Combined Automated Annotation using Multiple IEA Methods
The FBXL family of F-box proteins: variations on a theme.
Suppression of breast cancer progression by FBXL16 via oxygen-independent regulation of HIF1α stability.
Falcon deep research report for human FBXL16
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FBXL16 binds SKP1 via its F-box but shows no detectable CUL1 interaction, implying it may act non-canonically rather than as a conventional SCF substrate receptor.
"breast cancer-focused mechanistic work reports that FBXL16 can associate with **SKP1** yet shows **no detectable interaction with CUL1**, implying **non-canonical behavior** for an F-box protein and leaving the precise E3 architecture context-dependent or unresolved."
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FBXL16 is a context-dependent regulator of protein stability that both promotes degradation of some substrates and stabilizes others.
"Recent literature converges on FBXL16 as a regulator of **protein stability** with at least two modes:
- **Promoting ubiquitination and proteasomal degradation** of certain proteins (e.g., APP in AD models).
- **Stabilizing** certain signaling proteins by increasing their half-life or decreasing their ubiquitination (e.g., IRS1 in KRAS-mutant LUAD; ERα in ER+ breast cancer)."
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In Alzheimer's disease models FBXL16 promotes ubiquitination-dependent proteasomal degradation of APP, and hippocampal FBXL16 overexpression reduces APP and improves cognition.
"FBXL16 promotes ubiquitination-dependent proteasomal degradation of APP. Evidence includes co-immunoprecipitation and proteasome inhibition (MG132), cycloheximide (CHX) experiments, and direct ubiquitination readouts."
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In KRAS-mutant lung adenocarcinoma FBXL16 stabilizes IRS1 (extending its half-life), enhancing IGF1/IRS1/AKT signaling and sotorasib resistance; both F-box and LRR domains are required.
"FBXL16 stabilizes IRS1 protein, thereby enhancing **IGF1/IRS1/AKT signaling** outputs (pAKT, pS6K/pS6) and supporting growth/migration."
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In ER-positive breast cancer FBXL16 stabilizes ERalpha by decreasing its polyubiquitination and antagonizing FBXO45-mediated degradation, and is reported to stabilize c-MYC, SRC-3 and beta-catenin.
"In ER+ breast cancer, FBXL16 is presented as a positive regulator of **ERα stability** and endocrine resistance (via reduced ubiquitination), and also reported to stabilize oncoproteins such as c-MYC and β-catenin in related contexts."
FBXL16 PN consistency notes
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The proteostasis-network projection treats FBXL16 as a Cul1 substrate receptor, but the local review identifies this as a caveated mapping because FBXL16 is SKP1-positive and CUL1-negative in reported assays.
"PN places FBXL16 as a canonical Cul1 substrate receptor, but falcon + review establish FBXL16 is **non-canonical**: it binds SKP1 but shows **no detectable CUL1 interaction** (Shah 2022)"
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The stabilizing, anti-degradative mode is a real curation and ontology pressure point because no precise GO molecular-function term exists for it yet.
"The novel pressure is the **stabilizing/anti-degradative mode** with no GO MF — review proposes a new term "protein stabilization by inhibition of ubiquitin-dependent degradation" (candidate, UNVERIFIED — not yet a real GO ID; defensible but needs OLS/GO submission)."
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