Affinage

ELFN2

Protein phosphatase 1 regulatory subunit 29 · UniProt Q5R3F8

Round 2 corrected
Length
820 aa
Mass
89.7 kDa
Annotated
2026-04-28
39 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ELFN2 is a postsynaptic transmembrane leucine-rich repeat (LRR) and fibronectin type III (FN3) domain-containing cell adhesion molecule that trans-synaptically recruits and functionally modulates all four group III metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7, mGluR8), thereby shaping glutamatergic synaptic transmission and circuit wiring in the brain and retina (PMID:31485013, PMID:32879010). ELFN2 forms obligate homodimers (and heterodimers with ELFN1) via its LRR domain prior to membrane trafficking, and its trans-synaptic binding to mGluR6 requires complex N-glycosylation at mGluR6-N445 (PMID:39675706, PMID:38428819). In cone photoreceptor terminals, ELFN2 acts in synergy with ELFN1 to specify cone-to-ON-bipolar cell connectivity and enable synaptic transmission, and Elfn2 knockout mice exhibit seizure susceptibility, hyperactivity, and anxiety-like behaviors that are rescued by group III mGluR agonists (PMID:32879010, PMID:31485013). ELFN2 also functions as a protein phosphatase 1 (PP1A) regulatory subunit, directly binding PP1A to inhibit YAP dephosphorylation and suppress metastatic dissemination in gastric cancer (PMID:41967793).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2007 Low

    Identification of ELFN2 as a member of a novel eLRR transmembrane subfamily with brain-restricted expression established its structural classification and hinted at a neural role, but no function was assigned.

    Evidence Bioinformatic cataloguing of eLRR proteins combined with RT-PCR/in situ hybridization in developing mouse brain

    PMID:17868438

    Open questions at the time
    • No functional data provided
    • Expression profiling only, no protein-level validation
    • No interaction partners identified
  2. 2018 Medium

    A cancer biology study revealed that ELFN2 can interact with AurkA and eIF2α to promote autophagy in glioblastoma, providing the first evidence of ELFN2 protein–protein interactions but in a non-neuronal context.

    Evidence Co-immunoprecipitation, siRNA knockdown, ChIP, and autophagy assays in GBM cell lines

    PMID:30037656

    Open questions at the time
    • Single-lab finding without independent replication
    • Relevance of AurkA/eIF2α interaction to normal ELFN2 physiology unclear
    • No structural basis for the interaction
  3. 2019 High

    A major functional breakthrough established ELFN2 as a postsynaptic cell adhesion molecule that trans-synaptically binds and modulates G protein coupling of all group III mGluRs, with Elfn2 KO mice showing seizures, hyperactivity, and mGluR downregulation — rescued by group III mGluR agonists — thereby defining ELFN2's core synaptic role.

    Evidence Transcellular GPCR signaling platform, Elfn2 KO mice, electrophysiology, pharmacological rescue, co-immunoprecipitation

    PMID:31485013

    Open questions at the time
    • Structural basis of ELFN2–mGluR interaction not resolved
    • Relative contributions of ELFN1 vs ELFN2 at specific synapse types unclear
    • Post-translational requirements for binding not yet explored
  4. 2020 High

    Unbiased proteomics in a cone-dominant retina revealed that ELFN2 localizes to cone photoreceptor terminals and transsynaptically recruits mGluR6 to specify cone-to-ON-bipolar cell wiring, demonstrating synergy with ELFN1 during circuit development.

    Evidence Proteomics, conditional knockout mice, electroretinography, immunohistochemistry, synaptogenesis assays

    PMID:32879010

    Open questions at the time
    • Mechanism by which ELFN1 and ELFN2 cooperate at molecular level not dissected
    • Whether ELFN2 instructs or merely maintains cone-ON bipolar synapses unclear
  5. 2024 High

    Biochemical dissection showed that complex N-glycosylation of mGluR6 — specifically at N445 — is required for ELFN2 trans-synaptic binding, and that ELFN2 forms obligate LRR-mediated homodimers (and ELFN1 heterodimers) before membrane delivery, revealing critical post-translational and quaternary structural requirements.

