{"gene":"EEIG1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2003,"finding":"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).","method":"cDNA microarray with pharmacological inhibitors (cycloheximide, puromycin, antiestrogens) in MCF-7 cells","journal":"Molecular Endocrinology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, multiple pharmacological conditions confirming primary transcriptional response, but no direct mechanistic reconstitution of the estrogen-receptor–EEIG1 interaction","pmids":["14605097"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Co-immunoprecipitation, inhibitory peptide, loss-of-function/gain-of-function in osteoclast differentiation assays, phosphorylation and NFATc1 induction assays","journal":"Cell Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing the RANK–EEIG1 complex, multiple binding partners identified, functional inhibitory peptide validates specificity, multiple orthogonal readouts (PLCγ2 phosphorylation, NFATc1, osteoclast formation, bone destruction model)","pmids":["23478294"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation (EEIG1–Blimp1 complex), siRNA knockdown, overexpression, EEIG1 knockout mice, LPS-induced bone destruction model, gene expression analysis","journal":"FASEB Journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for complex, genetic epistasis (Blimp1 siRNA/overexpression modulates EEIG1; KO mice), multiple orthogonal methods, in vivo validation","pmids":["32741026"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Genetic loss-of-function in C. elegans, FRET-based tension sensor, molecular epistasis with mec-8/sym double mutants","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with specific morphogenetic phenotype and epistasis analysis, but mechanism of SYM-3 within trafficking not biochemically reconstituted","pmids":["25798732"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Fluorescence colocalization, proteomics (interactome), loss-of-function genetics in C. elegans embryos","journal":"Biology Open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — colocalization and proteomics support complex formation and trafficking role; negative result for aECM deposition explicitly reported, single lab","pmids":["37345480"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-immunoprecipitation/binding interaction assays, live-cell imaging of ER–PM contact sites, loss-of-function analysis showing vacuole accumulation","journal":"Journal of Cell Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction identified with functional consequence (PM dynamics), but abstract-level detail limits mechanistic depth; peer-reviewed single lab","pmids":["40899996"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Genetic knockout (Fam102a KO mice), functional mutation of Rbpjl, nuclear translocation assays, gene expression analysis (Osterix), histological bone analysis","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model with defined skeletal phenotype, nuclear translocation assay placing Fam102a upstream of Rbpjl–Osterix axis, functional Rbpjl mutation validates the pathway, multiple orthogonal methods","pmids":["39747056"],"is_preprint":false},{"year":2018,"finding":"FAM102A was identified as a novel interactor of SKAP2 (SRC kinase adaptor phosphoprotein 2), with the interaction domain/binding motif precisely defined.","method":"Protein interaction mapping (domain-level binding assays, yeast two-hybrid or equivalent), interactome study","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single interaction discovery without reciprocal validation or functional follow-up for FAM102A specifically","pmids":["29568343"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Sequence profile searches, phylogenetic analysis, structure prediction","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 4 / Weak — purely computational/evolutionary prediction, no direct biochemical validation of EEIG1 lipid binding reported","pmids":["20713135"],"is_preprint":false}],"current_model":"EEIG1/FAM102A is an early estrogen-induced adaptor protein that functions as a RANK signaling component in osteoclasts—physically associating with RANK, Gab2, PLCγ2, and Tec/Btk kinases to facilitate PLCγ2 phosphorylation and NFATc1-driven osteoclastogenesis—and also forms a complex with Blimp1 to repress IRF8 expression; in osteoblasts, it controls nuclear translocation of Runx2 and Rbpjl to drive Osterix expression and bone formation; it additionally acts as an adaptor for the BLTP2 lipid transfer protein at ER–plasma membrane contacts to regulate membrane dynamics, and its C. elegans ortholog SYM-3 localizes to trafficking compartments and is required for epidermal resistance to mechanical deformation during embryogenesis."