id: Q9H469 gene_symbol: FBXL15 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXL15 (F-box/LRR-repeat protein 15; F-box only protein 37, FBXO37) is a substrate-recognition subunit of an SCF (SKP1-CUL1-RBX1) E3 ubiquitin ligase complex. Its F-box motif binds SKP1 to dock it onto the CUL1-RBX1 catalytic scaffold, while its leucine-rich repeat domain provides substrate selectivity. SCF(FBXL15) targets the HECT-type E3 ubiquitin ligase SMURF1 for ubiquitination and proteasomal degradation; by lowering SMURF1 levels it acts as a positive regulator of bone morphogenetic protein (BMP) signaling. FBXL15 recognizes the large subdomain within the N-lobe of the SMURF1 HECT domain and promotes SMURF1 ubiquitination on lysines in the WW-HECT linker (Lys357 primary, Lys355 secondary), and it can also ubiquitinate the related HECT ligases SMURF2 and WWP2. Because SMURF1 is an inhibitor of BMP signaling, SCF(FBXL15)-driven SMURF1 turnover relieves this inhibition and enhances BMP/SMAD transcriptional output, including induction of canonical BMP target genes such as ID1 and SMAD6. Through this control of SMURF1 stability, FBXL15 contributes to dorsal/ventral pattern formation during embryonic development and to bone mass maintenance. It acts in the cytoplasm. existing_annotations: - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location; supported by IDA evidence. action: ACCEPT reason: Correct localization, directly supported (IDA) in the SMURF1/BMP study. supported_by: - reference_id: file:human/FBXL15/FBXL15-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:21572392}' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21572392 qualifier: enables review: summary: IntAct interactions with the HECT ligases SMURF1/SMURF2/WWP2 (the FBXL15 substrates) from the BMP-signaling study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally important FBXL15-SMURF1/SMURF2/WWP2 substrate interactions, but bare protein binding is uninformative; the relationship is captured by the catabolic-process annotations. supported_by: - reference_id: file:human/FBXL15/FBXL15-uniprot.txt supporting_text: INTERACTION WITH SMURF1; SMURF2 AND WWP2 - term: id: GO:0030282 label: bone mineralization evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Ortholog-based electronic assignment of a bone-mineralization role, consistent with the rat study showing FBXL15 knockdown reduces bone mass and mineral density. action: KEEP_AS_NON_CORE reason: Supported downstream physiological role (via SMURF1/BMP control) but a generic developmental/physiological process distinct from the core substrate-receptor activity. supported_by: - reference_id: PMID:21572392 supporting_text: Injection of FBXL15 siRNAs into rat bone tissues leads to a significant loss of bone mass and decrease in bone mineral density - term: id: GO:0016567 label: protein ubiquitination evidence_type: IEA original_reference_id: GO_REF:0000041 qualifier: involved_in review: summary: UniPathway-derived general protein ubiquitination process, consistent with FBXL15's role in SMURF1 ubiquitination. action: ACCEPT reason: Correct but generic; the SCF-dependent catabolic process term better captures the role. Supported by direct SMURF1 ubiquitination. supported_by: - reference_id: file:human/FBXL15/FBXL15-uniprot.txt supporting_text: mediates the ubiquitination and subsequent proteasomal degradation of SMURF1 - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: IPI original_reference_id: PMID:21572392 qualifier: part_of review: summary: Evidence (ComplexPortal) that FBXL15 is part of the SCF(FBXL15) E3 ubiquitin ligase complex. Core cellular component. action: ACCEPT reason: Core complex membership; FBXL15 is the substrate-recognition subunit of SCF(FBXL15) (CUL1, SKP1, RBX1, FBXL15). supported_by: - reference_id: file:human/FBXL15/FBXL15-uniprot.txt supporting_text: Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXL15) composed of CUL1, SKP1, RBX1 and FBXL15 - term: id: GO:0030510 label: regulation of BMP signaling pathway evidence_type: NAS original_reference_id: PMID:21572392 qualifier: involved_in review: summary: Author statement (ComplexPortal NAS) that FBXL15 regulates BMP signaling, consistent with its positive regulation via SMURF1 degradation. action: KEEP_AS_NON_CORE reason: Supported regulatory role downstream of SMURF1 turnover; a context-specific pathway outcome rather than the core ligase substrate-receptor function. The more specific positive-regulation term is also annotated. supported_by: - reference_id: file:human/FBXL15/FBXL15-uniprot.txt supporting_text: thereby acting as a positive regulator of the BMP signaling pathway - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:21572392 qualifier: involved_in review: summary: Author