FBXW7 PN Consistency Notes
- Generated: 2026-06-18
- Project: PROTEOSTASIS
- Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
- UniProt: Q969H0
- AIGR review status: COMPLETE
- Review batch: proteostasis-batch-2026-06-13
- Batch change status: added
Source Files Checked
Deep Research Files
AIGR Review Snapshot
- Description: FBXW7 (also known as hCdc4, SEL-10, FBW7, Archipelago homolog) is the F-box/WD40 substrate-recognition subunit of an SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex. Its N-terminal F-box domain binds SKP1 (and thereby connects to the CUL1-RBX1 catalytic core), while its C-terminal eight-bladed WD40 beta-propeller forms a phosphodegron-binding pocket that recognizes Cdc4 phosphodegron (CPD) motifs (a high-affinity consensus is pThr-Pro-Pro-X-pSer, with the central phosphothreonine at the P0 position), typically generated by GSK3, CDK1/2, or ERK/MAPK priming-plus-phosphorylation schemes; low-affinity and noncanonical CPDs can also be biologically decisive. By recruiting these phosphorylated substrates to the SCF complex, FBXW7 directs their polyubiquitination and subsequent proteasomal degradation. FBXW7 is a major tumor suppressor: it targets a network of oncoproteins and regulatory proteins for destruction, including cyclin E (CCNE1/CCNE2), MYC and N-MYC, the NOTCH1/NOTCH2/NOTCH4 intracellular domains, JUN, MCL1, MLST8, RICTOR, NR1D1 (REV-ERBalpha), presenilin 1, EGFR (via CPD-like motifs in its cytoplasmic tail), the Wnt effectors LEF1 and TCF7L2, and the mitophagy kinase PINK1. FBXW7 functions as a homodimer, which tunes substrate turnover and processivity. Three N-terminally distinct isoforms (alpha/nucleoplasm, beta/cytoplasm, gamma/nucleolus) localize to different subcellular compartments and access partly distinct substrate pools. Through this substrate-receptor activity FBXW7 governs cell-cycle progression (G1/S transition), Notch signaling, MYC-driven proliferation, EGFR/MAPK and Wnt/beta-catenin signaling, lipid and circadian metabolism, mitochondrial quality control, and bone homeostasis. Beyond canonical degradative K48-type ubiquitination, an ATM-phosphorylated SCF(FBXW7) pool can promote non-degradative K63-linked polyubiquitination of XRCC4 at DNA double-strand breaks to facilitate non-homologous end joining. Loss-of-function mutations, frequently clustered in the WD40 substrate-binding arginines (hotspots R465, R479, R505), are among the most common in human cancers, where they stabilize oncogenic substrates and can drive resistance to anti-EGFR and anti-Wnt therapies; germline FBXW7 variants cause an autosomal dominant neurodevelopmental disorder (DEDHIL).
- Existing/core annotation action counts: ACCEPT: 39; KEEP_AS_NON_CORE: 81; MARK_AS_OVER_ANNOTATED: 5; MODIFY: 2; UNDECIDED: 3
PN Consistency Summary
- Consistency: Rows 1–2 consistent. FBXW7 is the textbook tumor-suppressor SCF receptor; review has GO:1990756 (IDA x2, ACCEPT) — matching Row2 "already_in_goa_exact" — plus GO:0050816 phosphothreonine binding, GO:0030332 cyclin binding, and a large substrate set (cyclin E, MYC, NOTCH ICD, MCL1, RICTOR, MLST8, NR1D1, EGFR). Row1 mTORC1/SHOC2 role corresponds to KEEP_AS_NON_CORE downstream outputs. Row3 INCONSISTENT: PN projects GO:0061630 ubiquitin protein ligase activity from PMID:21070969 (Pashkova 2010, DOI), a paper (per PubMed) about WD40 propellers as ubiquitin-binding domains regulating F-box turnover — with Cdc4 (the FBXW7 ortholog) shown to use Ub-binding to promote its own auto-ubiquitination, not substrate ligation. The review independently flags exactly this: GO:0043130 ubiquitin binding (IBA) is MARK_AS_OVER_ANNOTATED ("FBXW7 recognizes phosphodegrons, not free ubiquitin"). So the YAML directly contradicts the PN Row3 catalytic projection.
- PN story / NEW pressure: Row2 GO:1990756 already in GOA (IDA) and accepted — no new pressure. Row3 GO:0061630 over-reaches (wrong activity class for a non-catalytic receptor; and the source paper is about Ub binding/auto-turnover). Both GO:0061630 and GO:0043130 verified real via OLS. No defensible NEW catalytic term.
