{"gene":"FBXO10","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2016,"finding":"FBXO10 functions as an E3 ubiquitin ligase subunit that targets BCL2 for protein degradation in mantle cell lymphoma; loss of FBXO10 expression leads to BCL2 protein accumulation due to impaired ubiquitin-proteasome degradation.","method":"Protein expression analysis in MCL patient tissue microarray and cell lines; RNA-seq with BTK shRNA knockdown; BCL2 protein level assessment after FBXO10 loss","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, correlative and knockdown-based evidence across multiple MCL samples and cell lines, but no direct reconstitution of FBXO10-mediated BCL2 ubiquitination","pmids":["27157620"],"is_preprint":false},{"year":2017,"finding":"FBXO10 directly associates with RAGE (receptor for advanced glycation end products) to mediate its monoubiquitination at K374 and lysosomal degradation; PKCζ phosphorylates RAGE to promote this FBXO10-mediated degradation; FBXO10 depletion stabilizes RAGE and prevents ODN2006-mediated degradation.","method":"Co-immunoprecipitation of FBXO10 and RAGE; FBXO10 knockdown with RAGE protein stability assay; PKCζ overexpression/knockdown; identification of ubiquitination site K374","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, knockdown with defined phenotype (substrate stabilization), identified ubiquitination site; single lab","pmids":["28515150"],"is_preprint":false},{"year":2019,"finding":"BCR stimulation induces rapid and reversible palmitoylation of the SCF-FBXO10 E3 ligase complex, causing FBXO10 relocalization from cytosol to the cell membrane, where it targets HGAL for ubiquitylation and degradation; FBXO10 recognition of HGAL is phosphorylation-independent and requires a single conserved HGAL residue H91; HGAL degradation via FBXO10 decreases BCR-induced calcium influx and phosphorylation of proximal BCR effectors, creating a negative autoregulatory feedback loop.","method":"Palmitoylation assay, subcellular fractionation/localization, ubiquitination assay, site-directed mutagenesis (H91), calcium influx measurements, phosphorylation assays of BCR effectors","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (palmitoylation assay, localization, mutagenesis, functional signaling readouts), single lab with rigorous mechanistic dissection","pmids":["31570756"],"is_preprint":false},{"year":2021,"finding":"FBXO10 promotes ubiquitination and degradation of RAGE in BV2 microglia cells; FBXO10 overexpression reduces RAGE accumulation, inhibits p38 MAPK and NF-κB signaling, and promotes M2 microglial polarization, while FBXO10 loss leads to RAGE stabilization and M1-skewed neuroinflammation.","method":"FBXO10 overexpression and RAGE knockdown in BV2 cells; ubiquitination assay; cytokine ELISA; in vivo CUS mouse model with viral FBXO10 overexpression; immunofluorescence for microglial phenotype","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro ubiquitination and in vivo rescue experiments, multiple readouts; single lab, partially replicates RAGE-FBXO10 axis from prior study","pmids":["34492157"],"is_preprint":false},{"year":2024,"finding":"FBXO10 undergoes geranylgeranyl lipid modification at cysteine 953 (C953), which is required for its trafficking to the outer mitochondrial membrane (OMM); this trafficking is orchestrated by interaction with PDE6δ (prenyl group-binding protein) and HSP90 chaperone; at the OMM, FBXO10 targets PGAM5 for polyubiquitylation and proteasomal degradation; the geranylgeranylation-deficient C953S mutant redistributes away from the OMM, fails to degrade PGAM5, and causes impaired mitochondrial ATP production, decreased membrane potential, increased fragmentation, and impaired myogenic differentiation.","method":"Geranylgeranylation site identification and C953S mutagenesis; subcellular fractionation and live-cell imaging; co-immunoprecipitation with PDE6δ and HSP90; comparative quantitative mass spectrometry (LFQ-MS/MS) of enriched mitochondria for substrate identification; PGAM5 ubiquitination assay; mitochondrial function assays (ATP, membrane potential); iPSC and murine myoblast differentiation assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis combined with multiple orthogonal methods (MS substrate identification, ubiquitination assay, functional mitochondrial readouts, differentiation assays), replicated in peer-reviewed and preprint versions","pmids":["39306844","38659932"],"is_preprint":false},{"year":2021,"finding":"CRISPR/Cas9-engineered Fbxo10 loss-of-function mutations (D54K missense in FBOX domain and frameshift truncation) in mice did not increase BCL2 protein levels in B cells, nor did they increase mature B cell, germinal center B cell, or other BCL2-regulated lymphocyte subset numbers — indicating that FBXO10 does not regulate BCL2 as a sole non-redundant E3 ligase in mouse B lymphocytes.","method":"CRISPR/Cas9 knock-in mice with two distinct Fbxo10 mutations; Western blot