Existing Annotations Review

Core Functions

Fe65 is a canonical adaptor protein with WW and PTB domains that scaffolds multiple protein interactions. It links APP to nuclear signaling, phosphorylated H2AX to JNK1, and insulin signaling to ARF6-Rac1 for neurite outgrowth. IBA and IDA evidence (PMID:36250347).

Molecular Function:

molecular adaptor activity

Directly Involved In:

DNA damage response positive regulation of apoptotic process positive regulation of neuron projection development

Cellular Locations:

nucleus cytoplasm plasma membrane

Fe65 binds the intracellular domain of APP via its PTB2 domain. This interaction is central to Fe65's biology, tethering it to the membrane under normal conditions and releasing it under stress. IBA evidence supported by multiple structural studies.

Molecular Function:

amyloid-beta binding

Cellular Locations:

plasma membrane

Fe65 functions as a transcription coregulator forming complexes with AICD and Tip60 for activation. It also has corepressor activity with TSHZ3, SET, and HDAC1 for repression of targets like CASP4. IBA and TAS evidence (PMID:12153398, PMID:19343227).

Molecular Function:

transcription coactivator activity

Directly Involved In:

regulation of DNA-templated transcription

Cellular Locations:

nucleus

Fe65 binds phosphorylated histone H2AX (Y142) via its PTB2 domain. This binding mediates DNA damage-induced apoptosis by recruiting JNK1. IPI evidence (PMID:19234442).

Molecular Function:

histone binding

Directly Involved In:

positive regulation of apoptotic process

Cellular Locations:

nucleoplasm

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:12153398

Characterization of an amyloid precursor protein-binding protein Fe65L2 and its novel isoforms lacking phosphotyrosine-interaction domains.

PMID:12843239

The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo.

PMID:12972431

Novel cadherin-related membrane proteins, Alcadeins, enhance the X11-like protein-mediated stabilization of amyloid beta-protein precursor metabolism.

PMID:16049941

A pilot proteomic study of amyloid precursor interactors in Alzheimer's disease.

PMID:16273093

A quantitative protein interaction network for the ErbB receptors using protein microarrays.

PMID:17332754

The novel cargo Alcadein induces vesicle association of kinesin-1 motor components and activates axonal transport.

PMID:17686488

Structural basis for polyproline recognition by the FE65 WW domain.

PMID:18468999

Regulation of FE65 nuclear translocation and function by amyloid beta-protein precursor in osmotically stressed cells.

PMID:19234442

Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions.

PMID:19343227

FE65 binds Teashirt, inhibiting expression of the primate-specific caspase-4.

PMID:21803450

The APP intracellular domain (AICD) potentiates ER stress-induced apoptosis.

PMID:21968187

Phosphorylation of LRP1 regulates the interaction with Fe65.

PMID:24056087

FE65 interacts with ADP-ribosylation factor 6 to promote neurite outgrowth.

PMID:24284412

Amyloid beta a4 precursor protein-binding family B member 1 (FE65) interactomics revealed synaptic vesicle glycoprotein 2A (SV2A) and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) as new binding proteins in the human brain.

PMID:25342469

Regulation of neuronal survival and morphology by the E3 ubiquitin ligase RNF157.

PMID:26045787

Screening of APP interaction proteins by DUALmembrane yeast two-hybrid system.

PMID:30664241

Quantitative interaction proteomics reveals differences in the interactomes of amyloid precursor protein isoforms.

PMID:31413325

HENA, heterogeneous network-based data set for Alzheimer's disease.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:35914814

Chr21 protein-protein interactions: enrichment in proteins involved in intellectual disability, autism, and late-onset Alzheimer's disease.

PMID:36250347

Insulin stimulates atypical protein kinase C-mediated phosphorylation of the neuronal adaptor FE65 to potentiate neurite outgrowth by activating ARF6-Rac1 signaling.

PMID:8887653

The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein.

