id: Q8N461 gene_symbol: FBXL16 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXL16 (F-box/LRR-repeat protein 16, C16orf22) is a member of the FBXL subfamily of F-box proteins, with an N-terminal (proline-rich/disordered) region, an F-box domain, and a C-terminal leucine-rich repeat (LRR) array. Its F-box motif mediates SKP1 binding, but unlike canonical F-box proteins FBXL16 shows no detectable CUL1 interaction in reported assays, suggesting it may act non-canonically rather than as a conventional SCF (SKP1-CUL1-F-box) substrate receptor. FBXL16 is a context-dependent regulator of protein stability acting in the cytoplasm, with two opposing modes: it promotes ubiquitination-dependent proteasomal degradation of some clients (e.g. the transcription factor HIF1alpha, where it limits HIF1alpha-driven epithelial-mesenchymal transition and angiogenesis as a tumor suppressor in triple-negative breast cancer, and the amyloid precursor protein APP, where neuronal/hippocampal FBXL16 reduces APP and improves cognition in Alzheimer's disease models), but it stabilizes other signaling regulators by decreasing their ubiquitination or antagonizing other ligases (e.g. IRS1, sustaining IGF1/IRS1/AKT signaling and sotorasib resistance in KRAS-mutant lung adenocarcinoma; and estrogen receptor alpha (ERalpha), c-MYC, SRC-3 and beta-catenin in ER-positive breast cancer, where it antagonizes FBXO45-mediated ERalpha degradation). Both the F-box and LRR domains are required for its substrate effects. It is expressed most highly in brain. alternative_products: - name: '1' id: Q8N461-1 - name: '2' id: Q8N461-2 sequence_note: VSP_056996 existing_annotations: - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:34818544 qualifier: enables review: summary: IntAct interaction with HIF1A (WITH/FROM UniProtKB:Q16665), the substrate FBXL16 binds and targets for degradation in the breast cancer study. The HIF1alpha interaction is functionally meaningful, but the bare protein binding term is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally important FBXL16-HIF1alpha substrate interaction, but bare protein binding is uninformative per curation guidelines; the substrate relationship is better captured by the SCF-degradation process annotation. supported_by: - reference_id: file:human/FBXL16/FBXL16-uniprot.txt supporting_text: 'Q8N461; Q16665: HIF1A; NbExp=6; IntAct=EBI-7208098, EBI-447269;' - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Combined automated electronic assignment of cytoplasmic localization, now corroborated by FBXL16-specific experimental evidence (FBXL16 co-localizes with APP in the cytoplasm of neuronal cell models), consistent with FBXL16 engaging substrates in the cytoplasm. action: KEEP_AS_NON_CORE reason: Cytoplasm is where FBXL16 is reported to act on substrates (e.g. cytoplasmic colocalization with APP), but the generic cytoplasm term is broad; retained as a supporting, non-core localization. additional_reference_ids: - file:human/FBXL16/FBXL16-deep-research-falcon.md supported_by: - reference_id: file:human/FBXL16/FBXL16-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. - reference_id: file:human/FBXL16/FBXL16-deep-research-falcon.md supporting_text: "FBXL16 and APP co-localize in the cytoplasm in neuronal cell models and co-immunoprecipitate (Flag-FBXL16 with Myc-APP)." - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:33234069 qualifier: involved_in review: summary: Family/ComplexPortal assignment that FBXL16 acts in SCF-dependent proteasomal degradation. Consistent with reported FBXL16-driven ubiquitination and proteasomal degradation of HIF1alpha and of APP (in Alzheimer's models). However, FBXL16 binds SKP1 but shows no detectable CUL1 interaction, so whether it assembles a canonical SCF for these events is unresolved; and for several other clients (IRS1, ERalpha, c-MYC) FBXL16 stabilizes rather than degrades, an outcome not captured by this term. action: ACCEPT reason: Ubiquitin-dependent proteasomal degradation of substrates is a documented FBXL16 function (HIF1alpha; APP). Retained as the core catabolic process, though the precise E3 architecture may be non-canonical (no detectable CUL1 binding) and FBXL16 also acts as a stabilizer for other substrates. additional_reference_ids: - file:human/FBXL16/FBXL16-deep-research-falcon.md