for BCL2 protein; flow cytometry for lymphocyte subsets","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rigorous genetic loss-of-function in vivo with two independent alleles; this is a well-controlled NEGATIVE result regarding BCL2 regulation in mice","pmids":["33914737"],"is_preprint":false},{"year":2025,"finding":"FBXO10 directly interacts with ACSL4 and mediates its ubiquitination and proteasomal degradation; FBXO10 silencing stabilizes ACSL4 and potentiates ferroptosis through amplified lipid peroxidation and Fe2+ accumulation in esophageal squamous cell carcinoma cells; this axis operates independently of the GPX4/SLC7A11 pathway.","method":"Co-immunoprecipitation and immunofluorescence colocalization of FBXO10 and ACSL4; FBXO10 silencing with ACSL4 ubiquitination and protein stability assay; ferroptosis markers (lipid peroxidation, Fe2+); in vivo xenograft with FBXO10 knockdown","journal":"Journal of molecular histology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus functional ferroptosis readouts in vitro and in vivo; single lab","pmids":["40616744"],"is_preprint":false},{"year":2025,"finding":"FBXO10 directly interacts with FRMPD1 and mediates its K63-linked polyubiquitination, leading to FRMPD1 stabilization (not degradation); this post-translational stabilization of FRMPD1 promotes hepatocellular carcinoma cell proliferation.","method":"Co-immunoprecipitation of FBXO10 and FRMPD1; K63-linkage ubiquitination assay; FBXO10 silencing and overexpression with FRMPD1 protein level measurement; FRMPD1 rescue experiment","journal":"Current issues in molecular biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP and ubiquitination assay without independent replication; K63-linked stabilization is an unusual finding for a canonical SCF/F-box ligase and lacks structural or reconstitution support","pmids":["40699790"],"is_preprint":false},{"year":2026,"finding":"FBXO10 promotes ubiquitin-dependent degradation of RAS, thereby inactivating the RAS/ERK axis and suppressing Golgi stress and neuronal apoptosis; EZH2 represses FBXO10 expression by promoting H3K27me3 modification at the FBXO10 promoter, thus indirectly activating RAS/ERK-driven Golgi stress.","method":"Co-immunoprecipitation of FBXO10 and RAS; RAS ubiquitination assay; ChIP for H3K27me3 at FBXO10 promoter; FBXO10 knockdown/overexpression in H2O2-treated neuronal cell lines (HT-22, NSC34); Western blot for RAS, ERK, Golgi markers","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, ChIP, and functional rescue experiments; single lab with multiple orthogonal methods","pmids":["41999223"],"is_preprint":false},{"year":2013,"finding":"FBXO10/Fbxo10 transcription is activated via a PKC-dependent pathway: TPA activates PKCµ (an atypical PKC isoform), which signals through c-Fos/AP1 transcription factor binding to AP1-specific DNA elements in the Fbxo10 promoter; TPA induces endogenous FBXO10 mRNA and protein in Jurkat T cells with peak expression at 1.5–2.5 h.","method":"Luciferase reporter assays with Fbxo10 promoter constructs; PKC inhibitors; c-Fos identification as AP1 mediator; endogenous FBXO10 mRNA/protein induction by TPA in Jurkat cells","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter-reporter assays with pharmacological dissection and endogenous mRNA/protein validation; single lab","pmids":["24008983"],"is_preprint":false}],"current_model":"FBXO10 is a substrate-recognition F-box subunit of the SCF (SKP1/CUL1/F-box) E3 ubiquitin ligase complex that targets multiple substrates for ubiquitination and degradation (BCL2, RAGE, HGAL, PGAM5, ACSL4, RAS) or, unusually, K63-linked stabilization (FRMPD1); its subcellular targeting to distinct membrane compartments — including the cell membrane via palmitoylation and the outer mitochondrial membrane via geranylgeranylation at C953 with PDE6δ/HSP90 chaperones — determines substrate specificity and downstream effects on apoptosis, BCR signaling, mitochondrial proteostasis, and ferroptosis."},"narrative":{"mechanistic_narrative":"FBXO10 is a substrate-recognition F-box subunit of the SCF (SKP1/CUL1/F-box) E3 ubiquitin ligase that controls the abundance of diverse substrates and, through compartment-specific targeting, couples ubiquitination to apoptosis, B-cell receptor signaling, mitochondrial proteostasis, and ferroptosis [PMID:27157620, PMID:31570756, PMID:39306844, PMID:38659932]. Its substrate engagement is governed by where the ligase is positioned: BCR stimulation triggers reversible palmitoylation that relocalizes SCF-FBXO10 from cytosol to the plasma membrane, where it ubiquitylates and degrades HGAL through recognition of a single conserved residue (H91), dampening BCR-induced calcium influx in a negative-feedback loop [PMID:31570756]; geranylgeranylation at C953, read out by the prenyl-binding chaperone PDE6δ together with HSP90, traffics FBXO10 to the outer mitochondrial membrane where it degrades PGAM5 to sustain mitochondrial membrane