PMID:8894693

cDNA cloning and chromosome mapping of the human Fe65 gene: interaction of the conserved cytoplasmic domains of the human beta-amyloid precursor protein and its homologues with the mouse Fe65 protein.

PMID:9461550

Fe65L2: a new member of the Fe65 protein family interacting with the intracellular domain of the Alzheimer's beta-amyloid precursor protein.

Reactome:R-HSA-5683986

APBB1 and MAPK8 bind diphosphorylated H2AFX

file:human/APBB1/APBB1-deep-research-falcon.md

Deep research report on APBB1

📚 Additional Documentation

Deep Research Falcon

(APBB1-deep-research-falcon.md)

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organism: human
gene_id: APBB1
gene_symbol: APBB1
uniprot_accession: O00213
protein_description: 'RecName: Full=Amyloid beta precursor protein binding family
B member 1 {ECO:0000312|HGNC:HGNC:581}; AltName: Full=Amyloid-beta A4 precursor
protein-binding family B member 1 {ECO:0000250|UniProtKB:Q9QXJ1}; AltName: Full=Protein
Fe65 {ECO:0000250|UniProtKB:Q9QXJ1};'
gene_info: Name=APBB1 {ECO:0000312|HGNC:HGNC:581}; Synonyms=FE65 {ECO:0000303|PubMed:8894693},
RIR {ECO:0000312|HGNC:HGNC:581};
organism_full: Homo sapiens (Human).
protein_family: Not specified in UniProt
protein_domains: APBB1/2/3. (IPR039576); PH-like_dom_sf. (IPR011993); PTB/PI_dom.
(IPR006020); WW_dom. (IPR001202); WW_dom_sf. (IPR036020)
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: O00213
Protein Description: RecName: Full=Amyloid beta precursor protein binding family B member 1 {ECO:0000312|HGNC:HGNC:581}; AltName: Full=Amyloid-beta A4 precursor protein-binding family B member 1 {ECO:0000250|UniProtKB:Q9QXJ1}; AltName: Full=Protein Fe65 {ECO:0000250|UniProtKB:Q9QXJ1};
Gene Information: Name=APBB1 {ECO:0000312|HGNC:HGNC:581}; Synonyms=FE65 {ECO:0000303|PubMed:8894693}, RIR {ECO:0000312|HGNC:HGNC:581};
Organism (full): Homo sapiens (Human).
Protein Family: Not specified in UniProt
Key Domains: APBB1/2/3. (IPR039576); PH-like_dom_sf. (IPR011993); PTB/PI_dom. (IPR006020); WW_dom. (IPR001202); WW_dom_sf. (IPR036020)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "APBB1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'APBB1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene APBB1 (gene ID: APBB1, UniProt: O00213) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: O00213
Protein Description: RecName: Full=Amyloid beta precursor protein binding family B member 1 {ECO:0000312|HGNC:HGNC:581}; AltName: Full=Amyloid-beta A4 precursor protein-binding family B member 1 {ECO:0000250|UniProtKB:Q9QXJ1}; AltName: Full=Protein Fe65 {ECO:0000250|UniProtKB:Q9QXJ1};
Gene Information: Name=APBB1 {ECO:0000312|HGNC:HGNC:581}; Synonyms=FE65 {ECO:0000303|PubMed:8894693}, RIR {ECO:0000312|HGNC:HGNC:581};
Organism (full): Homo sapiens (Human).
Protein Family: Not specified in UniProt
Key Domains: APBB1/2/3. (IPR039576); PH-like_dom_sf. (IPR011993); PTB/PI_dom. (IPR006020); WW_dom. (IPR001202); WW_dom_sf. (IPR036020)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "APBB1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene APBB1 (gene ID: APBB1, UniProt: O00213) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Plan and verification
- Identity check: APBB1 (UniProt O00213) encodes FE65, a brain-enriched adaptor protein with an N‑terminal WW domain and two C‑terminal phosphotyrosine-binding (PTB) domains, often referred to as PTB1 and PTB2. These features and synonyms (FE65) are consistently reported in the human literature cited below, matching the user-provided UniProt entry and domain annotations. The organism is Homo sapiens (human). (chow2015fe65rolesbeyond pages 1-3, augustin2021fe65ascaffolding pages 11-13)