- Evidence alignment: Strong overlap on the receptor story; Row2 PN PMID:15340381 (family review) vs review's gene-specific PMID:17434132 (cyclin E structure), PMID:15103331/15150404 (MYC), PMID:28007894 (STYX), PMID:35395208 (DEDHIL). Row3 PMID:21070969 is NOT cited in the FBXW7 review (only its IBA-derived ubiquitin-binding term is, via GO_REF:0000033) and is mischaracterized by the GO:0061630 mapping.
- Verdict: Rows 1–2 CONSISTENT; Row3 PN node OVER-REACHES (contradicts the review's own over-annotation call). Recommended edits: [MAP] change Row3
Ubiquitin and UBL binding|E3 ligase projection for FBXW7 from GO:0061630 ubiquitin protein ligase activity to GO:0043130 ubiquitin binding or no_mapping — PMID:21070969 = WD40 ubiquitin BINDING controlling F-box auto-turnover, not catalytic ligase; the FBXW7 review already marks ubiquitin binding as over-annotated.
Full Consistency Review
- UniProt: Q969H0 · batch: proteostasis-batch-2026-06-13 · review status: COMPLETE (very comprehensive, ~2220 lines)
- PN placement (3 rows): Row1 ALP
Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, direct|Modulator of mTORC1 activity (SHOC2-Raptor); Row2 UPS|...|Cul1 substrate receptor|F-box|WD40; Row3 UPS|Ubiquitin and UBL binding|E3 ligase|CUL1 receptor|idiosyncratic Ub binding / WD40 (PMID:21070969). PN-node mapping: Row2 group=mapped GO:1990756 (already_in_goa_exact); Row3 group=mapped GO:0061630 (new_to_goa); Row1 ALP no_mapping (GO:0010506 reg. of autophagy held too_broad).
- Consistency: Rows 1–2 consistent. FBXW7 is the textbook tumor-suppressor SCF receptor; review has GO:1990756 (IDA x2, ACCEPT) — matching Row2 "already_in_goa_exact" — plus GO:0050816 phosphothreonine binding, GO:0030332 cyclin binding, and a large substrate set (cyclin E, MYC, NOTCH ICD, MCL1, RICTOR, MLST8, NR1D1, EGFR). Row1 mTORC1/SHOC2 role corresponds to KEEP_AS_NON_CORE downstream outputs. Row3 INCONSISTENT: PN projects GO:0061630 ubiquitin protein ligase activity from PMID:21070969 (Pashkova 2010, DOI), a paper (per PubMed) about WD40 propellers as ubiquitin-binding domains regulating F-box turnover — with Cdc4 (the FBXW7 ortholog) shown to use Ub-binding to promote its own auto-ubiquitination, not substrate ligation. The review independently flags exactly this: GO:0043130 ubiquitin binding (IBA) is MARK_AS_OVER_ANNOTATED ("FBXW7 recognizes phosphodegrons, not free ubiquitin"). So the YAML directly contradicts the PN Row3 catalytic projection.
- PN story / NEW pressure: Row2 GO:1990756 already in GOA (IDA) and accepted — no new pressure. Row3 GO:0061630 over-reaches (wrong activity class for a non-catalytic receptor; and the source paper is about Ub binding/auto-turnover). Both GO:0061630 and GO:0043130 verified real via OLS. No defensible NEW catalytic term.
- Mapping strategy: Row2 correct (GO:1990756 matches review core MF; already_in_goa_exact). Row1 ALP no_mapping correct. Row3 mapping wrong: GO:0061630 should be GO:0043130 ubiquitin binding (and even that the review judges over-annotated for FBXW7 since recognition is phosphodegron-based) or no_mapping. Not broader/narrower issue — it is a wrong-activity issue.
- Evidence alignment: Strong overlap on the receptor story; Row2 PN PMID:15340381 (family review) vs review's gene-specific PMID:17434132 (cyclin E structure), PMID:15103331/15150404 (MYC), PMID:28007894 (STYX), PMID:35395208 (DEDHIL). Row3 PMID:21070969 is NOT cited in the FBXW7 review (only its IBA-derived ubiquitin-binding term is, via GO_REF:0000033) and is mischaracterized by the GO:0061630 mapping.