potential, ATP production, and myogenic differentiation [PMID:39306844, PMID:38659932]. Across cell types FBXO10 directs proteasomal or lysosomal turnover of additional substrates including BCL2 in mantle cell lymphoma [PMID:27157620], RAGE following PKCζ phosphorylation [PMID:28515150, PMID:34492157], ACSL4 (constraining ferroptotic lipid peroxidation independently of GPX4/SLC7A11) [PMID:40616744], and RAS (suppressing RAS/ERK-driven Golgi stress and neuronal apoptosis) [PMID:41999223]. FBXO10 transcription is itself induced through a PKC–c-Fos/AP1 axis acting on its promoter and is repressed by EZH2-deposited H3K27me3 [PMID:24008983, PMID:41999223]. A well-controlled CRISPR knock-in mouse study found that FBXO10 loss does not elevate B-cell BCL2 or alter BCL2-regulated lymphocyte subsets, indicating it is not the sole non-redundant BCL2 ligase in vivo [PMID:33914737].","teleology":[{"year":2013,"claim":"Established how FBXO10 expression is controlled, defining an inducible signaling input rather than a constitutive ligase.","evidence":"Promoter-luciferase reporters, PKC inhibitors, and endogenous mRNA/protein induction by TPA in Jurkat T cells","pmids":["24008983"],"confidence":"Medium","gaps":["Does not connect transcriptional induction to a specific substrate or physiological outcome","AP1/c-Fos regulation shown in T-cell line only"]},{"year":2016,"claim":"Defined the first FBXO10 substrate by linking its E3 ligase activity to BCL2 turnover in a disease context.","evidence":"Protein/expression analysis across MCL patient tissue and cell lines with FBXO10 knockdown and BCL2 stability readout","pmids":["27157620"],"confidence":"Medium","gaps":["No reconstituted FBXO10-mediated BCL2 ubiquitination","Correlative/knockdown evidence rather than direct enzymatic assay"]},{"year":2017,"claim":"Showed FBXO10 directs a substrate to a non-proteasomal fate and is gated by upstream phosphorylation, expanding its mechanistic repertoire.","evidence":"Reciprocal Co-IP of FBXO10/RAGE, K374 ubiquitination site mapping, PKCζ manipulation, and RAGE stability assays","pmids":["28515150"],"confidence":"Medium","gaps":["Monoubiquitination versus polyubiquitination determinants not resolved","Single lab; lysosomal routing mechanism not defined"]},{"year":2019,"claim":"Revealed that lipid-modification-driven relocalization, not phosphorylation, dictates FBXO10 substrate access at the membrane and feeds back on BCR signaling.","evidence":"Palmitoylation assay, subcellular fractionation, H91 mutagenesis, ubiquitination assay, and calcium/phospho-effector readouts","pmids":["31570756"],"confidence":"High","gaps":["Palmitoyltransferase responsible for FBXO10 modification not identified","Generality of phosphorylation-independent recognition to other substrates untested"]},{"year":2021,"claim":"Tested the BCL2-ligase model in vivo and found FBXO10 is not the non-redundant BCL2 E3 in mouse B cells, qualifying the lymphoma model.","evidence":"Two independent CRISPR/Cas9 knock-in Fbxo10 alleles with BCL2 Western blot and lymphocyte flow cytometry","pmids":["33914737"],"confidence":"Medium","gaps":["Does not exclude redundant ligases masking a BCL2 phenotype","Species/context differences from human MCL unaddressed"]},{"year":2021,"claim":"Extended the RAGE axis to neuroinflammatory control, linking FBXO10 substrate degradation to microglial polarization in vivo.","evidence":"FBXO10 overexpression/RAGE knockdown in BV2 cells with ubiquitination, cytokine ELISA, and a CUS mouse model","pmids":["34492157"],"confidence":"Medium","gaps":["Direct FBXO10–RAGE binding in microglia not re-demonstrated","p38/NF-κB effects could be indirect"]},{"year":2024,"claim":"Defined a second lipid-modification route—geranylgeranylation with a dedicated chaperone system—that targets FBXO10 to mitochondria for a specific substrate and physiological output.","evidence":"C953S mutagenesis, PDE6δ/HSP90 Co-IP, LFQ-MS substrate identification, PGAM5 ubiquitination, and mitochondrial/differentiation assays","pmids":["39306844","38659932"],"confidence":"High","gaps":["How prenylation versus palmitoylation is selected in a given cell is unknown","Structural basis of PGAM5 recognition undefined"]},{"year":2025,"claim":"Connected FBXO10 to ferroptosis control by degrading ACSL4 through a pathway parallel to canonical GPX4/SLC7A11 axes.","evidence":"Co-IP/colocalization, FBXO10 silencing with ACSL4 ubiquitination/stability, ferroptosis markers, and xenograft","pmids":["40616744"],"confidence":"Medium","gaps":["Ubiquitin linkage type on ACSL4 not specified","Single lab; no reconstitution"]},{"year":2025,"claim":"Reported an atypical activity—K63-linked ubiquitination that stabilizes rather than degrades a substrate—broadening FBXO10's possible output modes.","evidence":"Co-IP of FBXO10/FRMPD1, K63-linkage assay, silencing/overexpression with FRMPD1 levels and rescue in HCC cells","pmids":["40699790"],"confidence":"Low","gaps":["Not independently confirmed