Comprehensive research report on APBB1 (FE65)

1) Key concepts and definitions
- Gene/protein: APBB1 encodes FE65, a modular scaffolding/adaptor concentrated in neurons. It contains a WW domain and two PTB domains (PTB1, PTB2), enabling assembly of multimolecular complexes. (chow2015fe65rolesbeyond pages 1-3, augustin2021fe65ascaffolding pages 11-13)
• Domain organization: WW domain binds proline-rich ligands; PTB1/2 bind NPXY/YENPTY motifs; PTB2 mediates high-affinity binding to APP/AICD. (chow2015fe65rolesbeyond pages 1-3, koistinen2017nuclearlocalizationof pages 7-10)
- Primary molecular role: non-enzymatic scaffold/adaptor that links the APP intracellular domain (AICD) to nuclear co-regulators (e.g., Tip60/KAT5) and to trafficking and cytoskeletal regulators at membranes and synapses. (augustin2021fe65ascaffolding pages 11-13, augustin2021fe65ascaffoldinga pages 13-14)
- Canonical complex: AICD–FE65–Tip60 (KAT5) “AFT” complex implicated in nuclear signaling/transcriptional regulation downstream of APP proteolysis. (augustin2021fe65ascaffoldinga pages 13-14)

2) Structure and domains (current understanding)
- FE65 architecture: N‑terminal WW domain; C‑terminal PTB1 and PTB2. PTB2 binds the APP YENPTY motif; WW and PTB1 contribute to other interactions and transcriptional activity. (chow2015fe65rolesbeyond pages 1-3, koistinen2017nuclearlocalizationof pages 7-10)
- Functional domain requirements for nuclear transactivation: WW+PTB1+PTB2 are required to stimulate APP/AICD-dependent transcription in a Gal4-based system. (koistinen2017nuclearlocalizationof pages 7-10)

3) Interactions, complexes, and pathways
- APP/AICD binding and nuclear signaling: FE65 interacts with APP via PTB2 and supports AICD-dependent transcription. FE65 forms transcriptional complexes with AICD and Tip60 (KAT5), originally described for AFT complexes; FE65 has dominant roles in APP-related nuclear signaling and can act as a transcriptional regulator/co-regulator. (augustin2021fe65ascaffoldinga pages 13-14)
- Tip60/KAT5 linkage: FE65–Tip60 interaction is part of AFT complexes; Tip60 function in these complexes and broader chromatin/DNA damage pathways is discussed in compiled reviews cited within the 2021 synthesis. (augustin2021fe65ascaffoldinga pages 13-14)
- Post-translational regulation: Multiple FE65 phosphorylation sites are documented, including Y547 (c-Abl) that modulates APP/FE65-dependent transcription and S610 (SGK1) affecting localization; broader phosphoregulation of FE65 is summarized. (chow2015fe65rolesbeyond pages 13-16)
- Cytoskeletal and synaptic network: FE65 scaffolds actin regulators and synaptic effectors; it couples to Arf6/ELMO1/DOCK1→Rac1→cofilin/Arp2/3 to promote lamellipodia and dendritic spine plasticity; via Mena/profilin/G‑actin, it supports filopodia/spine initiation. (augustin2021fe65ascaffolding pages 11-13)
- Receptor/trafficking coupling: FE65 binds APP family members with high affinity and can link APP to ApoE receptors (e.g., LRP family), modulating trafficking and processing, implicating roles in endocytosis and receptor-dependent APP handling. (augustin2021fe65ascaffolding pages 11-13)