supported_by: - reference_id: PMID:34818544 supporting_text: FBXL16 directly binds to HIF1α and induces its ubiquitination and degradation - reference_id: file:human/FBXL16/FBXL16-deep-research-falcon.md supporting_text: "Promoting ubiquitination and proteasomal degradation of certain proteins (e.g., APP in AD models)." - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952618 qualifier: located_in review: summary: Reactome pathway-level cytosol annotation propagated across the generic CRL1/neddylation reaction set. action: KEEP_AS_NON_CORE reason: Plausible localization for a cytosolic SCF component, but derived from generic CRL pathway membership rather than FBXL16-specific evidence. supported_by: - reference_id: file:human/FBXL16/FBXL16-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952620 qualifier: located_in review: summary: Reactome pathway-level cytosol annotation from the generic CRL1 neddylation reaction set. action: KEEP_AS_NON_CORE reason: Plausible but redundant generic-pathway localization; not FBXL16-specific. supported_by: - reference_id: file:human/FBXL16/FBXL16-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955241 qualifier: located_in review: summary: Reactome pathway-level cytosol annotation from the generic CRL (CAND1) reaction set. action: KEEP_AS_NON_CORE reason: Plausible but redundant generic-pathway localization; not FBXL16-specific. supported_by: - reference_id: file:human/FBXL16/FBXL16-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955289 qualifier: located_in review: summary: Reactome pathway-level cytosol annotation from the generic CRL (COMMD/CAND1) reaction set. action: KEEP_AS_NON_CORE reason: Plausible but redundant generic-pathway localization; not FBXL16-specific. supported_by: - reference_id: file:human/FBXL16/FBXL16-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956040 qualifier: located_in review: summary: Reactome pathway-level cytosol annotation from the generic CRL deneddylation (COP9) reaction set. action: KEEP_AS_NON_CORE reason: Plausible but redundant generic-pathway localization; not FBXL16-specific. supported_by: - reference_id: file:human/FBXL16/FBXL16-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956200 qualifier: located_in review: summary: Reactome pathway-level cytosol annotation from the generic CRL1 (DCUN1D3) reaction set. action: KEEP_AS_NON_CORE reason: Plausible but redundant generic-pathway localization; not FBXL16-specific. supported_by: - reference_id: file:human/FBXL16/FBXL16-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983140 qualifier: located_in review: summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (transfer of Ub from E2 to substrate). action: KEEP_AS_NON_CORE reason: Plausible but redundant generic-pathway localization; not FBXL16-specific. supported_by: - reference_id: file:human/FBXL16/FBXL16-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983147 qualifier: located_in review: summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (release of E3 from substrate). action: KEEP_AS_NON_CORE reason: Plausible but redundant generic-pathway localization; not FBXL16-specific. supported_by: - reference_id: file:human/FBXL16/FBXL16-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983156 qualifier: located_in review: summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (polyubiquitination of substrate). action: KEEP_AS_NON_CORE reason: Plausible but redundant generic-pathway localization; not FBXL16-specific. supported_by: - reference_id: file:human/FBXL16/FBXL16-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983157 qualifier: located_in review: summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (interaction of E3 with substrate and E2-Ub). action: KEEP_AS_NON_CORE reason: Plausible but redundant generic-pathway localization; not FBXL16-specific. supported_by: - reference_id: file:human/FBXL16/FBXL16-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. references: - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:33234069 title: 'The FBXL family of F-box proteins: variations on a theme.' findings: - statement: FBXL-family F-box proteins serve as substrate-recognition subunits of SCF E3 ubiquitin ligases, using their LRR domains for substrate binding and the F-box for