    Evidence Reconstituted pull-down with purified extracellular domains, glycosidase treatment, site-directed mutagenesis, domain deletion/co-IP, membrane trafficking assays

    PMID:38428819 PMID:39675706

    Open questions at the time
    • Crystal or cryo-EM structure of ELFN2–mGluR complex not available
    • Functional consequences of heterodimerization vs homodimerization on mGluR signaling not tested
    • Whether glycosylation requirements extend to mGluR4/7/8 binding untested
  6. 2026 Medium

    ELFN2 was shown to directly bind PP1A (protein phosphatase 1 catalytic subunit alpha) and inhibit PP1A-mediated YAP dephosphorylation, suppressing metastatic dissemination in gastric cancer — establishing ELFN2 as a bona fide PP1 regulatory subunit outside the nervous system.

    Evidence Co-immunoprecipitation (ELFN2–PP1A), PP1A pharmacological inhibition, YAP phosphorylation assays, in vivo metastasis models

    PMID:41967793

    Open questions at the time
    • Single-lab study; independent replication needed
    • Whether PP1A regulatory activity is relevant in neurons not explored
    • Structural basis of PP1A binding (RVxF motif usage) not characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • No high-resolution structure of ELFN2 alone or in complex with any mGluR exists, and the relative physiological roles of ELFN2 homodimers versus ELFN1–ELFN2 heterodimers at distinct synapse types remain unresolved.
  • Structural model of ELFN2–mGluR complex needed
  • Cell-type-resolved functions of homo- vs heterodimers unknown
  • Whether PP1A regulatory and synaptic adhesion functions are coordinated or context-exclusive is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 2 GO:0098772 molecular function regulator activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-9709957 Sensory Perception 2 R-HSA-1266738 Developmental Biology 1
Partners
AURKAEIF2S1ELFN1MGLUR4MGLUR6MGLUR7MGLUR8PPP1CA

