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Showing EEIG1 — FAM102A is a alias.

EEIG1

Early estrogen-induced gene 1 protein · UniProt Q5T9C2

Length
384 aa
Mass
41.8 kDa
Annotated
2026-06-09
23 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EEIG1 (FAM102A) is an estrogen-inducible adaptor protein that functions as a signaling and trafficking scaffold, with its best-characterized roles in bone cell differentiation (PMID:14605097, PMID:23478294). In osteoclasts, EEIG1 is induced by RANKL and physically assembles with RANK, recruiting Gab2, PLCγ2, and Tec/Btk kinases to facilitate PLCγ2 phosphorylation and downstream NFATc1 induction, thereby promoting osteoclastogenesis; a peptide disrupting the RANK–EEIG1 interaction blocks RANKL-induced bone destruction (PMID:23478294). EEIG1 also forms a complex with Blimp1 and acts downstream of it to repress the anti-osteoclastogenic transcription factor IRF8, reinforcing NFATc1-driven differentiation (PMID:32741026). In osteoblasts, EEIG1 instead drives bone formation by controlling the nuclear translocation of Runx2 and Rbpjl to enhance Osterix expression, and its loss produces osteopenia (PMID:39747056). Beyond bone, EEIG1 serves as an adaptor for the bridge-like lipid transfer protein BLTP2 at ER–plasma membrane contact sites, contributing to BLTP2 membrane association and plasma membrane dynamics (PMID:40899996). Its C. elegans ortholog SYM-3 localizes with SYM-4/WDR44 to intracellular trafficking puncta and is required for epidermal resistance to mechanical deformation during embryogenesis (PMID:25798732, PMID:37345480).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2003 Medium

    Established EEIG1 as a primary estrogen-responsive gene, defining the hormonal context for its expression before any function was known.

    Evidence cDNA microarray with cycloheximide/puromycin and antiestrogen treatments in MCF-7 cells

    PMID:14605097

    Open questions at the time
    • No protein-level function assigned
    • Direct ER–EEIG1 promoter interaction not reconstituted
    • Role outside breast cancer cells unexplored
  2. 2010 Low

    Predicted a structural basis for EEIG1 function by placing it in a distinct C2 domain family with putative non-canonical lipid binding, framing a possible membrane/trafficking role.

    Evidence Sequence profile searches, phylogenetic analysis, and structure prediction

    PMID:20713135

    Open questions at the time
    • Purely computational — lipid binding not biochemically validated
    • No experimental localization
    • Functional consequence of the C2 domain untested
  3. 2013 High

    Defined EEIG1's first signaling role: a RANK-proximal adaptor coupling receptor engagement to PLCγ2 phosphorylation and NFATc1 induction in osteoclasts.

    Evidence Reciprocal Co-IP, RANK–EEIG1 blocking peptide, loss/gain-of-function osteoclast differentiation and in vivo bone destruction assays

    PMID:23478294

    Open questions at the time
    • Order/stoichiometry of the RANK–Gab2–PLCγ2–Tec/Btk assembly not resolved
    • Whether EEIG1 directly binds each partner or scaffolds indirectly unclear
    • Structural basis of RANK–EEIG1 contact undefined
  4. 2015 Medium

    Linked the FAM102A ortholog SYM-3 to protein trafficking and tissue mechanics, suggesting a conserved trafficking function independent of vertebrate bone signaling.

    Evidence C. elegans loss-of-function, FRET tension sensor, and epistasis with mec-8/sym double mutants

    PMID:25798732

    Open questions at the time
    • Trafficking mechanism not biochemically reconstituted
    • Molecular cargo of SYM-3 unidentified
    • Relationship to vertebrate EEIG1 functions not established
  5. 2018 Low

    Identified SKAP2 as a domain-mapped interactor, hinting at additional adaptor partnerships beyond the RANK pathway.

    Evidence Domain-level protein interaction mapping / interactome study

    PMID:29568343

    Open questions at the time
    • Single interaction without reciprocal validation
    • No functional consequence demonstrated for FAM102A
    • Cellular context of the interaction unknown
  6. 2020 High

    Extended the osteoclast role by placing EEIG1 in a Blimp1 complex that represses IRF8, providing a transcriptional arm to its pro-osteoclastogenic function.

    Evidence Reciprocal Co-IP, Blimp1 siRNA/overexpression epistasis, EEIG1 KO mice, LPS-induced bone destruction model

    PMID:32741026

    Open questions at the time
    • Direct mechanism of IRF8 repression by the EEIG1–Blimp1 complex unresolved
    • How a membrane adaptor contributes to nuclear transcriptional repression unclear
    • Whether EEIG1 binds DNA or chromatin not tested
  7. 2025 High

    Revealed an opposing role in osteoblasts — controlling Runx2/Rbpjl nuclear translocation to drive Osterix and bone formation — showing EEIG1 acts on both arms of bone remodeling.

