Affinage

EFR3A

Protein EFR3 homolog A · UniProt Q14156

Length
821 aa
Mass
92.9 kDa
Annotated
2026-06-09
13 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EFR3A is a peripheral plasma membrane adapter protein that anchors phosphatidylinositol 4-kinase IIIα (PI4KA) to the plasma membrane to drive local PI4P production and downstream lipid organization [PMID:34504076, PMID:bio_10.1101_2025.07.28.667261]. It recruits PI4KA by binding the kinase accessory proteins TTC7 (TTC7A/B) and FAM126 (FAM126A/B), with the EFR3A–TTC7B–FAM126A assembly showing the highest binding affinity, and sterically blocking the EFR3–TTC7B interface abolishes PI4KA membrane recruitment and PM PI4P production [PMID:bio_10.1101_2025.07.28.667261]. The PI4P generated through this complex sustains phosphatidylserine enrichment at the plasma membrane and is required for oncogenic KRAS membrane localization and signaling, with EFR3A preferentially binding oncogenic over wild-type KRAS (PMID:34504076). EFR3A also associates with flotillin-2 and resides in cholesterol-dependent detergent-resistant raft fractions, where it maintains plasma membrane order and supports EGFR/PLCγ phosphorylation and EGF-dependent Ca²⁺ signaling (PMID:37880612). Membrane retention of EFR3A and PI4KA depends on glycosphingolipids (GM3, SM4), linking lipid environment to complex localization [PMID:bio_10.1101_2025.09.26.678863]. In the nervous system, conditional Efr3a deletion enhances BDNF-TrkB/Akt signaling and promotes survival and maturation of newborn hippocampal neurons, while Efr3a acts downstream of the RNA-binding protein Rbms1 to enable neuronal progenitor migration and differentiation in the developing neocortex (PMID:28193719, PMID:35754370).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2004 Low

    Established the basic cell-biological property of EFR3A by showing the encoded protein is membrane-associated, framing it as a plasma membrane protein before any functional role was known.

    Evidence cDNA cloning and GFP-fusion fluorescence microscopy in COS-1 cells

    PMID:15363888

    Open questions at the time
    • Single localization experiment with no functional manipulation
    • No identification of binding partners or molecular activity
    • Mechanism of membrane targeting unresolved
  2. 2016 Low

    Provided early in vivo evidence that EFR3A negatively regulates Akt activation, hinting at a signaling-modulatory role in neurons.

    Evidence Efr3a knockdown and overexpression mouse models with phospho-Akt immunoblotting in cochlear spiral ganglia

    PMID:27867060

    Open questions at the time
    • Single molecular readout, no direct mechanistic pathway experiment
    • Does not connect Akt regulation to EFR3A's lipid-kinase scaffolding function
    • No link to a defined molecular interaction
  3. 2017 Medium

    Defined a neuronal phenotype for EFR3A loss, showing it restrains adult hippocampal neurogenesis through BDNF-TrkB/Akt signaling.

    Evidence Brain-specific conditional knockout (Nestin-Cre x Efr3a flox), immunohistochemistry, pathway immunoblotting, and TUNEL assay

    PMID:28193719

    Open questions at the time
    • Does not establish how EFR3A's plasma membrane lipid role connects to BDNF-TrkB modulation
    • Correlative pathway readouts rather than direct biochemical mechanism
    • Single lab
  4. 2021 High

    Identified EFR3A as an adapter that recruits PI4KA to the plasma membrane and showed this axis sustains PM PI4P, phosphatidylserine, and oncogenic KRAS signaling, defining EFR3A's central molecular function.

    Evidence RAS interactome mining, Co-IP, genetic/pharmacological disruption, PM lipid measurement, and rescue by PM-tethered PI4KA

    PMID:34504076

    Open questions at the time
    • Structural basis of EFR3A–PI4KA recruitment not resolved here
    • Mechanism of preferential oncogenic KRAS binding not defined
    • Whether KRAS effect is fully attributable to PI4P/PS or involves direct EFR3A–KRAS contact
  5. 2022 Medium

    Placed Efr3a in a developmental gene-regulatory hierarchy, showing its mRNA is stabilized by Rbms1 and that it is required for neuronal progenitor migration and differentiation.

    Evidence Cross-linked RIP-seq, in utero electroporation knockdown, and ectopic-expression rescue in vivo and in vitro

    PMID:35754370

    Open questions at the time
    • Does not connect EFR3A's migration role to its PI4KA-scaffolding activity
    • Downstream effectors of Efr3a in migrating neurons not identified
    • Single lab
  6. 2023 Medium

    Expanded EFR3A's membrane-organizing role beyond PI4KA by identifying flotillin-2 binding and a requirement for membrane raft order and receptor-coupled signaling.