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 ELFN2 (along with ELFN1) was identified as a member of a novel subfamily of extracellular leucine-rich repeat (eLRR) transmembrane proteins containing an FN3 domain. The two ELFN genes were shown to be expressed in discrete patterns in the developing mouse brain, notably in the thalamus and cortex, establishing the founding structural characterization of the ELFN family. Bioinformatic eLRR protein catalogue combined with mouse brain expression profiling (RT-PCR/in situ) BMC genomics Low 17868438
2018 ELFN2 was identified as a hypomethylation-driven oncogene in glioblastoma (GBM) that promotes autophagy by directly interacting with Aurora kinase A (AurkA) and eIF2α, inhibiting AurkA activation. LINC00470 was shown to upregulate ELFN2 by sponging miR-101 and reducing H3K27me3 occupancy at the ELFN2 promoter. Co-immunoprecipitation (AurkA/eIF2α binding), loss-of-function (siRNA knockdown), promoter methylation and ChIP assays, autophagy functional assays Molecular therapy Medium 30037656
2019 ELFN2 was characterized as a postsynaptic cell adhesion molecule with a distinct expression pattern throughout the brain that selectively binds group III metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7, mGluR8) in trans. Using a transcellular GPCR signaling platform, ELFN2 was shown to directly alter G protein coupling kinetics and efficacy of group III mGluRs. Loss of ELFN2 in mice caused selective downregulation of group III mGluRs and dysregulated glutamatergic synaptic transmission, and Elfn2 KO mice displayed seizure susceptibility, hyperactivity, and anxiety/compulsivity that were rescued by pharmacological augmentation of group III mGluRs. Transcellular GPCR signaling platform, Elfn2 knockout mice, electrophysiology, pharmacological rescue, Co-immunoprecipitation Molecular psychiatry High 31485013
2020 Using an unbiased proteomic strategy in a cone-dominant species, ELFN2 was identified as selectively expressed in cone photoreceptor terminals, where it transsynaptically recruits the neurotransmitter receptor mGluR6 in ON-type bipolar cells to enable synaptic transmission. ELFN2 was found to function in synergy with ELFN1, and their concerted interplay during development specifies selective cone-to-ON-bipolar cell wiring and transmission. Unbiased proteomics, immunohistochemistry/localization, conditional knockout mice, electroretinography, synaptogenesis assays Proceedings of the National Academy of Sciences of the United States of America High 32879010
2021 Review synthesis establishing that ELFN2 (and ELFN1) can interact trans-synaptically with all four group III mGluRs (mGluR4, mGluR6, mGluR7, mGluR8), and that these interactions alter mGluR-mediated signaling across hippocampal, cortical, and retinal synapses. ELFN2 postsynaptically modulates group III mGluR signaling properties and synaptic transmission characteristics. Review/synthesis of experimental literature including functional assays and genetic models Frontiers in neural circuits Medium 33790745
2023 Single-cell RNA sequencing and enhanced crosslinking immunoprecipitation (eCLIP-seq) identified Elfn2 as a key hub gene targeted by the RNA helicase DDX43 during spermiogenesis, placing ELFN2 downstream of DDX43-mediated RNA regulatory processes required for spermatid chromatin remodeling and differentiation. Single-cell RNA-seq, enhanced CLIP-seq (eCLIP), Ddx43 knockout mice, ATPase-dead missense mutant Nature communications Medium 37120627
2024 Complex N-glycosylation of mGluR6 acquired in the Golgi is required for trans-synaptic interaction with ELFN1 and ELFN2 extracellular domains. Pull-down experiments with ELFN1 and ELFN2 extracellular domains showed that they interact exclusively with the complex glycosylated form of mGluR6. Mutation of N-glycosylation site N445 on mGluR6 severely impaired both ELFN1 and ELFN2 binding, identifying N445 as a critical glycosylation site for ELFN interaction. Glycosidase treatment (PNGase F, Endo H), pull-down assays with ELFN1/ELFN2 extracellular domains, site-directed mutagenesis of N-glycosylation sites, heterologous expression, rod bipolar cell dendritic tip localization assays The Journal of biological chemistry High 38428819
2024 ELFN2 (like its closest homolog ELFN1) forms obligate homodimers prior to membrane trafficking, with homodimerization mediated by the extracellular leucine-rich repeat (LRR) domain rather than the intracellular region. ELFN2 also participates in heterodimerization with ELFN1, indicating conserved dimerization mechanisms across the ELFN subfamily. A single membrane-targeting motif in one protomer is sufficient for trafficking of the ELFN homodimer. Domain deletion/mutagenesis, co-immunoprecipitation, co-expression heterologous cell assays, fluorescence-based membrane trafficking assays The Journal of biological chemistry Medium 39675706
2026 ELFN2 directly interacts with the catalytic subunit alpha of protein phosphatase-1 (PP1A) and inhibits PP1A-mediated dephosphorylation of YAP at Ser127, thereby promoting YAP nuclear export and functional inactivation. Pharmacological inhibition of PP1A abrogated ELFN2-induced YAP inactivation, confirming that PP1A is required in the ELFN2/PP1A/YAP signaling axis. In vivo lymph node metastasis models confirmed that ELFN2 suppresses metastatic dissemination in gastric cancer through this axis. Co-immunoprecipitation (ELFN2-PP1A direct interaction), PP1A pharmacological inhibition, YAP phosphorylation assays, in vivo lymph node metastasis and peritoneal carcinomatosis models, loss-of-function studies Experimental cell research Medium 41967793