statement (ComplexPortal NAS) that FBXL15 functions in SCF-dependent proteasomal protein catabolism. Captures the core biological process. action: ACCEPT reason: Core biological process for an SCF F-box substrate receptor; directly supported by SMURF1 degradation. supported_by: - reference_id: file:human/FBXL15/FBXL15-uniprot.txt supporting_text: mediates the ubiquitination and subsequent proteasomal degradation of SMURF1 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952618 qualifier: located_in review: summary: Reactome cytosolic localization within generic CRL1/NEDD8-cycle reactions. action: KEEP_AS_NON_CORE reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery rather than FBXL15-specific function. Consistent with cytoplasmic localization. supported_by: - reference_id: file:human/FBXL15/FBXL15-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:21572392}' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952620 qualifier: located_in review: summary: Reactome cytosolic localization within a generic CRL1 NEDD8-binding reaction. action: KEEP_AS_NON_CORE reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. supported_by: - reference_id: file:human/FBXL15/FBXL15-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:21572392}' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955241 qualifier: located_in review: summary: Reactome cytosolic localization within a generic CAND1/CRL reaction. action: KEEP_AS_NON_CORE reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. supported_by: - reference_id: file:human/FBXL15/FBXL15-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:21572392}' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955289 qualifier: located_in review: summary: Reactome cytosolic localization within a generic COMMD/CAND1/CRL reaction. action: KEEP_AS_NON_CORE reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. supported_by: - reference_id: file:human/FBXL15/FBXL15-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:21572392}' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956040 qualifier: located_in review: summary: Reactome cytosolic localization within a generic COP9-signalosome deneddylation reaction. action: KEEP_AS_NON_CORE reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. supported_by: - reference_id: file:human/FBXL15/FBXL15-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:21572392}' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956200 qualifier: located_in review: summary: Reactome cytosolic localization within a generic DCUN1D3/CRL1 reaction. action: KEEP_AS_NON_CORE reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. supported_by: - reference_id: file:human/FBXL15/FBXL15-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:21572392}' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983140 qualifier: located_in review: summary: Reactome cytosolic localization within a generic E2-to-substrate ubiquitin-transfer reaction. action: KEEP_AS_NON_CORE reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery. supported_by: - reference_id: file:human/FBXL15/FBXL15-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:21572392}' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983147 qualifier: located_in review: summary: Reactome cytosolic localization within a generic E3-release reaction. action: KEEP_AS_NON_CORE reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery. supported_by: - reference_id: file:human/FBXL15/FBXL15-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:21572392}' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983156 qualifier: located_in review: summary: Reactome cytosolic localization within a generic substrate-polyubiquitination reaction. action: KEEP_AS_NON_CORE reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery. supported_by: - reference_id: file:human/FBXL15/FBXL15-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:21572392}' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983157 qualifier: located_in review: summary: Reactome cytosolic localization within a generic E3-substrate-E2 interaction reaction. action: KEEP_AS_NON_CORE reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery. supported_by: - reference_id: file:human/FBXL15/FBXL15-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:21572392}' - term: id: GO:0000086 label: G2/M transition of mitotic cell cycle evidence_type: IMP original_reference_id: PMID:21572392 qualifier: involved_in review: summary: Mutant-phenotype annotation of a G2/M transition role from the SMURF1/BMP study. The cached abstract emphasizes BMP signaling, dorsoventral patterning and bone, not cell-cycle phenotypes; the supporting full-text evidence cannot be verified here. action: UNDECIDED reason: Experimental (IMP) annotation whose supporting data are not visible in the abstract-level cache; per curation guidance, an experimental annotation should not be removed merely because the abstract foregrounds a different phenotype. Cannot verify the G2/M evidence, so left undecided. - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:21572392 qualifier: located_in review: summary: Direct evidence for cytoplasmic localization from the SMURF1/BMP study. Core localization. action: ACCEPT reason: IDA-supported cytoplasmic localization, consistent with the UniProt subcellular location. supported_by: - reference_id: file:human/FBXL15/FBXL15-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:21572392}' - term: id: GO:0009953 label: dorsal/ventral pattern formation evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Sequence-similarity transfer of a dorsoventral patterning role, consistent with the zebrafish phenotype where fbxl15 knockdown causes dorsalization phenocopying BMP-deficient mutants. action: KEEP_AS_NON_CORE reason: Supported developmental role via BMP control, but downstream of and distinct from the core substrate-receptor activity. supported_by: - reference_id: PMID:21572392 supporting_text: Knockdown of fbxl15 expression in zebrafish embryos by specific antisense morpholinos causes embryonic dorsalization phenocoping BMP-deficient mutants - term: id: GO:0016567 label: protein ubiquitination evidence_type: IDA original_reference_id: PMID:21572392 qualifier: involved_in review: summary: Direct evidence that SCF(FBXL15) ubiquitinates SMURF1. A general parent of the SCF-dependent catabolic process. action: ACCEPT reason: Directly demonstrated substrate ubiquitination; accurate, though the SCF-dependent catabolic process term is more specific. supported_by: - reference_id: PMID:21572392 supporting_text: targets Smurf1 for ubiquitination and proteasomal degradation - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:21572392 qualifier: part_of review: summary: Direct evidence that FBXL15 forms an SCF(FBXL15) ubiquitin ligase complex. Core cellular component. action: ACCEPT reason: Core complex membership directly demonstrated. supported_by: - reference_id: PMID:21572392 supporting_text: forms an Skp1-Cullin1-F-box protein-Roc1 (SCF)(FBXL15) ubiquitin ligase complex - term: id: GO:0030282 label: bone mineralization evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Sequence-similarity transfer of a bone-mineralization role, consistent with the rat study showing FBXL15 knockdown reduces bone mass and mineral density. action: KEEP_AS_NON_CORE reason: Supported downstream physiological role via SMURF1/BMP control; a generic physiological process distinct from the core substrate-receptor activity. supported_by: - reference_id: PMID:21572392 supporting_text: Injection of FBXL15 siRNAs into rat bone tissues leads to a significant loss of bone mass and decrease in bone mineral density - term: id: GO:0030513 label: positive regulation of BMP signaling pathway evidence_type: IMP original_reference_id: PMID:21572392 qualifier: involved_in review: summary: Mutant-phenotype evidence that FBXL15, by degrading SMURF1, positively regulates BMP signaling. A well-supported downstream regulatory role. action: KEEP_AS_NON_CORE reason: Directly supported positive regulation of BMP signaling via SMURF1 turnover, but a context-specific pathway outcome rather than the core ligase substrate-receptor function. Falcon confirms the downstream transcriptional readout (reduced ID1/SMAD6 induction on FBXL15 knockdown). supported_by: - reference_id: PMID:21572392 supporting_text: FBXL15 positively regulates BMP signalling in mammalian cells - reference_id: file:human/FBXL15/FBXL15-deep-research-falcon.md supporting_text: >- FBXL15 knockdown reduces BMP-2-stimulated signaling outputs, including reduced BRE reporter activity and decreased induction of BMP/Smad target genes ID1 and SMAD6 by qRT-PCR - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:21572392 qualifier: involved_in review: summary: Direct evidence that SCF(FBXL15) drives proteasomal degradation of SMURF1. Core biological process. action: ACCEPT reason: Core biological process directly supported by SMURF1 turnover. supported_by: - reference_id: PMID:21572392 supporting_text: Smurf1 stability is suppressed by SCF(FBXL15)-mediated ubiquitination - term: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity evidence_type: IDA original_reference_id: PMID:21572392 qualifier: enables review: summary: Proposed core molecular function. As the LRR substrate-recognition subunit of SCF(FBXL15), FBXL15 selects the HECT ligase SMURF1 (and SMURF2/WWP2) for SCF-dependent ubiquitination. This more informative MF term is not in the GOA. action: NEW