and lacks structural/reconstitution support","Stabilizing K63 chains are unusual for an SCF/F-box ligase and need orthogonal validation"]},{"year":2026,"claim":"Linked FBXO10 to RAS turnover and placed it under epigenetic repression, integrating its activity into RAS/ERK-driven Golgi stress.","evidence":"FBXO10/RAS Co-IP, RAS ubiquitination assay, H3K27me3 ChIP at the FBXO10 promoter, and rescue in H2O2-treated neuronal lines","pmids":["41999223"],"confidence":"Medium","gaps":["Which RAS isoform is targeted not resolved","EZH2 repression shown by ChIP/manipulation but direct promoter occupancy mechanism limited"]},{"year":null,"claim":"It remains unknown what unifies FBXO10 substrate selection across compartments and whether a common structural determinant or chaperone code governs its palmitoylation-versus-prenylation choice and degradative-versus-stabilizing outputs.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of FBXO10 with any substrate","No unifying rule for ubiquitin linkage choice","Cross-substrate competition and tissue-specific dominance untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,4,6,8]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[2,4,6]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,4,6,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,6,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,8]}],"complexes":["SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase"],"partners":["BCL2","RAGE","HGAL","PGAM5","PDE6D","HSP90","ACSL4","FRMPD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UK96","full_name":"F-box only protein 10","aliases":[],"length_aa":956,"mass_kda":105.2,"function":"Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Mediates the ubiquitination and degradation of BCL2, an antiapoptotic protein, thereby playing a role in apoptosis by controlling the stability of BCL2. Targets also the receptor for advanced glycation end products RAGE for ubiquitination and subsequent lysosomal degradation (PubMed:28515150). Directly controls HGAL/GCSAM ubiquitination and degradation and thereby decreases BCR signaling (PubMed:31570756)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9UK96/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBXO10","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FBXO10","total_profiled":1310},"omim":[{"mim_id":"614409","title":"SPASTIC PARAPLEGIA 46, AUTOSOMAL RECESSIVE; SPG46","url":"https://www.omim.org/entry/614409"},{"mim_id":"609092","title":"F-BOX ONLY PROTEIN 10; FBXO10","url":"https://www.omim.org/entry/609092"},{"mim_id":"605496","title":"CENTRIOLIN; CNTRL","url":"https://www.omim.org/entry/605496"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":27.4}],"url":"https://www.proteinatlas.org/search/FBXO10"},"hgnc":{"alias_symbol":["FBX10"],"prev_symbol":[]},"alphafold":{"accession":"Q9UK96","domains":[{"cath_id":"-","chopping":"15-89","consensus_level":"medium","plddt":63.0387,"start":15,"end":89},{"cath_id":"-","chopping":"107-211","consensus_level":"medium","plddt":91.193,"start":107,"end":211},{"cath_id":"-","chopping":"231-281_408-559","consensus_level":"medium","plddt":94.1773,"start":231,"end":559},{"cath_id":"2.160.20.10","chopping":"628-680_720-896","consensus_level":"medium","plddt":89.7562,"start":628,"end":896}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UK96","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UK96-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UK96-F1-predicted_aligned_error_v6.png","plddt_mean":75.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBXO10","jax_strain_url":"https://www.jax.org/strain/search?query=FBXO10"},"sequence":{"accession":"Q9UK96","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UK96.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UK96/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UK96"}},"corpus_meta":[{"pmid":"27157620","id":"PMC_27157620","title":"FBXO10 deficiency and BTK activation upregulate BCL2 expression in mantle cell lymphoma.","date":"2016","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/27157620","citation_count":60,"is_preprint":false},{"pmid":"23138933","id":"PMC_23138933","title":"Human MCS5A1 candidate breast cancer susceptibility gene FBXO10 is induced by cellular stress and correlated with lens epithelium-derived growth factor (LEDGF).","date":"2012","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/23138933","citation_count":22,"is_preprint":false},{"pmid":"28515150","id":"PMC_28515150","title":"Receptor for advanced glycation end products is targeted by FBXO10 for ubiquitination and degradation.","date":"2017","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/28515150","citation_count":18,"is_preprint":false},{"pmid":"31570756","id":"PMC_31570756","title":"Recent BCR stimulation induces a negative autoregulatory loop via FBXO10 mediated degradation of HGAL.","date":"2019","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/31570756","citation_count":15,"is_preprint":false},{"pmid":"34492157","id":"PMC_34492157","title":"FBXO10 prevents chronic unpredictable stress-induced behavioral despair and cognitive impairment through promoting RAGE degradation.","date":"2021","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/34492157","citation_count":9,"is_preprint":false},{"pmid":"39306844","id":"PMC_39306844","title":"Geranylgeranylated SCFFBXO10 regulates selective outer mitochondrial membrane proteostasis and function.