id: Q9UH90 gene_symbol: FBXO40 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXO40 (F-box only protein 40; "muscle disease-related protein") is a 709-residue FBXO-class F-box protein that serves as the substrate-recognition subunit of a cullin-RING SCF (SKP1-CUL1-RBX1-F-box) E3 ubiquitin ligase complex. Like other F-box proteins, it docks onto the SCF scaffold through its C-terminal F-box domain (interacting with SKP1/CUL1) while presenting an N-terminal substrate-binding module; FBXO40 carries a TRAF-type zinc finger and is not itself the catalytic RING subunit (catalysis is provided by RBX1, which recruits the ubiquitin-charged E2). FBXO40 expression is restricted essentially to heart and skeletal muscle, appears postnatally during muscle development, and is upregulated in denervation-induced (but not starvation-induced) muscle atrophy and reduced in Limb-girdle muscular dystrophy muscle. Its best-supported direct substrate is insulin receptor substrate 1 (IRS1): the SCF(FBXO40) complex (with co-precipitating SKP1, CUL1 and RBX1) ubiquitinates recombinant IRS1 in vitro in a manner enhanced by IGF1R-dependent IRS1 tyrosine phosphorylation, targeting IRS1 for proteasomal degradation and thereby attenuating the IGF-1/insulin -> IRS1 -> PI3K/AKT anabolic signaling axis in skeletal muscle. Loss of Fbxo40 increases IRS1 protein abundance (without changing Irs1 mRNA), prolongs IRS1 half-life, and produces myotube and whole-muscle hypertrophy in mice (and increased muscle mass in knockout pigs), a phenotype that is IRS1-dependent. FBXO40 transcription is induced by inflammatory STAT3 signaling (e.g. downstream of IL-6), linking it to catabolic insulin-resistance states. The protein localizes to the cytoplasm/cytosol. existing_annotations: - term: id: GO:0005737 label: cytoplasm evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Phylogenetic (PAN-GO/IBA) assignment of cytoplasmic localization, consistent with FBXO40 acting as the substrate-recognition subunit of a cytoplasmic SCF complex. action: ACCEPT reason: Cytoplasmic localization is corroborated by direct overexpression in C2C12 myoblasts and by the UniProt subcellular location; it is the compartment in which an SCF substrate receptor would act. supported_by: - reference_id: PMID:17928169 supporting_text: "By overexpressing in C2C12 cells, FBXO40 localized in cytoplasm." - reference_id: file:human/FBXO40/FBXO40-uniprot.txt supporting_text: "SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}." - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Combined automated electronic assignment of cytoplasmic localization, redundant with the IBA and ISS cytoplasm annotations. action: ACCEPT reason: Correct compartment; redundant with experimentally corroborated cytoplasmic localization. supported_by: - reference_id: file:human/FBXO40/FBXO40-uniprot.txt supporting_text: "SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}." - term: id: GO:0008270 label: zinc ion binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: InterPro-based electronic assignment of zinc ion binding from the TRAF-type zinc finger (IPR001293) present in FBXO40. A structural feature supporting substrate/protein interaction rather than a core function. action: KEEP_AS_NON_CORE reason: FBXO40 contains a TRAF-type zinc finger (residues 53-112) that plausibly coordinates zinc, but this is a structural domain attribute subsidiary to its role as an SCF substrate adaptor, not a standalone core molecular function. supported_by: - reference_id: file:human/FBXO40/FBXO40-uniprot.txt supporting_text: "ZN_FING 53..112" - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: InterPro-based electronic assignment of ubiquitin protein ligase activity. F-box proteins are substrate-recognition adaptors, not the catalytic core of the SCF ligase; the catalytic RING activity resides in RBX1. action: MODIFY reason: As an F-box substrate receptor, FBXO40 does not itself catalyze ubiquitin transfer (that is the RBX1 RING subunit); its molecular function is better captured as a ubiquitin-like ligase-substrate adaptor. This IEA term is propagated from the InterPro Fbxo30/Fbxo40 signature and over-attributes catalytic ligase activity to the adaptor. proposed_replacement_terms: - id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: file:human/FBXO40/FBXO40-uniprot.txt supporting_text: "Probable substrate-recognition component of the SCF (SKP1-" - term: id: GO:0042692 label: muscle cell differentiation evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Ensembl-Compara ortholog-based electronic transfer of muscle cell differentiation, mirroring the ISS annotation derived from the mouse ortholog and the muscle-restricted expression of FBXO40. action: KEEP_AS_NON_CORE reason: Consistent with FBXO40's muscle-restricted, postnatal-myogenesis-associated expression, but the involvement rests on expression correlation and family/ortholog propagation rather than direct experimental demonstration in human; keep as a non-core process. supported_by: - reference_id: PMID:17928169 supporting_text: "All our data suggest that FBXO40 may function as a regulator involved in the postnatal myogenesis." - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:34445249 qualifier: part_of review: summary: ComplexPortal NAS assignment (CPX-7981, SCF FBXO40 variant) that FBXO40 is part of an SCF E3 ubiquitin ligase complex, consistent with its F-box domain and reported direct interactions with SKP1 and CUL1. action: ACCEPT reason: Core localization/complex membership for an F-box protein; supported by the F-box domain, the UniProt SUBUNIT statement, and the general SCF biology described in the cited review. supported_by: - reference_id: file:human/FBXO40/FBXO40-uniprot.txt supporting_text: "SUBUNIT: Directly interacts with SKP1 and CUL1. {ECO:0000250}." - reference_id: PMID:34445249 supporting_text: "These SCF complexes are distinguishable by variable F-box proteins, which determine substrate specificity." - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:34445249 qualifier: involved_in review: summary: ComplexPortal NAS assignment that FBXO40, as an SCF F-box receptor, participates in SCF-dependent proteasomal protein degradation. This is the expected biological process for an SCF substrate adaptor. action: ACCEPT reason: Consistent with the canonical role of F-box proteins in directing substrates to SCF-dependent proteasomal degradation, and now corroborated by FBXO40-specific evidence that SCF-FBXO40 ubiquitinates IRS1 to drive its proteasomal degradation (Shi et al. 2011, via the Falcon report). supported_by: - reference_id: PMID:34445249 supporting_text: "group of 69 SCF E3 ubiquitin ligase complexes that primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation" - reference_id: file:human/FBXO40/FBXO40-uniprot.txt supporting_text: "Ubl conjugation pathway" - reference_id: file:human/FBXO40/FBXO40-deep-research-falcon.md supporting_text: 'FBXO40 acts as the **substrate-recognition subunit** of an SCF E3 ligase complex (**SCF-FBXO40**) that **ubiquitinates IRS1**, promoting its **ubiquitin–proteasome-dependent degradation** in skeletal muscle, thereby **limiting IGF-1/insulin signaling** through the IRS1–PI3K–AKT axis' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952618 qualifier: located_in review: summary: Reactome TAS cytosol localization derived from generic CRL1/neddylation pathway reactions in which the SCF complex participates. Consistent with cytoplasmic localization but pathway-context, not FBXO40-specific evidence. action: KEEP_AS_NON_CORE reason: Cytosol is a correct, more specific child of the cytoplasm localization, but this and the other identical Reactome cytosol annotations are propagated from generic cullin-RING-ligase pathway reactions rather than direct FBXO40 evidence. supported_by: - reference_id: file:human/FBXO40/FBXO40-uniprot.txt supporting_text: "SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}." - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952620 qualifier: located_in review: summary: Reactome TAS cytosol localization from a generic CRL1/NEDD8 pathway reaction. Redundant with the other Reactome cytosol annotations. action: KEEP_AS_NON_CORE reason: Correct compartment but propagated from generic CRL pathway reactions rather than FBXO40-specific evidence. supported_by: - reference_id: file:human/FBXO40/FBXO40-uniprot.txt supporting_text: "SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}." - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955241 