Source papers

Stage 0 corpus · 39 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
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
2006 A germline-specific class of small RNAs binds mammalian Piwi proteins. Nature 1362 16751776
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
1999 The DNA sequence of human chromosome 22. Nature 808 10591208
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2020 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis. Nature 292 32322062
2009 Docking motif-guided mapping of the interactome of protein phosphatase-1. Chemistry & biology 269 19389623
2014 E-cadherin interactome complexity and robustness resolved by quantitative proteomics. Science signaling 162 25468996
2015 Cell Surface Proteomic Map of HIV Infection Reveals Antagonism of Amino Acid Metabolism by Vpu and Nef. Cell host & microbe 146 26439863
2007 The extracellular leucine-rich repeat superfamily; a comparative survey and analysis of evolutionary relationships and expression patterns. BMC genomics 145 17868438
2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
2007 Toward a confocal subcellular atlas of the human proteome. Molecular & cellular proteomics : MCP 114 18029348
2014 Unbiased analysis of pancreatic cancer radiation resistance reveals cholesterol biosynthesis as a novel target for radiosensitisation. British journal of cancer 91 25025965
2012 Comparison of tear protein levels in breast cancer patients and healthy controls using a de novo proteomic approach. Oncology reports 79 22664934
2017 DNA-Methylation and Body Composition in Preschool Children: Epigenome-Wide-Analysis in the European Childhood Obesity Project (CHOP)-Study. Scientific reports 58 29084944
2018 LINC00470 Coordinates the Epigenetic Regulation of ELFN2 to Distract GBM Cell Autophagy. Molecular therapy : the journal of the American Society of Gene Therapy 56 30037656
2016 High-throughput analyses of hnRNP H1 dissects its multi-functional aspect. RNA biology 50 26760575
2014 Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases. The pharmacogenomics journal 42 24709693
2023 Single-cell RNA-seq uncovers dynamic processes orchestrated by RNA-binding protein DDX43 in chromatin remodeling during spermiogenesis. Nature communications 35 37120627
2020 Interplay between cell-adhesion molecules governs synaptic wiring of cone photoreceptors. Proceedings of the National Academy of Sciences of the United States of America 35 32879010
2001 Prediction of the coding sequences of unidentified human genes. XXI. The complete sequences of 60 new cDNA clones from brain which code for large proteins. DNA research : an international journal for rapid publication of reports on genes and genomes 35 11572484
2019 ELFN2 is a postsynaptic cell adhesion molecule with essential roles in controlling group III mGluRs in the brain and neuropsychiatric behavior. Molecular psychiatry 31 31485013
2020 SUMOylation of DDX39A Alters Binding and Export of Antiviral Transcripts to Control Innate Immunity. Journal of immunology (Baltimore, Md. : 1950) 27 32393512
2017 Overexpression of CST4 promotes gastric cancer aggressiveness by activating the ELFN2 signaling pathway. American journal of cancer research 27 29218251
2021 Trans-Synaptic Regulation of Metabotropic Glutamate Receptors by Elfn Proteins in Health and Disease. Frontiers in neural circuits 18 33790745
2014 Novel candidate genes putatively involved in stress fracture predisposition detected by whole-exome sequencing. Genetics research 13 25023003
2024 Extracellular proximal interaction profiling by cell surface-targeted TurboID reveals LDLR as a partner of liganded EGFR. Science signaling 11 39499777
2024 Complex N-glycosylation of mGluR6 is required for trans-synaptic interaction with ELFN adhesion proteins. The Journal of biological chemistry 8 38428819
2023 Pulse-SILAC and Interactomics Reveal Distinct DDB1-CUL4-Associated Factors, Cellular Functions, and Protein Substrates. Molecular & cellular proteomics : MCP 8 37689310
2024 Cone Synaptic function is modulated by the leucine rich repeat (LRR) adhesion molecule LRFN2. eNeuro 4 38408870
2024 Distinct autoregulatory roles of ELFN1 intracellular and extracellular domains on membrane trafficking, synaptic localization, and dimerization. The Journal of biological chemistry 4 39675706
2019 LRRC62 attenuates Toll-like receptor signaling by deubiquitinating TAK1 via CYLD. Experimental cell research 3 31301291
2022 Identification of Key Prognostic-Related miRNA-mRNA Pairs in the Progression of Endometrial Carcinoma. Gynecologic and obstetric investigation 1 35081534
2026 ELFN2 inhibits YAP-driven lymph node metastasis in gastric cancer by blocking PP1A-mediated dephosphorylation. Experimental cell research 0 41967793
2025 Profiling the Impact of mGlu7/Elfn1 Protein Interactions on the Pharmacology of mGlu7 Allosteric Modulators. ACS chemical neuroscience 0 40689847