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39306844","citation_count":8,"is_preprint":false},{"pmid":"33914737","id":"PMC_33914737","title":"Loss-of-function of Fbxo10, encoding a post-translational regulator of BCL2 in lymphomas, has no discernible effect on BCL2 or B lymphocyte accumulation in mice.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/33914737","citation_count":5,"is_preprint":false},{"pmid":"40616744","id":"PMC_40616744","title":"FBXO10 inhibits ferroptosis and promotes the progression of esophageal squamous cell carcinoma by post-translational mediation of ACSL4 degradation.","date":"2025","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/40616744","citation_count":4,"is_preprint":false},{"pmid":"24008983","id":"PMC_24008983","title":"Differential 12-O-Tetradecanoylphorbol-13-acetate-induced activation of rat mammary carcinoma susceptibility Fbxo10 variant promoters via a PKC-AP1 pathway.","date":"2013","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/24008983","citation_count":4,"is_preprint":false},{"pmid":"38659932","id":"PMC_38659932","title":"Geranylgeranylated-SCFFBXO10 Regulates Selective Outer Mitochondrial Membrane Proteostasis and Function.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38659932","citation_count":1,"is_preprint":false},{"pmid":"40699790","id":"PMC_40699790","title":"FBXO10 Drives Hepatocellular Carcinoma Proliferation via K63-Linked Ubiquitination and Stabilization of FRMPD1.","date":"2025","source":"Current issues in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/40699790","citation_count":0,"is_preprint":false},{"pmid":"41999223","id":"PMC_41999223","title":"H3K27me3 Modified FBXO10 Promotes Golgi Stress to Accelerate Traumatic Brain Injury via Activation of the RAS/ERK Axis.","date":"2026","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/41999223","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9096,"output_tokens":3172,"usd":0.037434,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10541,"output_tokens":3696,"usd":0.072553,"stage2_stop_reason":"end_turn"},"total_usd":0.109987,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"FBXO10 functions as an E3 ubiquitin ligase subunit that targets BCL2 for protein degradation in mantle cell lymphoma; loss of FBXO10 expression leads to BCL2 protein accumulation due to impaired ubiquitin-proteasome degradation.\",\n      \"method\": \"Protein expression analysis in MCL patient tissue microarray and cell lines; RNA-seq with BTK shRNA knockdown; BCL2 protein level assessment after FBXO10 loss\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, correlative and knockdown-based evidence across multiple MCL samples and cell lines, but no direct reconstitution of FBXO10-mediated BCL2 ubiquitination\",\n      \"pmids\": [\"27157620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FBXO10 directly associates with RAGE (receptor for advanced glycation end products) to mediate its monoubiquitination at K374 and lysosomal degradation; PKCζ phosphorylates RAGE to promote this FBXO10-mediated degradation; FBXO10 depletion stabilizes RAGE and prevents ODN2006-mediated degradation.\",\n      \"method\": \"Co-immunoprecipitation of FBXO10 and RAGE; FBXO10 knockdown with RAGE protein stability assay; PKCζ overexpression/knockdown; identification of ubiquitination site K374\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, knockdown with defined phenotype (substrate stabilization), identified ubiquitination site; single lab\",\n      \"pmids\": [\"28515150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BCR stimulation induces rapid and reversible palmitoylation of the SCF-FBXO10 E3 ligase complex, causing FBXO10 relocalization from cytosol to the cell membrane, where it targets HGAL for ubiquitylation and degradation; FBXO10 recognition of HGAL is phosphorylation-independent and requires a single conserved HGAL residue H91; HGAL degradation via FBXO10 decreases BCR-induced calcium influx and phosphorylation of proximal BCR effectors, creating a negative autoregulatory feedback loop.\",\n      \"method\": \"Palmitoylation assay, subcellular fractionation/localization, ubiquitination assay, site-directed mutagenesis (H91), calcium influx measurements, phosphorylation assays of BCR effectors\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (palmitoylation assay, localization, mutagenesis, functional signaling readouts), single lab with rigorous mechanistic dissection\",\n      \"pmids\": [\"31570756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBXO10 promotes ubiquitination and degradation of RAGE in BV2 microglia cells; FBXO10 overexpression reduces RAGE accumulation, inhibits p38 MAPK and NF-κB signaling, and promotes M2 microglial polarization, while FBXO10 loss leads to RAGE stabilization and M1-skewed neuroinflammation.