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2003,"claim":"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","pmids":["14605097"],"confidence":"Medium","gaps":["No protein-level function assigned","Direct ER–EEIG1 promoter interaction not reconstituted","Role outside breast cancer cells unexplored"]},{"year":2010,"claim":"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","pmids":["20713135"],"confidence":"Low","gaps":["Purely computational — lipid binding not biochemically validated","No experimental localization","Functional consequence of the C2 domain untested"]},{"year":2013,"claim":"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","pmids":["23478294"],"confidence":"High","gaps":["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"]},{"year":2015,"claim":"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","pmids":["25798732"],"confidence":"Medium","gaps":["Trafficking mechanism not biochemically reconstituted","Molecular cargo of SYM-3 unidentified","Relationship to vertebrate EEIG1 functions not established"]},{"year":2018,"claim":"Identified SKAP2 as a domain-mapped interactor, hinting at additional adaptor partnerships beyond the RANK pathway.","evidence":"Domain-level protein interaction mapping / interactome study","pmids":["29568343"],"confidence":"Low","gaps":["Single interaction without reciprocal validation","No functional consequence demonstrated for FAM102A","Cellular context of the interaction unknown"]},{"year":2020,"claim":"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","pmids":["32741026"],"confidence":"High","gaps":["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"]},{"year":2025,"claim":"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","pmids":["39747056"],"confidence":"High","gaps":["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"]},{"year":2025,"claim":"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","pmids":["40899996"],"confidence":"Medium","gaps":["Abstract-level mechanistic depth","How BLTP2 adaptor function relates to bone signaling roles unknown","Structural basis of BLTP2 recruitment to PM undefined"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,5]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[5]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[5]}],"complexes":["RANK signaling complex (RANK–Gab2–PLCγ2–Tec/Btk)","EEIG1–Blimp1 complex","SYM-3/SYM-4 (WDR44) trafficking complex"],"partners":["RANK","GAB2","PLCG2","BLIMP1","BLTP2","RBPJL","RUNX2","SKAP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5T9C2","full_name":"Early estrogen-induced gene 1 protein","aliases":[],"length_aa":384,"mass_kda":41.8,"function":"Key component of TNFSF11/RANKL- and TNF-induced osteoclastogenesis pathways, thereby mediates bone resorption in pathological bone loss conditions (By similarity). Required for TNFSF11/RANKL-induced osteoclastogenesis via its interaction with TNFRSF11A/RANK, thereby facilitates the downsteam transcription of NFATC1 and activation of PLCG2 (By similarity). Facilitates recruitment of the transcriptional repressor PRDM1/BLIMP1 to the promoter of the anti-osteoclastogenesis gene IRF8, thereby resulting in transcription of osteoclast differentiation factors (By similarity). May play a role in estrogen action (PubMed:14605097)","subcellular_location":"Nucleus; Cytoplasm; Membrane raft","url":"https://www.uniprot.org/uniprotkb/Q5T9C2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EEIG1","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EEIG1","total_profiled":1310},"omim":[{"mim_id":"610891","title":"FAMILY WITH SEQUENCE SIMILARITY 102, MEMBER A; FAM102A","url":"https://www.omim.org/entry/610891"}],"hpa":{"profiled":true,"resolved_as":"FAM102A","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FAM102A"},"hgnc":{"alias_symbol":["Eeig1","bA203J24.7","SYM-3A"],"prev_symbol":["C9orf132","FAM102A"]},"alphafold":{"accession":"Q5T9C2","domains":[{"cath_id":"2.60.40.150","chopping":"7-146","consensus_level":"high","plddt":91.6062,"start":7,"end":146},{"cath_id":"-","chopping":"348-384","consensus_level":"medium","plddt":71.2092,"start":348,"end":384}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T9C2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T9C2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T9C2-F1-predicted_aligned_error_v6.png","plddt_mean":68.