SKP1/CUL1 recruitment. reference_section_type: LITERATURE_REVIEW reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Family-level review (full text available) supporting the general FBXL SCF substrate-receptor model. - id: PMID:34818544 title: Suppression of breast cancer progression by FBXL16 via oxygen-independent regulation of HIF1α stability. findings: - statement: FBXL16 directly binds HIF1alpha and induces its ubiquitination and proteasomal degradation independently of oxygen, blocking HIF1alpha-mediated EMT and angiogenesis; FBXL16 acts as a tumor suppressor in triple-negative breast cancer and is downregulated via the p38/miR-135b-3p axis. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Establishes a FBXL16 substrate (HIF1alpha) and a tumor-suppressor role via SCF-dependent degradation; abstract-only in cache but the binding/ubiquitination/degradation claims are explicit. Source of the GO:0005515 HIF1A interaction. - id: file:human/FBXL16/FBXL16-deep-research-falcon.md title: Falcon deep research report for human FBXL16 findings: - statement: 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. supporting_text: "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." - statement: FBXL16 is a context-dependent regulator of protein stability that both promotes degradation of some substrates and stabilizes others. supporting_text: "Recent literature converges on FBXL16 as a regulator of **protein stability** with at least two modes:\n- **Promoting ubiquitination and proteasomal degradation** of certain proteins (e.g., APP in AD models).\n- **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)." - statement: In Alzheimer's disease models FBXL16 promotes ubiquitination-dependent proteasomal degradation of APP, and hippocampal FBXL16 overexpression reduces APP and improves cognition. supporting_text: "FBXL16 promotes ubiquitination-dependent proteasomal degradation of APP. Evidence includes co-immunoprecipitation and proteasome inhibition (MG132), cycloheximide (CHX) experiments, and direct ubiquitination readouts." - statement: 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. supporting_text: "FBXL16 stabilizes IRS1 protein, thereby enhancing **IGF1/IRS1/AKT signaling** outputs (pAKT, pS6K/pS6) and supporting growth/migration." - statement: 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. supporting_text: "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." reference_review: relevance: HIGH correctness: UNVERIFIED review_notes: Falcon (Edison Scientific) deep research synthesis. Substantially expands FBXL16 beyond the HIF1alpha/TNBC story (PMID:34818544) to a context-dependent stability regulator with both degradative (HIF1alpha, APP) and stabilizing (IRS1, ERalpha, c-MYC, beta-catenin) modes, and surfaces the key non-canonical caveat that FBXL16 binds SKP1 but not CUL1. Primary leads (Qu et al. 2024 Biomarker Research; Morel & Long 2024 Molecular Oncology; Shah 2022; Yao et al. 2024 Respiratory Research) cite DOIs not PMIDs and are not in the local cache, so are not independently PubMed-verified here; treated as leads informing the description and core-function framing. - id: file:human/FBXL16/FBXL16-pn-notes.md title: FBXL16 PN consistency notes findings: - statement: 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. supporting_text: "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)" - statement: The stabilizing, anti-degradative mode is a real curation and ontology pressure point because no precise GO molecular-function term exists for it yet. supporting_text: 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). reference_review: relevance: HIGH correctness: VERIFIED review_notes: Local PN consistency note comparing the FBXL16 review with the Proteostasis Network mapping. Used here to record the unresolved mapping pressure around non-canonical CUL1 association and the proposed anti-degradative stabilization term. - 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: [] core_functions: - description: F-box protein that acts as a context-dependent regulator of substrate protein stability through the ubiquitin system. As a substrate-binding adaptor it promotes ubiquitination-dependent proteasomal degradation of clients such as HIF1alpha (oxygen-independent; limiting EMT/angiogenesis, tumor-suppressive in TNBC) and APP (in Alzheimer's models). Engages substrates via its LRR region (both F-box and LRR domains are required); binds SKP1 through its F-box but shows no detectable CUL1 interaction, so the precise E3 architecture may be non-canonical. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: PMID:34818544 supporting_text: FBXL16 directly binds to HIF1α and induces its ubiquitination and degradation - reference_id: file:human/FBXL16/FBXL16-deep-research-falcon.md supporting_text: "Promoting ubiquitination and proteasomal degradation of certain proteins (e.g., APP in AD models)." directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process - description: In a second, opposing mode, FBXL16 binds and stabilizes signaling regulators by decreasing their ubiquitination or antagonizing other ubiquitin ligases, increasing their half-life. Documented stabilized clients include IRS1 (sustaining IGF1/IRS1/AKT signaling and sotorasib resistance in KRAS-mutant LUAD) and ERalpha, c-MYC, SRC-3 and beta-catenin in ER-positive breast cancer (antagonizing FBXO45-mediated ERalpha degradation). No precise GO molecular-function term captures this anti-degradative protein-stabilizing activity (see proposed_new_terms). molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: file:human/FBXL16/FBXL16-deep-research-falcon.md supporting_text: "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)." proposed_new_terms: - proposed_name: protein stabilization by inhibition of ubiquitin-dependent degradation proposed_definition: A molecular function or process by which a protein increases the stability/half-life of a target protein by preventing or antagonizing its ubiquitination and consequent proteasomal degradation (e.g. by competing with or inhibiting a ubiquitin ligase). Proposed to capture the stabilizing, anti-degradative mode of FBXL16 on substrates such as IRS1 and ERalpha, which is not described by existing SCF/ligase-adaptor or generic protein-stabilization terms. suggested_questions: - question: Does FBXL16 assemble a canonical, catalytically productive SCF complex with CUL1/RBX1, or does its lack of detectable CUL1 binding mean it works through a non-canonical E3 mechanism or by modulating other ligases? - question: What molecular features determine whether FBXL16 degrades a substrate (HIF1alpha, APP) versus stabilizes it (IRS1, ERalpha, c-MYC), and is the stabilizing mode mediated by antagonizing specific ligases such as FBXO45? - question: Beyond these substrates, what are the FBXL16 substrates in brain (its highest-expression tissue), and what is its physiological role there? suggested_experiments: - description: Test whether FBXL16 assembles a productive SCF (immunoprecipitate FBXL16 and probe for CUL1/RBX1/NEDD8) and whether neddylation inhibition (MLN4924) alters FBXL16-dependent turnover of HIF1alpha and APP versus stabilization of IRS1/ERalpha, distinguishing canonical-SCF from non-canonical mechanisms. - description: Identify the endogenous FBXL16 substrate repertoire by AP-MS and quantitative proteomics in FBXL16 knockout versus wild-type cells across brain-derived and cancer models, classifying each interactor as stabilized or degraded, and test whether stabilization requires antagonism of competing ligases (e.g. FBXO45 for ERalpha). knowledge_gaps: - gap_statement: >- The exact E3-ligase architecture used by FBXL16 remains unresolved. FBXL16 can bind SKP1 and is mapped here to ubiquitin-like ligase-substrate adaptor activity, but reported failure to detect CUL1 leaves open whether the degradative HIF1alpha/APP activities use a canonical productive SCF complex, a non-canonical cullin/RBX module, or modulation of other ligases. boundary: >- The review supports FBXL16 as an F-box/LRR substrate-recognition factor that can promote proteasomal degradation of HIF1alpha and APP, while excluding catalytic ubiquitin ligase activity from the core function. gap_kind: - BIOLOGY - CURATION dark_aspect: RESIDUAL_SUBGAP status: OPEN significance: >- This boundary determines how confidently GO:1990756 and SCF-dependent-proteasomal-catabolism annotations should be propagated to FBXL16. Treating it as an ordinary Cul1-SCF receptor may overstate the molecular mechanism if FBXL16 instead acts through a non-canonical complex or through