    Evidence Fam102a KO mice, functional Rbpjl mutation, nuclear translocation assays, Osterix expression and bone histology

    PMID:39747056

    Open questions at the time
    • Molecular mechanism by which EEIG1 promotes nuclear import undefined
    • Whether EEIG1 directly binds Runx2/Rbpjl or acts through trafficking machinery unknown
    • Reconciliation of osteoblast vs osteoclast roles not addressed
  8. 2025 Medium

    Connected EEIG1 to membrane lipid transport as a BLTP2 adaptor at ER–PM contacts, grounding the long-predicted membrane/trafficking activity in a defined molecular partnership.

    Evidence Binding assays, live-cell imaging of ER–PM contact sites, loss-of-function showing vacuole accumulation

    PMID:40899996

    Open questions at the time
    • Abstract-level mechanistic depth
    • How BLTP2 adaptor function relates to bone signaling roles unknown
    • Structural basis of BLTP2 recruitment to PM undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single adaptor reconciles membrane/lipid-transfer activity at ER–PM contacts with nuclear-translocation control of transcription factors in opposing bone lineages remains unresolved.
  • No unifying biochemical mechanism linking the trafficking and transcriptional roles
  • No structure of EEIG1 or its complexes
  • Whether the C2 domain mediates the diverse partner interactions untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0008289 lipid binding 1
Localization
GO:0031410 cytoplasmic vesicle 2 GO:0005783 endoplasmic reticulum 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1266738 Developmental Biology 1 R-HSA-5653656 Vesicle-mediated transport 1
Partners
BLIMP1BLTP2GAB2PLCG2RANKRBPJLRUNX2SKAP2
Complex memberships
EEIG1–Blimp1 complexRANK signaling complex (RANK–Gab2–PLCγ2–Tec/Btk)SYM-3/SYM-4 (WDR44) trafficking complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 EEIG1 is an early estrogen-induced gene whose transcription is induced by 17β-estradiol within 2 h of treatment in ER-positive MCF-7 cells; induction is not blocked by protein synthesis inhibitors (cycloheximide, puromycin), indicating a primary transcriptional response, but is repressed by antiestrogens (4-OH-tamoxifen, ICI 182,780). cDNA microarray with pharmacological inhibitors (cycloheximide, puromycin, antiestrogens) in MCF-7 cells Molecular Endocrinology Medium 14605097
2013 EEIG1 is induced by RANKL and physically interacts with RANK; upon RANKL stimulation EEIG1 further associates with Gab2, PLCγ2, and Tec/Btk kinases. EEIG1 positively regulates RANKL-induced osteoclast formation by facilitating PLCγ2 phosphorylation and NFATc1 induction. A peptide blocking RANK–EEIG1 interaction inhibits RANKL-induced bone destruction. Co-immunoprecipitation, inhibitory peptide, loss-of-function/gain-of-function in osteoclast differentiation assays, phosphorylation and NFATc1 induction assays Cell Research High 23478294
2020 EEIG1 forms a complex with Blimp1 and negatively regulates the expression of IRF8, an anti-osteoclastogenic transcription factor. EEIG1-deficient macrophages show elevated IRF8 and reduced NFATc1, resulting in decreased RANKL- and TNFα-mediated osteoclastogenesis. Blimp1 siRNA knockdown reduces EEIG1 levels, while Blimp1 overexpression potentiates EEIG1 levels, placing EEIG1 downstream of Blimp1 in osteoclast differentiation. Co-immunoprecipitation (EEIG1–Blimp1 complex), siRNA knockdown, overexpression, EEIG1 knockout mice, LPS-induced bone destruction model, gene expression analysis FASEB Journal High 32741026
2015 SYM-3/FAM102A (C. elegans ortholog of EEIG1/FAM102A) is required for resistance of the C. elegans epidermis to mechanical deformation during embryogenesis; it functions alongside SYM-4/WDR44 as linked proteins involved in protein trafficking, contributing to a network involving MEC-8/RBPMS-dependent fbn-1 mRNA processing. Genetic loss-of-function in C. elegans, FRET-based tension sensor, molecular epistasis with mec-8/sym double mutants eLife Medium 25798732
2023 SYM-3/FAM102A and SYM-4/WDR44 (C. elegans orthologs) colocalize to intracellular and membrane-associated puncta and likely function in a complex involved in intracellular trafficking, as supported by proteomics data. However, no evidence was found that SYM-3 or SYM-4 critically regulate apical deposition of aECM components NOAH-1 or FBN-1. Fluorescence colocalization, proteomics (interactome), loss-of-function genetics in C. elegans embryos Biology Open Medium 37345480
2025 FAM102A (EEIG1) acts as an adaptor protein that interacts with BLTP2/KIAA0100 (a bridge-like lipid transfer protein) at ER–plasma membrane contacts, contributing to BLTP2 binding to the plasma membrane and regulation of plasma membrane dynamics. Co-immunoprecipitation/binding interaction assays, live-cell imaging of ER–PM contact sites, loss-of-function analysis showing vacuole accumulation Journal of Cell Biology Medium 40899996
2025 Fam102a (EEIG1) promotes osteoblast differentiation by controlling nuclear translocation of Runx2 and Rbpjl. The Fam102a–Rbpjl axis enhances Osterix expression, a transcription factor essential for osteoblast differentiation. Deletion of Fam102a or functional mutation of Rbpjl leads to osteopenia with reduced osteoblastic bone formation. Genetic knockout (Fam102a KO mice), functional mutation of Rbpjl, nuclear translocation assays, gene expression analysis (Osterix), histological bone analysis Nature Communications High 39747056
2018 FAM102A was identified as a novel interactor of SKAP2 (SRC kinase adaptor phosphoprotein 2), with the interaction domain/binding motif precisely defined. Protein interaction mapping (domain-level binding assays, yeast two-hybrid or equivalent), interactome study Oncotarget Low 29568343
2010 Computational and evolutionary analysis placed EEIG1/Sym-3 in a distinct C2 domain family involved in endocytic recycling and organellar positioning, predicting lipid-binding activity through basic residues distinct from calcium-dependent PKC-C2 domains. Sequence profile searches, phylogenetic analysis, structure prediction Gene Low 20713135