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EEIG1","jax_strain_url":"https://www.jax.org/strain/search?query=EEIG1"},"sequence":{"accession":"Q5T9C2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5T9C2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5T9C2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T9C2"}},"corpus_meta":[{"pmid":"20713135","id":"PMC_20713135","title":"Identification of novel families and classification of the C2 domain superfamily elucidate the origin and evolution of membrane targeting activities in eukaryotes.","date":"2010","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/20713135","citation_count":116,"is_preprint":false},{"pmid":"14605097","id":"PMC_14605097","title":"Identification of estrogen-responsive genes by complementary deoxyribonucleic acid microarray and characterization of a novel early estrogen-induced gene: EEIG1.","date":"2003","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/14605097","citation_count":114,"is_preprint":false},{"pmid":"25798732","id":"PMC_25798732","title":"FBN-1, a fibrillin-related protein, is required for resistance of the epidermis to mechanical deformation during C. elegans embryogenesis.","date":"2015","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/25798732","citation_count":58,"is_preprint":false},{"pmid":"23478294","id":"PMC_23478294","title":"Early estrogen-induced gene 1, a novel RANK signaling component, is essential for osteoclastogenesis.","date":"2013","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/23478294","citation_count":33,"is_preprint":false},{"pmid":"25705109","id":"PMC_25705109","title":"Coding and noncoding expression patterns associated with rare obesity-related disorders: Prader-Willi and Alström syndromes.","date":"2015","source":"Advances in genomics and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25705109","citation_count":30,"is_preprint":false},{"pmid":"33196953","id":"PMC_33196953","title":"Genome-Wide Association Study Identifies Genomic Loci of Sex Determination and Gonadosomatic Index Traits in Large Yellow Croaker (Larimichthys crocea).","date":"2020","source":"Marine biotechnology (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/33196953","citation_count":25,"is_preprint":false},{"pmid":"32682838","id":"PMC_32682838","title":"Evaluation of Primary Angle-Closure Glaucoma Susceptibility Loci for Estimating Angle Closure Disease Severity.","date":"2020","source":"Ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/32682838","citation_count":18,"is_preprint":false},{"pmid":"29310965","id":"PMC_29310965","title":"Evaluation of Primary Angle-Closure Glaucoma Susceptibility Loci in Patients with Early Stages of Angle-Closure Disease.","date":"2018","source":"Ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/29310965","citation_count":17,"is_preprint":false},{"pmid":"31377279","id":"PMC_31377279","title":"Integration of Genetic and Biometric Risk Factors for Detection of Primary Angle Closure Glaucoma.","date":"2019","source":"American journal of 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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).\",\n      \"method\": \"cDNA microarray with pharmacological inhibitors (cycloheximide, puromycin, antiestrogens) in MCF-7 cells\",\n      \"journal\": \"Molecular Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, multiple pharmacological conditions confirming primary transcriptional response, but no direct mechanistic reconstitution of the estrogen-receptor–EEIG1 interaction\",\n      \"pmids\": [\"14605097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, inhibitory peptide, loss-of-function/gain-of-function in osteoclast differentiation assays, phosphorylation and NFATc1 induction assays\",\n      \"journal\": \"Cell Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing the RANK–EEIG1 complex, multiple binding partners identified, functional inhibitory peptide validates specificity, multiple orthogonal readouts (PLCγ2 phosphorylation, NFATc1, osteoclast formation, bone destruction model)\",\n      \"pmids\": [\"23478294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (EEIG1–Blimp1 complex), siRNA knockdown, overexpression, EEIG1 knockout mice, LPS-induced bone destruction model, gene expression analysis\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for complex, genetic epistasis (Blimp1 siRNA/overexpression modulates EEIG1; KO mice), multiple orthogonal methods, in vivo validation\",\n      \"pmids\": [\"32741026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic loss-of-function in