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, drives endocrine resistance, and stabilizes several additional oncoproteins.
"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)."
OpenScientist report on FBXL16 client stabilization
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FBXL16's anti-degradative c-MYC/IRS1/SRC-3/beta-catenin evidence and its HIF1alpha/LATS2 degradative evidence leave a dual-mode mechanism to resolve.
"the contradictory HIF1alpha/LATS2 degradation reports complicate a purely anti-degradative annotation and suggest that substrate-specific dual annotations may ultimately be needed."
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A targeted FBXL16/ESR1 literature search did not support treating ERalpha as a published FBXL16 client.
"ERalpha is not mentioned in any of the identified FBXL16 publications."
The F-box protein FBXL16 up-regulates the stability of C-MYC oncoprotein by antagonizing the activity of the F-box protein FBW7.
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FBXL16 antagonizes FBW7-mediated C-MYC ubiquitination, stabilizes C-MYC, up-regulates beta-catenin and SRC-3, and requires both its F-box and LRR domains for C-MYC stabilization.
"FBXL16 stabilizes C-MYC by antagonizing FBW7-mediated C-MYC ubiquitination and degradation"
FBXL16 modulates the proliferation and autophagy in breast cancer cells via activating SRC-3-AKT signaling pathway.
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FBXL16 maintains SRC-3 protein abundance in breast-cancer cell models and links FBXL16-dependent proliferation and apoptosis/autophagy effects to SRC-3-AKT signaling.
"FBXL16 deficiency was demonstrated to reduce the level of steroid receptor coactivator 3 (SRC-3) in MDA-MB-231 and MCF-7 cells."
FBXL16 promotes cell growth and drug resistance in lung adenocarcinomas with KRAS mutation by stabilizing IRS1 and upregulating IRS1/AKT signaling.
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FBXL16 stabilizes IRS1 in KRAS-mutant lung adenocarcinoma models, increasing IGF1/AKT signaling, cell growth, cell migration, and resistance to the KRASG12C inhibitor sotorasib.
"Mechanistically, FBXL16 upregulates insulin receptor substrate 1 (IRS1) protein stability, leading to an increase of IGF1/AKT signaling, thereby promoting cell growth and migration."
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