antagonism of other ligases. resolution: >- Endogenous and reconstituted FBXL16 complex profiling should test SKP1, CUL1, RBX1, neddylated cullin, and alternative ligase partners, then compare FBXL16-dependent HIF1alpha/APP turnover under cullin/neddylation inhibition and with F-box or LRR mutants. provenance: - reference_id: file:human/FBXL16/FBXL16-deep-research-falcon.md supporting_text: 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. - reference_id: file:human/FBXL16/FBXL16-pn-notes.md supporting_text: The group adaptor mapping (GO:1990756) is defensible for the degradative HIF1alpha/APP mode, but the "no CUL1 binding" finding means FBXL16 may not be a productive Cul1-SCF - gap_statement: >- The molecular basis of FBXL16's substrate-stabilizing mode is still dark. Current evidence indicates FBXL16 can degrade some clients while stabilizing others, but it is unresolved whether the stabilizing activity is direct substrate-adaptor behavior, competition with another E3 ligase, inhibition of ubiquitination, or an indirect signaling consequence. boundary: >- The review supports context-dependent regulation of substrate protein stability, including degradative and stabilizing modes, but the current GO molecular-function term captures the adaptor/degradative side better than anti-degradative stabilization. gap_kind: - BIOLOGY - ONTOLOGY - CURATION dark_aspect: MF_DARK status: OPEN significance: >- This is the main ontology pressure point for FBXL16. Without a resolved mechanism and a precise GO term, the stabilizing activities on IRS1, ERalpha, c-MYC, SRC-3, and beta-catenin can only be represented awkwardly by a broad adaptor function or by a proposed, not-yet-real term. resolution: >- For each stabilized client, measure direct FBXL16 binding, client ubiquitination, half-life, competing ligase involvement, and dependence on the FBXL16 F-box/LRR domains; in parallel, submit or refine a GO term if the direct anti-degradative activity is experimentally supported. provenance: - reference_id: file:human/FBXL16/FBXL16-deep-research-falcon.md supporting_text: Recent literature converges on FBXL16 as a regulator of **protein stability** with at least two modes - reference_id: file:human/FBXL16/FBXL16-deep-research-falcon.md supporting_text: 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. - reference_id: file:human/FBXL16/FBXL16-pn-notes.md supporting_text: 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). - gap_statement: >- The normal physiological substrate repertoire and tissue role of FBXL16, especially in brain, remain incompletely defined. APP and several cancer signaling proteins are useful leads, but it is not yet clear which clients and processes represent conserved endogenous FBXL16 biology rather than disease-model or tumor-context readouts. boundary: >- APP degradation, HIF1alpha degradation, and stabilization of selected signaling regulators are captured as supported examples, and brain is noted as the highest-expression tissue, but the review does not convert those examples into a broad normal brain or disease-process annotation. gap_kind: - BIOLOGY - CURATION dark_aspect: BP_DARK status: OPEN significance: >- Resolving this gap would decide whether FBXL16 should receive additional biological-process annotations for neuronal proteostasis, cognition, neuroinflammation, cancer signaling, or drug resistance, or whether those claims should remain context-specific findings rather than core function. resolution: >- Combine FBXL16 loss-of-function and rescue in physiological brain-derived systems with quantitative substrate proteomics, ubiquitinomics, and phenotype assays, then compare the validated endogenous clients with the APP, HIF1alpha, IRS1, and ERalpha disease-model literature. provenance: - reference_id: file:human/FBXL16/FBXL16-deep-research-falcon.md supporting_text: Direct localization evidence in the retrieved set includes **cytoplasmic co-localization of FBXL16 with APP** in neuronal cell models - reference_id: file:human/FBXL16/FBXL16-deep-research-falcon.md supporting_text: Overexpression + Flag-IP LC–MS/MS identified **141 interacting proteins**, enriched for ubiquitin-dependent catabolic processes - reference_id: file:human/FBXL16/FBXL16-pn-notes.md supporting_text: It is expressed most highly in brain.