\",\n      \"method\": \"FBXO10 overexpression and RAGE knockdown in BV2 cells; ubiquitination assay; cytokine ELISA; in vivo CUS mouse model with viral FBXO10 overexpression; immunofluorescence for microglial phenotype\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro ubiquitination and in vivo rescue experiments, multiple readouts; single lab, partially replicates RAGE-FBXO10 axis from prior study\",\n      \"pmids\": [\"34492157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXO10 undergoes geranylgeranyl lipid modification at cysteine 953 (C953), which is required for its trafficking to the outer mitochondrial membrane (OMM); this trafficking is orchestrated by interaction with PDE6δ (prenyl group-binding protein) and HSP90 chaperone; at the OMM, FBXO10 targets PGAM5 for polyubiquitylation and proteasomal degradation; the geranylgeranylation-deficient C953S mutant redistributes away from the OMM, fails to degrade PGAM5, and causes impaired mitochondrial ATP production, decreased membrane potential, increased fragmentation, and impaired myogenic differentiation.\",\n      \"method\": \"Geranylgeranylation site identification and C953S mutagenesis; subcellular fractionation and live-cell imaging; co-immunoprecipitation with PDE6δ and HSP90; comparative quantitative mass spectrometry (LFQ-MS/MS) of enriched mitochondria for substrate identification; PGAM5 ubiquitination assay; mitochondrial function assays (ATP, membrane potential); iPSC and murine myoblast differentiation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis combined with multiple orthogonal methods (MS substrate identification, ubiquitination assay, functional mitochondrial readouts, differentiation assays), replicated in peer-reviewed and preprint versions\",\n      \"pmids\": [\"39306844\", \"38659932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CRISPR/Cas9-engineered Fbxo10 loss-of-function mutations (D54K missense in FBOX domain and frameshift truncation) in mice did not increase BCL2 protein levels in B cells, nor did they increase mature B cell, germinal center B cell, or other BCL2-regulated lymphocyte subset numbers — indicating that FBXO10 does not regulate BCL2 as a sole non-redundant E3 ligase in mouse B lymphocytes.\",\n      \"method\": \"CRISPR/Cas9 knock-in mice with two distinct Fbxo10 mutations; Western blot for BCL2 protein; flow cytometry for lymphocyte subsets\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rigorous genetic loss-of-function in vivo with two independent alleles; this is a well-controlled NEGATIVE result regarding BCL2 regulation in mice\",\n      \"pmids\": [\"33914737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO10 directly interacts with ACSL4 and mediates its ubiquitination and proteasomal degradation; FBXO10 silencing stabilizes ACSL4 and potentiates ferroptosis through amplified lipid peroxidation and Fe2+ accumulation in esophageal squamous cell carcinoma cells; this axis operates independently of the GPX4/SLC7A11 pathway.\",\n      \"method\": \"Co-immunoprecipitation and immunofluorescence colocalization of FBXO10 and ACSL4; FBXO10 silencing with ACSL4 ubiquitination and protein stability assay; ferroptosis markers (lipid peroxidation, Fe2+); in vivo xenograft with FBXO10 knockdown\",\n      \"journal\": \"Journal of molecular histology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus functional ferroptosis readouts in vitro and in vivo; single lab\",\n      \"pmids\": [\"40616744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO10 directly interacts with FRMPD1 and mediates its K63-linked polyubiquitination, leading to FRMPD1 stabilization (not degradation); this post-translational stabilization of FRMPD1 promotes hepatocellular carcinoma cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation of FBXO10 and FRMPD1; K63-linkage ubiquitination assay; FBXO10 silencing and overexpression with FRMPD1 protein level measurement; FRMPD1 rescue experiment\",\n      \"journal\": \"Current issues in molecular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP and ubiquitination assay without independent replication; K63-linked stabilization is an unusual finding for a canonical SCF/F-box ligase and lacks structural or reconstitution support\",\n      \"pmids\": [\"40699790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FBXO10 promotes ubiquitin-dependent degradation of RAS, thereby inactivating the RAS/ERK axis and suppressing Golgi stress and neuronal apoptosis; EZH2 represses FBXO10 expression by promoting H3K27me3 modification at the FBXO10 promoter, thus indirectly activating RAS/ERK-driven Golgi stress.