reason: Captures the precise molecular function of FBXL15 as an SCF substrate-recognition adaptor, more informative than the bare protein binding annotation. supported_by: - reference_id: PMID:21572392 supporting_text: FBXL15, through its leucine-rich repeat domain, specifically recognizes the large subdomain within the N-lobe of the Smurf1 HECT domain references: - 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:0000041 title: Gene Ontology annotation based on UniPathway vocabulary mapping findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: PMID:21572392 title: SCFFBXL¹⁵ regulates BMP signalling by directing the degradation of HECT-type ubiquitin ligase Smurf1. findings: - statement: SCF(FBXL15) targets the HECT E3 ligase SMURF1 (also SMURF2/WWP2) for ubiquitination and proteasomal degradation, recognizing the N-lobe of the SMURF1 HECT domain; by lowering SMURF1 it positively regulates BMP signaling, affecting dorsoventral patterning (zebrafish) and bone mass (rat). reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified (EMBO J 2011), full text available; establishes SMURF1 as the defining SCF(FBXL15) substrate and the BMP/bone/dorsoventral roles. - 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: [] - id: file:human/FBXL15/FBXL15-deep-research-falcon.md title: Falcon deep research report for human FBXL15 findings: - statement: FBXL15 is the substrate-recognition adaptor of an SCF (SKP1-CUL1-RBX1/Roc1) E3 ligase that confers target specificity for K48-like degradative ubiquitination and proteasomal turnover, rather than catalyzing ubiquitin transfer itself. supporting_text: >- Its primary molecular function is as a **substrate-recognition adaptor** that confers target specificity to an **SCF-type RING E3 ligase**, thereby promoting **K48-like degradative ubiquitination** and **proteasomal turnover** of the recruited substrate(s). - statement: SCF(FBXL15)-mediated SMURF1 degradation maps primarily to SMURF1 WW-HECT linker lysine K357, with K355 secondary. supporting_text: >- K357 identified as the primary residue and K355 as a secondary residue for FBXL15-mediated degradation; a K355/K357 double mutant attenuates ubiquitination and stabilizes SMURF1 - statement: By counteracting the BMP-inhibitor SMURF1, FBXL15 is required for full BMP/SMAD transcriptional output, including BMP-2-stimulated induction of the target genes ID1 and SMAD6. supporting_text: >- FBXL15 knockdown reduces BMP-2-stimulated signaling outputs, including reduced BRE reporter activity and decreased induction of BMP/Smad target genes ID1 and SMAD6 by qRT-PCR reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Falcon synthesis is built almost entirely on Cui et al. 2011 (EMBO J; PMID:21572392, already the core reference here) plus 2024 induced-proximity degrader screens and DEGRONOPEDIA; cross-checked against UniProt and PMID:21572392. Refines the SMURF1 degron mapping (K357/K355) and the BMP/SMAD target-gene readout (ID1, SMAD6); no new GOA terms added. core_functions: - description: Substrate-recognition subunit of an SCF (SKP1-CUL1-RBX1) E3 ubiquitin ligase complex that selects the HECT-type ubiquitin ligase SMURF1 (and related SMURF2/WWP2) for SCF-dependent polyubiquitination and proteasomal degradation. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: PMID:21572392 supporting_text: FBXL15, through its leucine-rich repeat domain, specifically recognizes the large subdomain within the N-lobe of the Smurf1 HECT domain directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process - description: Positive regulator of BMP signaling that controls the abundance of the BMP-inhibitory HECT ligase SMURF1, thereby influencing dorsal/ventral pattern formation during development and bone mass maintenance. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: PMID:21572392 supporting_text: FBXL15 positively regulates BMP signalling in mammalian cells directly_involved_in: - id: GO:0030513 label: positive regulation of BMP signaling pathway proposed_new_terms: [] suggested_questions: - question: Beyond SMURF1/SMURF2/WWP2, does SCF(FBXL15) have additional substrates, and what degron does its LRR recognize on the HECT N-lobe? - question: Is the reported G2/M transition role (GO:0000086) a genuine SCF(FBXL15) function, and if so which substrate mediates it? suggested_experiments: - description: Reconstitute SCF(FBXL15)-mediated ubiquitination of SMURF1 in vitro with purified SKP1-CUL1-RBX1-FBXL15 and an E2 to confirm direct ubiquitination and map the WW-HECT linker lysines (e.g. K355/K357). - description: Generate FBXL15-knockout cells/animals and measure SMURF1 levels, BMP/SMAD signaling output, bone mineralization, and any cell-cycle (G2/M) phenotypes to test the breadth of FBXL15 function.