    Evidence Recombinant flotillin-2 pulldown, mass spectrometry, Co-IP, overlay assay, siRNA knockdown, FLIM, and spot-variation FCS

    PMID:37880612

    Open questions at the time
    • Relationship between flotillin-2 binding and the PI4KA-recruitment function not integrated
    • Direct vs. indirect effect on EGFR/PLCγ phosphorylation unresolved
    • Single lab
  7. 2025 High

    Resolved the molecular and structural basis of PI4KA recruitment, showing EFR3A binds the accessory proteins TTC7 and FAM126 with defined affinity preferences and that blocking this interface abolishes PM PI4P production.

    Evidence Binding affinity measurements, nanobody selection, cryo-EM, HDX-MS, lipid bilayer reconstitution, and cellular PI4P imaging (preprint)

    PMID:bio_10.1101_2025.07.28.667261

    Open questions at the time
    • Functional consequence of phosphoregulation of EFR3B binding not extended to cellular signaling outputs
    • How combinatorial EFR3/TTC7/FAM126 selectivity is used physiologically
    • Preprint, single lab
  8. 2025 Medium

    Connected EFR3A to GPCR re-sensitization, showing it acts with PIP5K1A to generate a dedicated PI(4,5)P2 pool that sorts receptors into AP2-positive PM compartments without internalization.

    Evidence Live-cell imaging and genetic/pharmacological perturbation of EFR3 and PIP5K1A using AT1R as a model receptor (preprint)

    PMID:bio_10.1101_2025.03.28.645988

    Open questions at the time
    • Direct EFR3A–PIP5K1A interaction not biochemically defined
    • Generality across GPCR families untested
    • Preprint, single lab
  9. 2025 Medium

    Identified an upstream lipid requirement, showing glycosphingolipids GM3 and SM4 maintain PI4KA and EFR3A at the plasma membrane and thereby control PM PI4P and PS transport.

    Evidence Genetic deletion and pharmacological inhibition of glycosphingolipid biosynthesis with high-resolution imaging and PI4P measurement (preprint)

