Nogo-A-/- mice. Binding assays, co-immunoprecipitation, G protein pathway analysis, siRNA, pharmacological S1PR2 blockade, Nogo-A knockout mice, LTP electrophysiology PLoS Biology High 24453941
2015 Tetraspanin-3 (TSPAN3) functions as a modulatory co-receptor in the Nogo-A-Δ20 signaling complex. Upon Nogo-A-Δ20 binding, TSPAN3 molecules show elevated membrane mobility, associate with S1PR2, and are co-internalized into early endosomes, then recycled to the cell surface. TSPAN3 knockdown strongly reduces Nogo-A-induced S1PR2 clustering, RhoA activation, cell spreading inhibition, and neurite outgrowth inhibition. Single-molecule tracking, co-immunoprecipitation, siRNA knockdown, RhoA activity assay, internalization assay, cell spreading and neurite outgrowth assays Journal of Cell Science High 26290381
2016 Nogo-A signaling rapidly modulates the actin cytoskeleton at dendritic spines within minutes. Acute Nogo-A loss-of-function transiently increases F-actin stability, dendritic spine density and length, and AMPAR insertion (mEPSC amplitude) at hippocampal CA3 synapses. Acute Nogo-A function-blocking, live imaging of F-actin (phalloidin/FRAP), dendritic spine morphometry, whole-cell patch-clamp (mEPSC recordings), AMPAR surface localization Hippocampus Medium 26748478
2017 Nogo-A-Δ20 binds heparin and brain-derived heparan sulfate glycosaminoglycans (but not chondroitin sulfate GAGs) and mediates inhibition of neurite outgrowth, cell spreading, and RhoA activation through HSPG family members syndecan-3 and syndecan-4, acting independently of S1PR2. Heparin-binding assay, HSPG knockdown/knockout, RhoA activation assay, neurite outgrowth and cell spreading assays, syndecan-3/4 identification as functional receptors, explant migration assay Developmental Cell High 28943240
2018 RTN4 knockdown in cancer cells reduces sphingomyelin synthesis, impairs plasma membrane localization of AKT (sphingolipid-dependent), and reduces AKT phosphorylation without affecting upstream kinases. RTN4 knockdown also destabilizes tubulin and retards cancer cell proliferation in vitro and in xenograft tumors. siRNA knockdown, mass spectrometry proteomics, AKT membrane fractionation, phospho-AKT Western blot, sphingomyelin assay, tubulin stability assay, in vitro proliferation, in vivo xenograft Molecular Therapy Medium 30078441
2021 RTN4 receptors (NgR1, NgR2, NgR3) are high-affinity ligands for BAI adhesion-GPCRs. A single thrombospondin type 1-repeat (TSR) domain of BAIs binds the leucine-rich repeat domain of all three RTN4-receptor isoforms with nanomolar affinity. The 1.65 Å crystal structure reveals that C-mannosylation of tryptophan and O-fucosylation of threonine in BAI TSR domains create an RTN4-receptor/BAI interface shaped by unusual glycoconjugates. In human neurons, RTN4 receptors regulate dendritic arborization, axonal elongation, and synapse formation through differential binding to glial versus neuronal BAIs. Unbiased interactome screen, quantitative binding assays, crystal structure (1.65 Å), glycan modification analysis, human neuron culture with loss-of-function, electrophysiology (network activity) Cell High 34758294
2022 RTN4 (Nogo-A) acting through S1PR2 promotes vascular autophagy and inhibits angiogenesis in the thalamus after cerebral cortical infarction. Mechanistically, RTN4-S1PR2 activates ROCK1, which phosphorylates BECN1 at Thr119, initiating autophagic flux and suppressing angiogenesis; RTN4 knockdown reduces BECN1 phosphorylation and enhances angiogenesis and neuronal survival. siRNA knockdown, lentiviral overexpression, S1PR2 pharmacological activation/inhibition, Western blot (MAP1LC3B, BECN1, SQSTM1, ROCK1, p-BECN1), autophagic flux assay, angiogenesis quantification, MCAO rat model, in vitro BMVEC experiments Autophagy Medium 35263212
2009 A class of dynamin-like GTPases (atlastins) interact physically with tubule-shaping proteins including RTN4/reticulons; RTN4/reticulons are required for ER tubule formation and interconnection, and loss of tubule-shaping proteins together with their GTPase partners causes ER morphology defects, placing RTN4 as an essential component of the tubular ER network. Co-immunoprecipitation, in vitro and in vivo ER morphology assays, dominant-negative expression, siRNA, yeast genetic interaction (Sey1p/Yop1p), electron microscopy Cell High 19665976
2021 Nogo-A (RTN4-A) is a regulator of pro-inflammatory gene expression in muscle and macrophages. In C2C12 myocytes, Nogo-A upregulation increases CHOP, IL-6, and TNF-α, while knockdown reduces them. In LPS-stimulated bone marrow-derived macrophages from Nogo-KO mice, CHOP, IL-6, and TNF-α mRNA are lower, and migratory and phagocytic activity is reduced compared to wild-type. siRNA knockdown, overexpression in C2C12, Nogo-KO bone marrow macrophage isolation, LPS stimulation, qRT-PCR, immunofluorescence, migration assay, phagocytosis assay, in vivo notexin/tunicamycin muscle injury model Cells Medium 33572505
2019 Extracellular phosphoglycerate kinase 1 (Pgk1), whose secretion is reduced by NogoA-overexpressing muscle cells, stimulates motoneuron neurite outgrowth through a novel Rac1-GTP/p-Pak1/p-P38/p-MK2/p-Limk1/p-Cofilin-S3 pathway that reduces growth cone collapse marker p-Cofilin-S3, independently of the Nogo66/NgR pathway. NogoA overexpression in muscle cells, Pgk1 secretion assay, phosphoproteomics pathway analysis, zebrafish morpholino knockdown, SOD1-G93A mouse injection, neurite outgrowth assay eLife Medium 31361595
2018 Nogo-B inhibition in cardiomyocytes promotes hypertrophy by activating ER stress through the PERK/ATF4 and ATF6 branches and impairing autophagic flux. Nogo-B siRNA exacerbates norepinephrine-induced hypertrophy and TGF-β1-induced cardiac fibroblast activation. siRNA knockdown of Nogo-B in NRCMs and cardiac fibroblasts, TAC mouse model, ER stress Western blot (PERK/ATF4/ATF6), autophagic flux monitoring, immunofluorescence, qRT-PCR Biomedicine & Pharmacotherapy Medium 29772440

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 3411 32353859
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2000 Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 1165 10667796
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2000 Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature 935 10667797
2001 Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 897 11201742
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2008 Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nature genetics 817 18583979
2000 DNA cloning using in vitro site-specific recombination. Genome research 815 11076863
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2003 Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS. Nature reviews. Neuroscience 676 12951563
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2011 Global landscape of HIV-human protein complexes. Nature 593 22190034
2002 Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature 569 12037567
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
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