C. elegans, FRET-based tension sensor, molecular epistasis with mec-8/sym double mutants\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with specific morphogenetic phenotype and epistasis analysis, but mechanism of SYM-3 within trafficking not biochemically reconstituted\",\n      \"pmids\": [\"25798732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Fluorescence colocalization, proteomics (interactome), loss-of-function genetics in C. elegans embryos\",\n      \"journal\": \"Biology Open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — colocalization and proteomics support complex formation and trafficking role; negative result for aECM deposition explicitly reported, single lab\",\n      \"pmids\": [\"37345480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation/binding interaction assays, live-cell imaging of ER–PM contact sites, loss-of-function analysis showing vacuole accumulation\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction identified with functional consequence (PM dynamics), but abstract-level detail limits mechanistic depth; peer-reviewed single lab\",\n      \"pmids\": [\"40899996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic knockout (Fam102a KO mice), functional mutation of Rbpjl, nuclear translocation assays, gene expression analysis (Osterix), histological bone analysis\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model with defined skeletal phenotype, nuclear translocation assay placing Fam102a upstream of Rbpjl–Osterix axis, functional Rbpjl mutation validates the pathway, multiple orthogonal methods\",\n      \"pmids\": [\"39747056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FAM102A was identified as a novel interactor of SKAP2 (SRC kinase adaptor phosphoprotein 2), with the interaction domain/binding motif precisely defined.\",\n      \"method\": \"Protein interaction mapping (domain-level binding assays, yeast two-hybrid or equivalent), interactome study\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single interaction discovery without reciprocal validation or functional follow-up for FAM102A specifically\",\n      \"pmids\": [\"29568343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Sequence profile searches, phylogenetic analysis, structure prediction\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — purely computational/evolutionary prediction, no direct biochemical validation of EEIG1 lipid binding reported\",\n      \"pmids\": [\"20713135\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EEIG1/FAM102A is an early estrogen-induced adaptor protein that functions as a RANK signaling component in osteoclasts—physically associating with RANK, Gab2, PLCγ2, and Tec/Btk kinases to facilitate PLCγ2 phosphorylation and NFATc1-driven osteoclastogenesis—and also forms a complex with Blimp1 to repress IRF8 expression; in osteoblasts, it controls nuclear translocation of Runx2 and Rbpjl to drive Osterix expression and bone formation; it additionally acts as an adaptor for the BLTP2 lipid transfer protein at ER–plasma membrane contacts to regulate membrane dynamics, and its C. elegans ortholog SYM-3 localizes to trafficking compartments and is required for epidermal resistance to mechanical deformation during embryogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #1]. In osteoclasts, EEIG1 is induced by RANKL and physically assembles with RANK, recruiting Gab2, PLC\\u03b32, and Tec/Btk kinases to facilitate PLC\\u03b32 phosphorylation and downstream NFATc1 induction, thereby promoting osteoclastogenesis; a peptide disrupting the RANK\\u2013EEIG1 interaction blocks RANKL-induced bone destruction [#1]. EEIG1 also forms a complex with Blimp1 and acts downstream of it to repress the anti-osteoclastogenic transcription factor IRF8, reinforcing NFATc1-driven differentiation [#2]. 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 [#6]. Beyond bone, EEIG1 serves as an adaptor for the bridge-like lipid transfer protein BLTP2 at ER\\u2013plasma membrane contact sites, contributing to BLTP2 membrane association and plasma membrane dynamics [#5]. 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 [#3, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established EEIG1 as a primary estrogen-responsive gene, defining the hormonal context for its expression before any function was known.