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Identification of novel families and classification of the C2 domain superfamily elucidate the origin and evolution of membrane targeting activities in eukaryotes. Gene 116 20713135
2003 Identification of estrogen-responsive genes by complementary deoxyribonucleic acid microarray and characterization of a novel early estrogen-induced gene: EEIG1. Molecular endocrinology (Baltimore, Md.) 114 14605097
2015 FBN-1, a fibrillin-related protein, is required for resistance of the epidermis to mechanical deformation during C. elegans embryogenesis. eLife 58 25798732
2013 Early estrogen-induced gene 1, a novel RANK signaling component, is essential for osteoclastogenesis. Cell research 33 23478294
2015 Coding and noncoding expression patterns associated with rare obesity-related disorders: Prader-Willi and Alström syndromes. Advances in genomics and genetics 30 25705109
2020 Genome-Wide Association Study Identifies Genomic Loci of Sex Determination and Gonadosomatic Index Traits in Large Yellow Croaker (Larimichthys crocea). Marine biotechnology (New York, N.Y.) 25 33196953
2020 Evaluation of Primary Angle-Closure Glaucoma Susceptibility Loci for Estimating Angle Closure Disease Severity. Ophthalmology 18 32682838
2018 Evaluation of Primary Angle-Closure Glaucoma Susceptibility Loci in Patients with Early Stages of Angle-Closure Disease. Ophthalmology 17 29310965
2019 Integration of Genetic and Biometric Risk Factors for Detection of Primary Angle Closure Glaucoma. American journal of ophthalmology 15 31377279
2025 Fam102a translocates Runx2 and Rbpjl to facilitate Osterix expression and bone formation. Nature communications 10 39747056
2023 Effectors of anterior morphogenesis in C. elegans embryos. Biology open 9 37345480
2020 Early estrogen-induced gene 1 facilitates osteoclast formation through the inhibition of interferon regulatory factor 8 expression. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 9 32741026
2018 The SRC-family tyrosine kinase HCK shapes the landscape of SKAP2 interactome. Oncotarget 9 29568343
2019 The use of apocynin inhibits osteoclastogenesis. Cell biology international 8 30761659
2020 Primary Angle Closure Glaucoma-associated Genetic Polymorphisms in Northeast Iran. Journal of ophthalmic & vision research 7 32095208
2025 Multiple interactions recruit BLTP2 to ER-PM contacts to control plasma membrane dynamics. The Journal of cell biology 6 40899996
2024 Perfluorooctanesulfonic acid (PFOS) induced cancer related DNA methylation alterations in human breast cells: A whole genome methylome study. The Science of the total environment 6 39032741
2023 Enantioselective activity and toxicity of chiral acaricide cyflumetofen toward target and non-target organisms. Chemosphere 6 36933840
2020 Evaluation of the association between five genetic variants and primary open-angle glaucoma in a Han Chinese population. Ophthalmic genetics 5 32281515
2022 Exploring biomarkers for ischemic stroke through integrated microarray data analysis. Brain research 2 35691413
2025 Multiple interactions mediate the localization of BLTP2 at ER-PM contacts to control plasma membrane dynamics. bioRxiv : the preprint server for biology 1 39974967
2025 Genetic diversity and dietary adaptations of the Central Plains Han Chinese population in East Asia. Communications biology 1 39987348
2023 Pathways that affect anterior morphogenesis in C. elegans embryos. bioRxiv : the preprint server for biology 0 37163004

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