FBXL15

UniProt ID: Q9H469
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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 Review

GO Term Evidence Action Reason
GO:0005737 cytoplasm
IEA
GO_REF:0000044 		ACCEPT
Summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location; supported by IDA evidence.
Reason: Correct localization, directly supported (IDA) in the SMURF1/BMP study.
Supporting Evidence:
file:human/FBXL15/FBXL15-uniprot.txt
Cytoplasm {ECO:0000269|PubMed:21572392}
GO:0005515 protein binding
IPI
PMID:21572392
SCFFBXL¹⁵ regulates BMP signalling by directing the degradat... 		KEEP AS NON CORE
Summary: IntAct interactions with the HECT ligases SMURF1/SMURF2/WWP2 (the FBXL15 substrates) from the BMP-signaling study. Bare protein binding is uninformative.
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.
Supporting Evidence:
file:human/FBXL15/FBXL15-uniprot.txt
INTERACTION WITH SMURF1; SMURF2 AND WWP2
GO:0030282 bone mineralization
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Ortholog-based electronic assignment of a bone-mineralization role, consistent with the rat study showing FBXL15 knockdown reduces bone mass and mineral density.
Reason: Supported downstream physiological role (via SMURF1/BMP control) but a generic developmental/physiological process distinct from the core substrate-receptor activity.
Supporting Evidence:
PMID:21572392
Injection of FBXL15 siRNAs into rat bone tissues leads to a significant loss of bone mass and decrease in bone mineral density
GO:0016567 protein ubiquitination
IEA
GO_REF:0000041 		ACCEPT
Summary: UniPathway-derived general protein ubiquitination process, consistent with FBXL15's role in SMURF1 ubiquitination.
Reason: Correct but generic; the SCF-dependent catabolic process term better captures the role. Supported by direct SMURF1 ubiquitination.
Supporting Evidence:
file:human/FBXL15/FBXL15-uniprot.txt
mediates the ubiquitination and subsequent proteasomal degradation of SMURF1
GO:0019005 SCF ubiquitin ligase complex
IPI
PMID:21572392
SCFFBXL¹⁵ regulates BMP signalling by directing the degradat... 		ACCEPT
Summary: Evidence (ComplexPortal) that FBXL15 is part of the SCF(FBXL15) E3 ubiquitin ligase complex. Core cellular component.
Reason: Core complex membership; FBXL15 is the substrate-recognition subunit of SCF(FBXL15) (CUL1, SKP1, RBX1, FBXL15).
Supporting Evidence:
file:human/FBXL15/FBXL15-uniprot.txt
Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXL15) composed of CUL1, SKP1, RBX1 and FBXL15
GO:0030510 regulation of BMP signaling pathway
NAS
PMID:21572392
SCFFBXL¹⁵ regulates BMP signalling by directing the degradat... 		KEEP AS NON CORE
Summary: Author statement (ComplexPortal NAS) that FBXL15 regulates BMP signaling, consistent with its positive regulation via SMURF1 degradation.
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.
Supporting Evidence:
file:human/FBXL15/FBXL15-uniprot.txt
thereby acting as a positive regulator of the BMP signaling pathway
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
NAS
PMID:21572392
SCFFBXL¹⁵ regulates BMP signalling by directing the degradat... 		ACCEPT
Summary: Author statement (ComplexPortal NAS) that FBXL15 functions in SCF-dependent proteasomal protein catabolism. Captures the core biological process.
Reason: Core biological process for an SCF F-box substrate receptor; directly supported by SMURF1 degradation.
Supporting Evidence:
file:human/FBXL15/FBXL15-uniprot.txt
mediates the ubiquitination and subsequent proteasomal degradation of SMURF1
GO:0005829 cytosol
TAS
Reactome:R-HSA-8952618 		KEEP AS NON CORE
Summary: Reactome cytosolic localization within generic CRL1/NEDD8-cycle reactions.
Reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery rather than FBXL15-specific function. Consistent with cytoplasmic localization.
Supporting Evidence:
file:human/FBXL15/FBXL15-uniprot.txt
Cytoplasm {ECO:0000269|PubMed:21572392}
GO:0005829 cytosol
TAS
Reactome:R-HSA-8952620 		KEEP AS NON CORE
Summary: Reactome cytosolic localization within a generic CRL1 NEDD8-binding reaction.
Reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery.
Supporting Evidence:
file:human/FBXL15/FBXL15-uniprot.txt
Cytoplasm {ECO:0000269|PubMed:21572392}
GO:0005829 cytosol
TAS
Reactome:R-HSA-8955241 		KEEP AS NON CORE
Summary: Reactome cytosolic localization within a generic CAND1/CRL reaction.
Reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery.
Supporting Evidence:
file:human/FBXL15/FBXL15-uniprot.txt
Cytoplasm {ECO:0000269|PubMed:21572392}
GO:0005829 cytosol
TAS
Reactome:R-HSA-8955289 		KEEP AS NON CORE
Summary: Reactome cytosolic localization within a generic COMMD/CAND1/CRL reaction.
Reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery.
Supporting Evidence:
file:human/FBXL15/FBXL15-uniprot.txt
Cytoplasm {ECO:0000269|PubMed:21572392}
GO:0005829 cytosol
TAS
Reactome:R-HSA-8956040 		KEEP AS NON CORE
Summary: Reactome cytosolic localization within a generic COP9-signalosome deneddylation reaction.
Reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery.
Supporting Evidence:
file:human/FBXL15/FBXL15-uniprot.txt
Cytoplasm {ECO:0000269|PubMed:21572392}
GO:0005829 cytosol
TAS
Reactome:R-HSA-8956200 		KEEP AS NON CORE
Summary: Reactome cytosolic localization within a generic DCUN1D3/CRL1 reaction.
Reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery.
Supporting Evidence:
file:human/FBXL15/FBXL15-uniprot.txt
Cytoplasm {ECO:0000269|PubMed:21572392}
GO:0005829 cytosol
TAS
Reactome:R-HSA-983140 		KEEP AS NON CORE
Summary: Reactome cytosolic localization within a generic E2-to-substrate ubiquitin-transfer reaction.
Reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery.
Supporting Evidence:
file:human/FBXL15/FBXL15-uniprot.txt
Cytoplasm {ECO:0000269|PubMed:21572392}
GO:0005829 cytosol
TAS
Reactome:R-HSA-983147 		KEEP AS NON CORE
Summary: Reactome cytosolic localization within a generic E3-release reaction.
Reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery.
Supporting Evidence:
file:human/FBXL15/FBXL15-uniprot.txt
Cytoplasm {ECO:0000269|PubMed:21572392}
GO:0005829 cytosol
TAS
Reactome:R-HSA-983156 		KEEP AS NON CORE
Summary: Reactome cytosolic localization within a generic substrate-polyubiquitination reaction.
Reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery.
Supporting Evidence:
file:human/FBXL15/FBXL15-uniprot.txt
Cytoplasm {ECO:0000269|PubMed:21572392}
GO:0005829 cytosol
TAS
Reactome:R-HSA-983157 		KEEP AS NON CORE
Summary: Reactome cytosolic localization within a generic E3-substrate-E2 interaction reaction.
Reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery.
Supporting Evidence:
file:human/FBXL15/FBXL15-uniprot.txt
Cytoplasm {ECO:0000269|PubMed:21572392}
GO:0000086 G2/M transition of mitotic cell cycle
IMP
PMID:21572392
SCFFBXL¹⁵ regulates BMP signalling by directing the degradat... 		UNDECIDED
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.
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.
GO:0005737 cytoplasm
IDA
PMID:21572392
SCFFBXL¹⁵ regulates BMP signalling by directing the degradat... 		ACCEPT
Summary: Direct evidence for cytoplasmic localization from the SMURF1/BMP study. Core localization.
Reason: IDA-supported cytoplasmic localization, consistent with the UniProt subcellular location.
Supporting Evidence:
file:human/FBXL15/FBXL15-uniprot.txt
Cytoplasm {ECO:0000269|PubMed:21572392}
GO:0009953 dorsal/ventral pattern formation
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Sequence-similarity transfer of a dorsoventral patterning role, consistent with the zebrafish phenotype where fbxl15 knockdown causes dorsalization phenocopying BMP-deficient mutants.
Reason: Supported developmental role via BMP control, but downstream of and distinct from the core substrate-receptor activity.
Supporting Evidence:
PMID:21572392
Knockdown of fbxl15 expression in zebrafish embryos by specific antisense morpholinos causes embryonic dorsalization phenocoping BMP-deficient mutants
GO:0016567 protein ubiquitination
IDA
PMID:21572392
SCFFBXL¹⁵ regulates BMP signalling by directing the degradat... 		ACCEPT
Summary: Direct evidence that SCF(FBXL15) ubiquitinates SMURF1. A general parent of the SCF-dependent catabolic process.
Reason: Directly demonstrated substrate ubiquitination; accurate, though the SCF-dependent catabolic process term is more specific.