\",\n      \"evidence\": \"cDNA microarray with cycloheximide/puromycin and antiestrogen treatments in MCF-7 cells\",\n      \"pmids\": [\"14605097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No protein-level function assigned\", \"Direct ER\\u2013EEIG1 promoter interaction not reconstituted\", \"Role outside breast cancer cells unexplored\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"Sequence profile searches, phylogenetic analysis, and structure prediction\",\n      \"pmids\": [\"20713135\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Purely computational \\u2014 lipid binding not biochemically validated\", \"No experimental localization\", \"Functional consequence of the C2 domain untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined EEIG1's first signaling role: a RANK-proximal adaptor coupling receptor engagement to PLC\\u03b32 phosphorylation and NFATc1 induction in osteoclasts.\",\n      \"evidence\": \"Reciprocal Co-IP, RANK\\u2013EEIG1 blocking peptide, loss/gain-of-function osteoclast differentiation and in vivo bone destruction assays\",\n      \"pmids\": [\"23478294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order/stoichiometry of the RANK\\u2013Gab2\\u2013PLC\\u03b32\\u2013Tec/Btk assembly not resolved\", \"Whether EEIG1 directly binds each partner or scaffolds indirectly unclear\", \"Structural basis of RANK\\u2013EEIG1 contact undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked the FAM102A ortholog SYM-3 to protein trafficking and tissue mechanics, suggesting a conserved trafficking function independent of vertebrate bone signaling.\",\n      \"evidence\": \"C. elegans loss-of-function, FRET tension sensor, and epistasis with mec-8/sym double mutants\",\n      \"pmids\": [\"25798732\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trafficking mechanism not biochemically reconstituted\", \"Molecular cargo of SYM-3 unidentified\", \"Relationship to vertebrate EEIG1 functions not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified SKAP2 as a domain-mapped interactor, hinting at additional adaptor partnerships beyond the RANK pathway.\",\n      \"evidence\": \"Domain-level protein interaction mapping / interactome study\",\n      \"pmids\": [\"29568343\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single interaction without reciprocal validation\", \"No functional consequence demonstrated for FAM102A\", \"Cellular context of the interaction unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended the osteoclast role by placing EEIG1 in a Blimp1 complex that represses IRF8, providing a transcriptional arm to its pro-osteoclastogenic function.\",\n      \"evidence\": \"Reciprocal Co-IP, Blimp1 siRNA/overexpression epistasis, EEIG1 KO mice, LPS-induced bone destruction model\",\n      \"pmids\": [\"32741026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism of IRF8 repression by the EEIG1\\u2013Blimp1 complex unresolved\", \"How a membrane adaptor contributes to nuclear transcriptional repression unclear\", \"Whether EEIG1 binds DNA or chromatin not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed an opposing role in osteoblasts \\u2014 controlling Runx2/Rbpjl nuclear translocation to drive Osterix and bone formation \\u2014 showing EEIG1 acts on both arms of bone remodeling.\",\n      \"evidence\": \"Fam102a KO mice, functional Rbpjl mutation, nuclear translocation assays, Osterix expression and bone histology\",\n      \"pmids\": [\"39747056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected EEIG1 to membrane lipid transport as a BLTP2 adaptor at ER\\u2013PM contacts, grounding the long-predicted membrane/trafficking activity in a defined molecular partnership.\",\n      \"evidence\": \"Binding assays, live-cell imaging of ER\\u2013PM contact sites, loss-of-function showing vacuole accumulation\",\n      \"pmids\": [\"40899996\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Abstract-level mechanistic depth\", \"How BLTP2 adaptor function relates to bone signaling roles unknown\", \"Structural basis of BLTP2 recruitment to PM undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single adaptor reconciles membrane/lipid-transfer activity at ER\\u2013PM contacts with nuclear-translocation control of transcription factors in opposing bone lineages remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 5]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"RANK signaling complex (RANK\\u2013Gab2\\u2013PLC\\u03b32\\u2013Tec/Btk)\",\n      \"EEIG1\\u2013Blimp1 complex\",\n      \"SYM-3/SYM-4 (WDR44) trafficking complex\"\n    ],\n    \"partners\": [\n      \"RANK\",\n      \"Gab2\",\n      \"PLCG2\",\n      \"Blimp1\",\n      \"BLTP2\",\n      \"Rbpjl\",\n      \"Runx2\",\n      \"SKAP2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}