qualifier: located_in review: summary: Reactome TAS cytosol localization from a generic CAND1/CRL pathway reaction. Redundant with the other Reactome cytosol annotations. action: KEEP_AS_NON_CORE reason: Correct compartment but propagated from generic CRL pathway reactions rather than FBXO40-specific evidence. supported_by: - reference_id: file:human/FBXO40/FBXO40-uniprot.txt supporting_text: "SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}." - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955289 qualifier: located_in review: summary: Reactome TAS cytosol localization from a generic COMMD/CAND1/CRL pathway reaction. Redundant with the other Reactome cytosol annotations. action: KEEP_AS_NON_CORE reason: Correct compartment but propagated from generic CRL pathway reactions rather than FBXO40-specific evidence. supported_by: - reference_id: file:human/FBXO40/FBXO40-uniprot.txt supporting_text: "SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}." - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956040 qualifier: located_in review: summary: Reactome TAS cytosol localization from a generic COP9-signalosome deneddylation pathway reaction. Redundant with the other Reactome cytosol annotations. action: KEEP_AS_NON_CORE reason: Correct compartment but propagated from generic CRL pathway reactions rather than FBXO40-specific evidence. supported_by: - reference_id: file:human/FBXO40/FBXO40-uniprot.txt supporting_text: "SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}." - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956200 qualifier: located_in review: summary: Reactome TAS cytosol localization from a generic DCUN1D3/CRL1 pathway reaction. Redundant with the other Reactome cytosol annotations. action: KEEP_AS_NON_CORE reason: Correct compartment but propagated from generic CRL pathway reactions rather than FBXO40-specific evidence. supported_by: - reference_id: file:human/FBXO40/FBXO40-uniprot.txt supporting_text: "SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}." - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983140 qualifier: located_in review: summary: Reactome TAS cytosol localization from a generic ubiquitin-transfer pathway reaction. Redundant with the other Reactome cytosol annotations. action: KEEP_AS_NON_CORE reason: Correct compartment but propagated from generic ubiquitin-conjugation pathway reactions rather than FBXO40-specific evidence. supported_by: - reference_id: file:human/FBXO40/FBXO40-uniprot.txt supporting_text: "SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}." - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983147 qualifier: located_in review: summary: Reactome TAS cytosol localization from a generic ubiquitin-transfer pathway reaction. Redundant with the other Reactome cytosol annotations. action: KEEP_AS_NON_CORE reason: Correct compartment but propagated from generic ubiquitin-conjugation pathway reactions rather than FBXO40-specific evidence. supported_by: - reference_id: file:human/FBXO40/FBXO40-uniprot.txt supporting_text: "SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}." - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983156 qualifier: located_in review: summary: Reactome TAS cytosol localization from a generic polyubiquitination pathway reaction. Redundant with the other Reactome cytosol annotations. action: KEEP_AS_NON_CORE reason: Correct compartment but propagated from generic ubiquitin-conjugation pathway reactions rather than FBXO40-specific evidence. supported_by: - reference_id: file:human/FBXO40/FBXO40-uniprot.txt supporting_text: "SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}." - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983157 qualifier: located_in review: summary: Reactome TAS cytosol localization from a generic E3-substrate-E2 interaction pathway reaction. Redundant with the other Reactome cytosol annotations. action: KEEP_AS_NON_CORE reason: Correct compartment but propagated from generic ubiquitin-conjugation pathway reactions rather than FBXO40-specific evidence. supported_by: - reference_id: file:human/FBXO40/FBXO40-uniprot.txt supporting_text: "SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}." - term: id: GO:0005737 label: cytoplasm evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: ISS transfer of cytoplasmic localization from the mouse ortholog (SKP1, UniProtKB:P62932 used as WITH). Consistent with the experimentally observed cytoplasmic localization of FBXO40. action: ACCEPT reason: Correct core compartment; corroborated by direct overexpression in C2C12 myoblasts and the UniProt subcellular location. supported_by: - reference_id: PMID:17928169 supporting_text: "By overexpressing in C2C12 cells, FBXO40 localized in cytoplasm." - term: id: GO:0042692 label: muscle cell differentiation evidence_type: ISS original_reference_id: PMID:17928169 qualifier: involved_in review: summary: ISS assignment of involvement in muscle cell differentiation, based on FBXO40's muscle-restricted, postnatal expression and its proposed role in postnatal myogenesis. action: KEEP_AS_NON_CORE reason: The cited study establishes muscle-specific expression and a postnatal-myogenesis association by expression/correlation, but does not directly demonstrate that FBXO40 drives muscle cell differentiation. The mechanistically best-defined muscle role of FBXO40 (Shi et al. 2011) is negative control of muscle growth/hypertrophy via SCF-dependent IRS1 degradation and attenuation of IGF-1/insulin-AKT signaling, rather than differentiation per se; retain this term as a plausible non-core process. supported_by: - reference_id: PMID:17928169 supporting_text: "All our data suggest that FBXO40 may function as a regulator involved in the postnatal myogenesis." - reference_id: file:human/FBXO40/FBXO40-deep-research-falcon.md supporting_text: Loss of Fbxo40 increases IRS1 abundance and produces muscle hypertrophy in animal models, including mice and pigs - term: id: GO:0046627 label: negative regulation of insulin receptor signaling pathway evidence_type: ISO original_reference_id: PMID:22033112 qualifier: involved_in review: summary: Proposed FBXO40-specific process inferred by orthology from mouse Fbxo40 (Shi et al. 2011, PMID:22033112; surfaced via the Falcon report) that SCF-FBXO40 ubiquitinates IRS1 to drive its proteasomal degradation, attenuating IGF-1/insulin -> IRS1 -> PI3K/AKT signaling in skeletal muscle. action: NEW reason: Not currently in GOA, but a well-supported FBXO40-specific biological process. SCF-FBXO40 degrades IRS1 (enhanced by IGF1R-dependent IRS1 tyrosine phosphorylation), and Fbxo40 loss stabilizes IRS1 and causes IRS1-dependent muscle hypertrophy, defining FBXO40 as a negative regulator of insulin/IGF-1 receptor signaling. Evidence is recorded as ISO (inferred from the mouse ortholog; Shi et al. 2011, Dev Cell, PMID:22033112, identified via the Falcon report). The PMID is confirmed to exist but its full text was not read here, so the falcon report is cited as the supporting lead rather than an asserted experimental human quote. supported_by: - reference_id: file:human/FBXO40/FBXO40-deep-research-falcon.md supporting_text: 'FBXO40 acts as the **substrate-recognition subunit** of an SCF E3 ligase complex (**SCF-FBXO40**) that **ubiquitinates IRS1**, promoting its **ubiquitin–proteasome-dependent degradation** in skeletal muscle, thereby **limiting IGF-1/insulin signaling** through the IRS1–PI3K–AKT axis' references: - id: PMID:22033112 title: The SCF-FBXO40 complex induces IRS1 ubiquitination in skeletal muscle, limiting IGF1 signaling. findings: [] reference_review: relevance: HIGH correctness: UNVERIFIED review_notes: Primary mouse/C2C12 study (Shi et al., Dev Cell 2011) identified by the Falcon deep-research report as the basis for the IRS1/insulin-signaling biology. PMID confirmed to exist via PubMed, but the full text was not read here; the FBXO40-specific NEW annotation is therefore recorded as ISO (ortholog inference) and the falcon report is cited as the supporting lead. - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:17928169 title: FBXO40, a gene encoding a novel muscle-specific F-box protein, is upregulated in denervation-related muscle atrophy. findings: - statement: FBXO40 is a novel muscle-specific F-box protein expressed only in heart and skeletal muscle, detectable postnatally (~2 weeks after birth), localizing to the cytoplasm in C2C12 cells, decreased in LGMD dystrophic muscle, and upregulated in denervation- but not starvation-related muscle atrophy; proposed to regulate postnatal myogenesis. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified (Gene 2007;404:53-60, DOI 10.1016/j.gene.2007.08.020); abstract-only in cache (full_text_available false). Directly establishes muscle-specific expression, cytoplasmic localization, and the postnatal-myogenesis association underlying the muscle cell differentiation annotations. - id: PMID:34445249 title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability. findings: - statement: Review describing the SCF (SKP1-CUL1-F-box) family of ~69 E3 ubiquitin ligase complexes in which variable F-box proteins determine substrate specificity and target substrates with poly-ubiquitin chains for proteasomal degradation. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-verified (Int J Mol Sci 2021;22:8544, DOI 10.3390/ijms22168544); abstract-only in cache. A family-level SCF review (not FBXO40-specific) used by ComplexPortal as the NAS basis for SCF-complex membership and SCF-dependent catabolic process; supports the generic SCF framing but not FBXO40-specific substrate claims. - id: file:human/FBXO40/FBXO40-deep-research-falcon.md title: Falcon deep research report for human FBXO40 findings: - statement: FBXO40 is the muscle-enriched substrate-recognition subunit of an SCF (SKP1-CUL1-RBX1) E3 ubiquitin ligase that ubiquitinates IRS1 to promote its proteasomal degradation, limiting IGF-1/insulin signaling through the IRS1-PI3K-AKT axis. supporting_text: 'FBXO40 acts as the **substrate-recognition subunit** of an SCF E3 ligase complex (**SCF-FBXO40**) that **ubiquitinates IRS1**, promoting its **ubiquitin–proteasome-dependent degradation** in skeletal muscle, thereby **limiting IGF-1/insulin signaling** through the IRS1–PI3K–AKT axis' - statement: FBXO40 co-immunoprecipitates with IRS1 and the canonical SCF components SKP1, CUL1 and RBX1, and immunoprecipitated SCF-FBXO40 ubiquitinates recombinant IRS1 in vitro. supporting_text: co-immunoprecipitation experiments show that **IRS1 and each SCF component (Skp1, Cullin1, Rbx1)** can be co-precipitated with Fbxo40, consistent with SCF assembly and adaptor function - statement: IRS1 tyrosine phosphorylation downstream of IGF1R activation markedly enhances IRS1 polyubiquitination by SCF-FBXO40, indicating phosphorylation-dependent substrate recognition. supporting_text: '**tyrosine phosphorylation** of IRS1 (in the context of **IGF1R activation**) markedly enhances IRS1 polyubiquitination by SCF-Fbxo40 in vitro, supporting phosphorylation-dependent substrate recognition/processing' - statement: Loss of Fbxo40 increases IRS1 abundance and produces muscle hypertrophy that is IRS1-dependent, including increased muscle mass in CRISPR knockout pigs. supporting_text: Loss of Fbxo40 increases IRS1 abundance and produces muscle hypertrophy in animal models, including mice and pigs - statement: FBXO40 transcription is induced by inflammatory STAT3 signaling (e.g. IL-6), linking it to catabolic insulin-resistance contexts. supporting_text: '**STAT3 activation** (e.g., via **IL-6**) increases Fbxo40 expression, reducing IRS1 and p-AKT; Fbxo40 knockdown preserves IRS1/p-AKT despite IL-6' reference_review: relevance: HIGH correctness: UNVERIFIED review_notes: 'Falcon (Edison Scientific) deep-research synthesis. Findings name primary literature (Shi et al., Dev Cell 2011, DOI 10.1016/j.devcel.2011.09.011, establishing IRS1 as the direct SCF-FBXO40 substrate and KO hypertrophy; Zhang et al., AJP Endocrinol Metab 2020, DOI 10.1152/ajpendo.00480.2019, STAT3/IL-6 induction). These are treated as leads supporting the IRS1/IGF-1 signaling core function; the primary full texts were not read here, so the synthesis is marked UNVERIFIED rather than VERIFIED.' - id: Reactome:R-HSA-8952618 title: AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex findings: [] - id: Reactome:R-HSA-8952620 title: NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex findings: [] - id: Reactome:R-HSA-8955241 title: CAND1 binds cytosolic CRL E3 ubiquitin ligases findings: [] - id: Reactome:R-HSA-8955289 title: COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes findings: [] - id: Reactome:R-HSA-8956040 title: COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes findings: [] - id: Reactome:R-HSA-8956200 title: MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex findings: [] - id: Reactome:R-HSA-983140 title: Transfer of Ub from E2 to substrate and release of E2 findings: [] - id: Reactome:R-HSA-983147 title: Release of E3 from polyubiquitinated substrate findings: [] - id: Reactome:R-HSA-983156 title: Polyubiquitination of substrate findings: [] - id: Reactome:R-HSA-983157 title: Interaction of E3 with substrate and E2-Ub complex findings: [] core_functions: - description: Substrate-recognition subunit (F-box adaptor) of a muscle-expressed SCF (SKP1-CUL1-RBX1-FBXO40) E3 ubiquitin ligase complex that recruits specific substrates and presents them for SCF-dependent poly-ubiquitination and proteasomal degradation. Catalytic ubiquitin transfer is provided by the RBX1 RING subunit, not by FBXO40 itself. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: file:human/FBXO40/FBXO40-uniprot.txt supporting_text: "Probable substrate-recognition component of the SCF (SKP1-" - reference_id: file:human/FBXO40/FBXO40-uniprot.txt supporting_text: "SUBUNIT: Directly interacts with SKP1 and CUL1. {ECO:0000250}." directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process - description: Muscle-specific negative regulator of IGF-1/insulin signaling that, as the SCF(FBXO40) substrate receptor, recognizes IRS1 (preferentially when tyrosine-phosphorylated downstream of activated IGF1R) and targets it for proteasomal degradation, thereby attenuating IRS1 -> PI3K/AKT anabolic signaling and limiting skeletal-muscle growth; loss of FBXO40 stabilizes IRS1 and causes IRS1-dependent muscle hypertrophy. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: file:human/FBXO40/FBXO40-deep-research-falcon.md supporting_text: 'FBXO40 acts as the **substrate-recognition subunit** of an SCF E3 ligase complex (**SCF-FBXO40**) that **ubiquitinates IRS1**, promoting its **ubiquitin–proteasome-dependent degradation** in skeletal muscle, thereby **limiting IGF-1/insulin signaling** through the IRS1–PI3K–AKT axis' - reference_id: file:human/FBXO40/FBXO40-deep-research-falcon.md supporting_text: '**tyrosine phosphorylation** of IRS1 (in the context of **IGF1R activation**) markedly enhances IRS1 polyubiquitination by SCF-Fbxo40 in vitro, supporting phosphorylation-dependent substrate recognition/processing' directly_involved_in: - id: GO:0046627 label: negative regulation of insulin receptor signaling pathway proposed_new_terms: [] suggested_questions: - question: What is the direct, experimentally validated substrate repertoire of FBXO40 in human skeletal muscle, and is IRS1 ubiquitination by the SCF-FBXO40 complex direct (e.g. reconstituted with purified components) rather than inferred from co-depletion phenotypes? - question: Does FBXO40 substrate recruitment depend on the TRAF-type zinc finger, and does substrate engagement require phosphodegron recognition downstream of IGF1R/insulin-Akt signaling? - question: Are the muscle cell differentiation and denervation-atrophy phenotypes a consequence of FBXO40-dependent substrate turnover, or do they reflect expression-correlated but indirect roles? - question: How is FBXO40 transcription controlled by inflammatory STAT3/IL-6 signaling in skeletal muscle, and does pharmacologic STAT3 inhibition preserve IRS1/p-AKT and improve insulin sensitivity primarily through FBXO40 downregulation? suggested_experiments: - description: Reconstitute the SCF-FBXO40 complex (SKP1, CUL1, RBX1, FBXO40) with a ubiquitin-charged E2 in vitro and assay ubiquitination of candidate substrates (e.g. IRS1) to establish direct adaptor function and chain topology. - description: Perform affinity purification-mass spectrometry of tagged FBXO40 from skeletal myotubes (with and without proteasome/neddylation inhibition) to define the endogenous substrate and complex interactome and confirm SKP1/CUL1/RBX1 association. - description: Generate FBXO40-knockout myoblasts/mice and quantify candidate-substrate levels and ubiquitination, myogenic differentiation, and the denervation-atrophy response to test whether phenotypes are substrate-turnover dependent.