Supporting Evidence:
PMID:21572392
targets Smurf1 for ubiquitination and proteasomal degradation
GO:0019005 SCF ubiquitin ligase complex
IDA
PMID:21572392
SCFFBXL¹⁵ regulates BMP signalling by directing the degradat... 		ACCEPT
Summary: Direct evidence that FBXL15 forms an SCF(FBXL15) ubiquitin ligase complex. Core cellular component.
Reason: Core complex membership directly demonstrated.
Supporting Evidence:
PMID:21572392
forms an Skp1-Cullin1-F-box protein-Roc1 (SCF)(FBXL15) ubiquitin ligase complex
GO:0030282 bone mineralization
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Sequence-similarity transfer of a bone-mineralization role, consistent with the rat study showing FBXL15 knockdown reduces bone mass and mineral density.
Reason: Supported downstream physiological role via SMURF1/BMP control; a generic physiological process distinct from the core substrate-receptor activity.
Supporting Evidence:
PMID:21572392
Injection of FBXL15 siRNAs into rat bone tissues leads to a significant loss of bone mass and decrease in bone mineral density
GO:0030513 positive regulation of BMP signaling pathway
IMP
PMID:21572392
SCFFBXL¹⁵ regulates BMP signalling by directing the degradat... 		KEEP AS NON CORE
Summary: Mutant-phenotype evidence that FBXL15, by degrading SMURF1, positively regulates BMP signaling. A well-supported downstream regulatory role.
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).
Supporting Evidence:
PMID:21572392
FBXL15 positively regulates BMP signalling in mammalian cells
file:human/FBXL15/FBXL15-deep-research-falcon.md
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
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
IDA
PMID:21572392
SCFFBXL¹⁵ regulates BMP signalling by directing the degradat... 		ACCEPT
Summary: Direct evidence that SCF(FBXL15) drives proteasomal degradation of SMURF1. Core biological process.
Reason: Core biological process directly supported by SMURF1 turnover.
Supporting Evidence:
PMID:21572392
Smurf1 stability is suppressed by SCF(FBXL15)-mediated ubiquitination
GO:1990756 ubiquitin-like ligase-substrate adaptor activity
IDA
PMID:21572392
SCFFBXL¹⁵ regulates BMP signalling by directing the degradat... 		NEW
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.
Reason: Captures the precise molecular function of FBXL15 as an SCF substrate-recognition adaptor, more informative than the bare protein binding annotation.
Supporting Evidence:
PMID:21572392
FBXL15, through its leucine-rich repeat domain, specifically recognizes the large subdomain within the N-lobe of the Smurf1 HECT domain

Core Functions

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:
ubiquitin-like ligase-substrate adaptor activity
Directly Involved In:
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
Cellular Locations:
cytoplasm
Supporting Evidence:
  • PMID:21572392
    FBXL15, through its leucine-rich repeat domain, specifically recognizes the large subdomain within the N-lobe of the Smurf1 HECT domain

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:
ubiquitin-like ligase-substrate adaptor activity
Directly Involved In:
positive regulation of BMP signaling pathway
Cellular Locations:
cytoplasm
Supporting Evidence:
  • PMID:21572392
    FBXL15 positively regulates BMP signalling in mammalian cells

References

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Suggested Questions for Experts

Q: Beyond SMURF1/SMURF2/WWP2, does SCF(FBXL15) have additional substrates, and what degron does its LRR recognize on the HECT N-lobe?

Q: Is the reported G2/M transition role (GO:0000086) a genuine SCF(FBXL15) function, and if so which substrate mediates it?

Suggested Experiments

Experiment: 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).

Experiment: 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.

Deep Research

Falcon

(FBXL15-deep-research-falcon.md)

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📚 Additional Documentation

Pn Notes

(FBXL15-pn-notes.md)

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📄 View Raw YAML

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