The SCF-FBXO40 complex induces IRS1 ubiquitination in skeletal muscle, limiting IGF1 signaling.
Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Combined Automated Annotation using Multiple IEA Methods
FBXO40, a gene encoding a novel muscle-specific F-box protein, is upregulated in denervation-related muscle atrophy.
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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.
The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
Falcon deep research report for human FBXO40
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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.
"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"
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FBXO40 co-immunoprecipitates with IRS1 and the canonical SCF components SKP1, CUL1 and RBX1, and immunoprecipitated SCF-FBXO40 ubiquitinates recombinant IRS1 in vitro.
"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"
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IRS1 tyrosine phosphorylation downstream of IGF1R activation markedly enhances IRS1 polyubiquitination by SCF-FBXO40, indicating phosphorylation-dependent substrate recognition.
"**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"
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Loss of Fbxo40 increases IRS1 abundance and produces muscle hypertrophy that is IRS1-dependent, including increased muscle mass in CRISPR knockout pigs.
"Loss of Fbxo40 increases IRS1 abundance and produces muscle hypertrophy in animal models, including mice and pigs"
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FBXO40 transcription is induced by inflammatory STAT3 signaling (e.g. IL-6), linking it to catabolic insulin-resistance contexts.
"**STAT3 activation** (e.g., via **IL-6**) increases Fbxo40 expression, reducing IRS1 and p-AKT; Fbxo40 knockdown preserves IRS1/p-AKT despite IL-6"
AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex
NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex
CAND1 binds cytosolic CRL E3 ubiquitin ligases
COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes
COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes
MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex
Transfer of Ub from E2 to substrate and release of E2
Release of E3 from polyubiquitinated substrate
Polyubiquitination of substrate
Interaction of E3 with substrate and E2-Ub complex