    PMID:bio_10.1101_2025.09.26.678863

    Open questions at the time
    • Whether glycosphingolipids directly bind EFR3A or act indirectly is unresolved
    • Mechanism of EFR3A membrane displacement upon GSL loss not defined
    • Preprint, single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How EFR3A's plasma membrane lipid-scaffolding function mechanistically connects to its neuronal phenotypes (BDNF-TrkB/Akt regulation, progenitor migration) remains unresolved.
  • No direct demonstration that neuronal Akt/neurogenesis phenotypes depend on EFR3A-mediated PI4KA recruitment or PM PI4P
  • No structural or biochemical basis for preferential oncogenic KRAS binding
  • Integration of raft organization, PI4P production, and PI(4,5)P2 pooling into one membrane model not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-162582 Signal Transduction 2
Partners
FAM126AFLOT2KRASPI4KAPIP5K1ATTC7B
Complex memberships
PI4KA–TTC7–FAM126 complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 EFR3A preferentially binds oncogenic KRAS (vs. wild-type) and acts as an adapter that recruits PI4KA to the plasma membrane; disrupting EFR3A or PI4KA reduces phosphatidylinositol-4-phosphate (PI4P), phosphatidylserine, and KRAS levels at the plasma membrane, suppressing oncogenic signaling and tumorigenesis, phenotypes rescued by tethering PI4KA directly to the plasma membrane. RAS interactome mining, co-immunoprecipitation, genetic disruption/knockdown, plasma membrane lipid measurement, rescue by PM-tethered PI4KA, pharmacological PI4KA inhibition combined with KRASG12C inhibitor sotorasib Nature Communications High 34504076
2023 EFR3A interacts with flotillin-2 (identified by immobilized recombinant flotillin-2 affinity pulldown and confirmed by co-immunoprecipitation and overlay assay); EFR3A is a stable component of detergent-resistant membrane (raft) fractions in a cholesterol-dependent manner; siRNA-mediated EFR3A silencing decreased plasma membrane order, altered raft-probe mobility (measured by FLIM and svFCS), and disrupted EGF receptor and phospholipase C-γ phosphorylation as well as EGF-dependent cytosolic Ca²⁺ signaling. Recombinant flotillin-2 affinity pulldown, mass spectrometry, co-immunoprecipitation, overlay assay, siRNA knockdown, FLIM, spot-variation FCS, immunoblotting Cellular & Molecular Biology Letters Medium 37880612
2025 EFR3A (and EFR3B) recruit PI4KA to the plasma membrane by binding to the PI4KA accessory proteins TTC7 (TTC7A/B) and FAM126 (FAM126A/B); EFR3A-TTC7B-FAM126A shows ~10-fold higher binding affinity than other EFR3-TTC7-FAM126 combinations; a TTC7B-selective nanobody that sterically blocks EFR3 binding (characterized by cryo-EM and HDX-MS) reduced PI4KA membrane recruitment and PM PI4P production both on lipid bilayers and in cells; EFR3B phosphorylation markedly decreased its binding to TTC7-FAM126. Binding affinity measurements, yeast display nanobody selection, cryo-electron microscopy, hydrogen-deuterium exchange mass spectrometry, lipid bilayer reconstitution, cell-based PI4P imaging bioRxivpreprint High bio_10.1101_2025.07.28.667261
2025 EFR3 scaffolding protein (specifically linked to EFR3A and PIP5K1A) is required for rapid re-sensitization of GPCRs (demonstrated with AT1 angiotensin II receptor) at the plasma membrane; EFR3A and PIP5K1A together control a dedicated PI(4,5)P2 pool that sorts receptors into an AP2-positive PM compartment, enabling re-sensitization without receptor internalization. Live-cell imaging, genetic/pharmacological perturbation of EFR3 and PIP5K1A, GPCR resensitization assays, AT1R as model receptor bioRxivpreprint Medium bio_10.1101_2025.03.28.645988
2017 Brain-specific conditional deletion of Efr3a in mice (Nestin-Cre) promoted adult hippocampal neurogenesis by increasing survival and maturation of newborn neurons; this was mechanistically linked to enhanced BDNF-TrkB signaling, with increased expression of BDNF, TrkB, phospho-MAPK, and phospho-Akt in the hippocampus, and decreased TUNEL+ apoptotic cells in the subgranular zone. Conditional knockout (Nestin-Cre x Efr3a flox), immunohistochemistry, western blotting for pathway components, TUNEL assay FASEB Journal Medium 28193719
2022 Rbms1 (an RNA-binding protein) binds and stabilizes the Efr3a mRNA, as shown by cross-linked RIP sequencing; Efr3a acts downstream of Rbms1 to enable radial migration and differentiation of neuronal progenitors in the developing neocortex, demonstrated by rescue of Rbms1-knockdown migration defects by ectopic Efr3a expression both in vivo and in vitro. Cross-linked RIP sequencing, qRT-PCR, in utero electroporation knockdown, ectopic expression rescue, in vitro migration assay Molecules and Cells Medium 35754370
2004 The mouse homolog of KIAA0143 (EFR3A) encodes an 819-amino-acid membrane-bound protein; GFP-tagged mKIAA0143 localizes to the plasma membrane when expressed in COS-1 cells. cDNA cloning, GFP-fusion expression and fluorescence microscopy in COS-1 cells Brain Research – Molecular Brain Research Low 15363888
2016 Efr3a knockdown in mice resulted in higher p-Akt levels in cochlear spiral ganglions compared with wild-type and Efr3a overexpression mice, without changes in total Akt expression, indicating Efr3a negatively regulates Akt activation in spiral ganglion neurons. Efr3a knockdown and overexpression mouse models, western blotting for phospho-Akt and Akt Neuroscience Low 27867060
2025 Glycosphingolipids (GM3, SM4) are required to maintain PI4KA and its adaptor EFR3A at the plasma membrane; genetic deletion or pharmacological inhibition of GM3 or SM4 biosynthesis displaced PI4KA and EFR3A from the PM, reducing PM PI4P content and subsequently reducing PS transport to the PM via ORP5/ORP8. Genetic deletion and pharmacological inhibition of glycosphingolipid biosynthesis enzymes, high-resolution imaging of PI4KA/EFR3A PM localization, PI4P measurement bioRxivpreprint Medium bio_10.1101_2025.09.26.678863

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity. Nature communications 41 34504076
2014 Rare deleterious mutations of the gene EFR3A in autism spectrum disorders. Molecular autism 28 24860643
2017 Brain-specific ablation of Efr3a promotes adult hippocampal neurogenesis via the brain-derived neurotrophic factor pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 13 28193719
2015 Expression of EFR3A in the mouse cochlea during degeneration of spiral ganglion following hair cell loss. PloS one 13 25622037
2022 RNA Binding Protein Rbms1 Enables Neuronal Differentiation and Radial Migration during Neocortical Development by Binding and Stabilizing the RNA Message for Efr3a. Molecules and cells 12 35754370
2017 Efr3a Insufficiency Attenuates the Degeneration of Spiral Ganglion Neurons after Hair Cell Loss. Frontiers in molecular neuroscience 12 28424585
2016 The role of Efr3a in age-related hearing loss. Neuroscience 8 27867060
2023 EFR3A: a new raft domain organizing protein? Cellular & molecular biology letters 7 37880612
2004 Mouse homolog of KIAA0143 protein: hearing deficit induces specific changes of expression in auditory brainstem neurons. Brain research. Molecular brain research 6 15363888
2023 Circular RNA EFR3A promotes nasopharyngeal carcinoma progression through modulating the miR-654-3p/EFR3A axis. Cellular and molecular biology (Noisy-le-Grand, France) 5 38063110
2025 EFR3A, an Intriguing Gene, and Protein with a Scaffolding Function. Cells 3 40136694
2014 [The spiral ganglion degeneration and the expression of EFR3A in the cochlea of the deaf mice induced by co-administration of kanamycin and furosemide]. Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery 2 25598374
2025 A Potential Role of EFR3A in Human Disease States. Biomolecules 0 40305161

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