- Verdict: Rows 1–2 CONSISTENT; Row3 PN node OVER-REACHES (contradicts the review's own over-annotation call). Recommended edits: [MAP] change Row3
Ubiquitin and UBL binding|E3 ligase projection for FBXW7 from GO:0061630 ubiquitin protein ligase activity to GO:0043130 ubiquitin binding or no_mapping — PMID:21070969 = WD40 ubiquitin BINDING controlling F-box auto-turnover, not catalytic ligase; the FBXW7 review already marks ubiquitin binding as over-annotated.
PN Dossier Context
- review_batch: proteostasis-batch-2026-06-13
- review_yaml: genes/human/FBXW7/FBXW7-ai-review.yaml
- PN workbook rows: 3
PN row 1: Autophagy-Lysosome Pathway | Pre-initiation autophagy signaling | mTORC1 pathway, direct | Modulator of mTORC1 activity
- UniProt: Q969H0
- In branches: ALP, UPS
- Notes: F-box protein, member of SCF E3 ubiquitin ligase. Mediates ubiquitination and thereby degradation of SHOC2, which binds and activates RPTOR to inhibit mTORC1, thereby activating mTORC1 and suppressing autophagy.
- PN references (titles):
- A Destiny for Degradation: Interplay between Cullin-RING E3 Ligases and Autophagy - ScienceDirect
- The FBXW7-SHOC2-Raptor Axis Controls the Cross-Talks between the RAS-ERK and mTORC1 Signaling Pathways - ScienceDirect
- PN-node mapping records (path + ancestors):
- [type] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, direct|Modulator of mTORC1 activity
status=no_mapping scope= GO=[]
rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
- [group] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, direct
status=no_mapping scope= GO=[]
rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling
status=context_only scope=too_broad_to_propagate GO=[GO:0010506 regulation of autophagy]
rationale: This class organizes upstream signaling inputs to autophagy initiation. Because the subtree contains generic insulin, AMPK, mTORC1, nutrient-sensing, and miscellaneous signaling components, class-level propagation to regulation of autophagy would over-annotate many genes.
- [branch] Autophagy-Lysosome Pathway
status=no_mapping scope= GO=[]
rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.
PN row 2: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | WD40
- UniProt: Q969H0
- In branches: ALP, UPS
- Signature domains: IPR001810
- Auxiliary domains: IPR001680
- PN references (titles):
- PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|WD40
status=no_mapping scope= GO=[]
rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box
status=no_mapping scope= GO=[]
rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor
status=mapped scope=ok_for_propagation_to_go GO=[GO:1990756 ubiquitin-like ligase-substrate adaptor activity]
rationale: This PN group captures substrate receptors/adaptors for cullin/UBL ligase systems. The shared GO molecular-function target is ubiquitin-like ligase-substrate adaptor activity.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
status=no_mapping scope= GO=[]
rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.
PN row 3: Ubiquitin Proteasome System | Ubiquitin and UBL binding | E3 ligase | CUL1 receptor | idiosyncratic Ub binding / WD40
- UniProt: Q969H0
- In branches: ALP, UPS
- Signature domains: PMID: 21070969 (IPR001680)
- Auxiliary domains: IPR001810
- PN references (titles):
- PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase|CUL1 receptor|idiosyncratic Ub binding / WD40
status=no_mapping scope= GO=[]
rationale: Reviewed as a narrower enzyme-family, domain, or architecture subdivision already covered by a curated parent enzyme mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase|CUL1 receptor
status=no_mapping scope= GO=[]
rationale: Reviewed as a narrower enzyme-family, domain, or architecture subdivision already covered by a curated parent enzyme mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase
status=mapped scope=ok_for_propagation_to_go GO=[GO:0061630 ubiquitin protein ligase activity]
rationale: This PN group captures ubiquitin/UBL-binding factors that are E3 ligases. The shared molecular-function target is ubiquitin protein ligase activity.
- [class] Ubiquitin Proteasome System|Ubiquitin and UBL binding
status=context_only scope=too_broad_to_propagate GO=[GO:0140036 ubiquitin-modified protein reader activity]
rationale: This class records ubiquitin/UBL-reader context, but the subtree mixes ubiquitin, SUMO, UBL-domain, domain-architecture, catalytic, signaling, trafficking, and nucleic-acid process buckets. It is useful context, not a safe direct propagation.
- [branch] Ubiquitin Proteasome System
status=no_mapping scope= GO=[]
rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.
Projected GO annotations (2)
- GO:1990756 ubiquitin-like ligase-substrate adaptor activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor
- GO:0061630 ubiquitin protein ligase activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase
Note
This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.