\",\n      \"method\": \"Co-immunoprecipitation of FBXO10 and RAS; RAS ubiquitination assay; ChIP for H3K27me3 at FBXO10 promoter; FBXO10 knockdown/overexpression in H2O2-treated neuronal cell lines (HT-22, NSC34); Western blot for RAS, ERK, Golgi markers\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, ChIP, and functional rescue experiments; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41999223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FBXO10/Fbxo10 transcription is activated via a PKC-dependent pathway: TPA activates PKCµ (an atypical PKC isoform), which signals through c-Fos/AP1 transcription factor binding to AP1-specific DNA elements in the Fbxo10 promoter; TPA induces endogenous FBXO10 mRNA and protein in Jurkat T cells with peak expression at 1.5–2.5 h.\",\n      \"method\": \"Luciferase reporter assays with Fbxo10 promoter constructs; PKC inhibitors; c-Fos identification as AP1 mediator; endogenous FBXO10 mRNA/protein induction by TPA in Jurkat cells\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter-reporter assays with pharmacological dissection and endogenous mRNA/protein validation; single lab\",\n      \"pmids\": [\"24008983\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXO10 is a substrate-recognition F-box subunit of the SCF (SKP1/CUL1/F-box) E3 ubiquitin ligase complex that targets multiple substrates for ubiquitination and degradation (BCL2, RAGE, HGAL, PGAM5, ACSL4, RAS) or, unusually, K63-linked stabilization (FRMPD1); its subcellular targeting to distinct membrane compartments — including the cell membrane via palmitoylation and the outer mitochondrial membrane via geranylgeranylation at C953 with PDE6δ/HSP90 chaperones — determines substrate specificity and downstream effects on apoptosis, BCR signaling, mitochondrial proteostasis, and ferroptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FBXO10 is a substrate-recognition F-box subunit of the SCF (SKP1/CUL1/F-box) E3 ubiquitin ligase that controls the abundance of diverse substrates and, through compartment-specific targeting, couples ubiquitination to apoptosis, B-cell receptor signaling, mitochondrial proteostasis, and ferroptosis [#0, #2, #4]. Its substrate engagement is governed by where the ligase is positioned: BCR stimulation triggers reversible palmitoylation that relocalizes SCF-FBXO10 from cytosol to the plasma membrane, where it ubiquitylates and degrades HGAL through recognition of a single conserved residue (H91), dampening BCR-induced calcium influx in a negative-feedback loop [#2]; geranylgeranylation at C953, read out by the prenyl-binding chaperone PDE6δ together with HSP90, traffics FBXO10 to the outer mitochondrial membrane where it degrades PGAM5 to sustain mitochondrial membrane potential, ATP production, and myogenic differentiation [#4]. Across cell types FBXO10 directs proteasomal or lysosomal turnover of additional substrates including BCL2 in mantle cell lymphoma [#0], RAGE following PKCζ phosphorylation [#1, #3], ACSL4 (constraining ferroptotic lipid peroxidation independently of GPX4/SLC7A11) [#6], and RAS (suppressing RAS/ERK-driven Golgi stress and neuronal apoptosis) [#8]. FBXO10 transcription is itself induced through a PKC–c-Fos/AP1 axis acting on its promoter and is repressed by EZH2-deposited H3K27me3 [#9, #8]. A well-controlled CRISPR knock-in mouse study found that FBXO10 loss does not elevate B-cell BCL2 or alter BCL2-regulated lymphocyte subsets, indicating it is not the sole non-redundant BCL2 ligase in vivo [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established how FBXO10 expression is controlled, defining an inducible signaling input rather than a constitutive ligase.\",\n      \"evidence\": \"Promoter-luciferase reporters, PKC inhibitors, and endogenous mRNA/protein induction by TPA in Jurkat T cells\",\n      \"pmids\": [\"24008983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not connect transcriptional induction to a specific substrate or physiological outcome\", \"AP1/c-Fos regulation shown in T-cell line only\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the first FBXO10 substrate by linking its E3 ligase activity to BCL2 turnover in a disease context.\",\n      \"evidence\": \"Protein/expression analysis across MCL patient tissue and cell lines with FBXO10 knockdown and BCL2 stability readout\",\n      \"pmids\": [\"27157620\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstituted FBXO10-mediated BCL2 ubiquitination\", \"Correlative/knockdown evidence rather than direct enzymatic assay\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed FBXO10 directs a substrate to a non-proteasomal fate and is gated by upstream phosphorylation, expanding its mechanistic repertoire.\",\n      \"evidence\": \"Reciprocal Co-IP of FBXO10/RAGE, K374 ubiquitination site mapping, PKCζ manipulation, and RAGE stability assays\",\n      \"pmids\": [\"28515150\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Monoubiquitination versus polyubiquitination determinants not resolved\", \"Single lab; lysosomal routing mechanism not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed that lipid-modification-driven relocalization, not phosphorylation, dictates FBXO10 substrate access at the membrane and feeds back on BCR signaling.\",\n      \"evidence\": \"Palmitoylation assay, subcellular fractionation, H91 mutagenesis, ubiquitination assay, and calcium/phospho-effector readouts\",\n      \"pmids\": [\"31570756\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Palmitoyltransferase responsible for FBXO10 modification not identified\", \"Generality of phosphorylation-independent recognition to other substrates untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tested the BCL2-ligase model in vivo and found FBXO10 is not the non-redundant BCL2 E3 in mouse B cells, qualifying the lymphoma model.\",\n      \"evidence\": \"Two independent CRISPR/Cas9 knock-in Fbxo10 alleles with BCL2 Western blot and lymphocyte flow cytometry\",\n      \"pmids\": [\"33914737\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not exclude redundant ligases masking a BCL2 phenotype\", \"Species/context differences from human MCL unaddressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the RAGE axis to neuroinflammatory control, linking FBXO10 substrate degradation to microglial polarization in vivo.\",\n      \"evidence\": \"FBXO10 overexpression/RAGE knockdown in BV2 cells with ubiquitination, cytokine ELISA, and a CUS mouse model\",\n      \"pmids\": [\"34492157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct FBXO10–RAGE binding in microglia not re-demonstrated\", \"p38/NF-κB effects could be indirect\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a second lipid-modification route—geranylgeranylation with a dedicated chaperone system—that targets FBXO10 to mitochondria for a specific substrate and physiological output.\",\n      \"evidence\": \"C953S mutagenesis, PDE6δ/HSP90 Co-IP, LFQ-MS substrate identification, PGAM5 ubiquitination, and mitochondrial/differentiation assays\",\n      \"pmids\": [\"39306844\", \"38659932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How prenylation versus palmitoylation is selected in a given cell is unknown\", \"Structural basis of PGAM5 recognition undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected FBXO10 to ferroptosis control by degrading ACSL4 through a pathway parallel to canonical GPX4/SLC7A11 axes.\",\n      \"evidence\": \"Co-IP/colocalization, FBXO10 silencing with ACSL4 ubiquitination/stability, ferroptosis markers, and xenograft\",\n      \"pmids\": [\"40616744\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage type on ACSL4 not specified\", \"Single lab; no reconstitution\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reported an atypical activity—K63-linked ubiquitination that stabilizes rather than degrades a substrate—broadening FBXO10's possible output modes.\",\n      \"evidence\": \"Co-IP of FBXO10/FRMPD1, K63-linkage assay, silencing/overexpression with FRMPD1 levels and rescue in HCC cells\",\n      \"pmids\": [\"40699790\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Not independently confirmed and lacks structural/reconstitution support\", \"Stabilizing K63 chains are unusual for an SCF/F-box ligase and need orthogonal validation\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked FBXO10 to RAS turnover and placed it under epigenetic repression, integrating its activity into RAS/ERK-driven Golgi stress.\",\n      \"evidence\": \"FBXO10/RAS Co-IP, RAS ubiquitination assay, H3K27me3 ChIP at the FBXO10 promoter, and rescue in H2O2-treated neuronal lines\",\n      \"pmids\": [\"41999223\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which RAS isoform is targeted not resolved\", \"EZH2 repression shown by ChIP/manipulation but direct promoter occupancy mechanism limited\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown what unifies FBXO10 substrate selection across compartments and whether a common structural determinant or chaperone code governs its palmitoylation-versus-prenylation choice and degradative-versus-stabilizing outputs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of FBXO10 with any substrate\", \"No unifying rule for ubiquitin linkage choice\", \"Cross-substrate competition and tissue-specific dominance untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 4, 6, 8]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [2, 4, 6]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 4, 6, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 6, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 8]}\n    ],\n    \"complexes\": [\"SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase\"],\n    \"partners\": [\"BCL2\", \"RAGE\", \"HGAL\", \"PGAM5\", \"PDE6D\", \"HSP90\", \"ACSL4\", \"FRMPD1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}