4) Subcellular localization and trafficking
- Localization: FE65 is enriched in neuronal growth cones and at pre- and post-synapses, consistent with roles in synaptic plasticity and actin remodeling. (augustin2021fe65ascaffolding pages 11-13)
- Membrane and nuclear pools: FE65 associates with plasma membrane/APP via PTB2 and translocates to the nucleus; nuclear localization depends on regulated intramembrane proteolysis of APP. Pharmacologic inhibition of γ‑secretase (DAPT) or α‑secretase (e.g., ADAM10 inhibitor GI254023X; broad ADAM inhibitor batimastat) reduces nuclear FE65, indicating dependence on APP processing. Phosphorylation in the N-terminus restricts nuclear entry. (koistinen2017nuclearlocalizationof pages 7-10, koistinen2017nuclearlocalizationof pages 11-13)

5) Recent developments and latest research (priority to 2023–2024)
- APBB1 is a substrate of ALK: Using proximity labeling and validation in neuroblastoma cells, APBB1 was identified as a downstream molecule of receptor ALK and directly phosphorylated on multiple tyrosines, with Y269 a major target; influencing NB-1 cell viability. This expands FE65 regulation by receptor tyrosine kinases with potential oncology relevance. Journal of Biochemistry, Aug 2024; DOI: 10.1093/jb/mvae055; https://doi.org/10.1093/jb/mvae055. (suzuki2024identificationofapbb1 pages 9-9)
- Autophagy linkage (neuronal): A 2025 study reports FE65 interacting with Beclin 1 to enhance PI3KC3‑C1 activity and PI3P production, thereby promoting autophagic nucleation; the authors propose FE65 may bridge APP to autophagy initiation and influence APP routing to autophagosomes. While 2025, it indicates a growing theme of FE65 in degradative trafficking. Biology (MDPI), Jan 2025; DOI: 10.3390/biology14010097; https://doi.org/10.3390/biology14010097. (chan2025beclin1mediatedautophagy pages 14-16, chan2025beclin1mediatedautophagy pages 1-2)
- Proteomics/AD context: Compilations highlight FE65 among proteins interacting with APP and enriched at synaptic/actin interfaces; contemporary integrative proteomics placing APP interactors in amyloid contexts has increasingly noted APBB1/Fe65, but specific 2024 plaque-proteome placement should be interpreted cautiously unless directly validated in the cited datasets. (augustin2021fe65ascaffolding pages 11-13)

6) Current applications and real-world implementations
- Neuroscience/AD pathway dissection: Modulating secretase activity alters FE65 nuclear translocation and thus AFT pathway output, a commonly used experimental approach to study APP-dependent transcriptional signaling in neuronal models. PLoS ONE, Mar 2017; https://doi.org/10.1371/journal.pone.0173888. (koistinen2017nuclearlocalizationof pages 7-10, koistinen2017nuclearlocalizationof pages 11-13)
- Oncology signaling: The ALK→APBB1 phosphorylation axis (Y269 and others) suggests FE65 is integrated into RTK signaling in ALK-driven cancers (e.g., neuroblastoma), providing a potential mechanistic link to cell viability. Journal of Biochemistry, Aug 2024; https://doi.org/10.1093/jb/mvae055. (suzuki2024identificationofapbb1 pages 9-9)

7) Expert opinions and authoritative analyses
- Reviews synthesize FE65 as a versatile adaptor: FE65 is portrayed as a central scaffold bridging APP to transcriptional co-regulators (Tip60), to receptors regulating trafficking (LRP family), and to actin/synaptic machineries, with pleiotropic yet mechanistically traceable roles via its WW/PTB domains. Cellular and Molecular Biology Letters, Mar 2015; https://doi.org/10.1515/cmble-2015-0002. (chow2015fe65rolesbeyond pages 1-3, chow2015fe65rolesbeyond pages 3-6, chow2015fe65rolesbeyond pages 13-16)
- Actin/synaptic specialization: The 2021 synthesis emphasizes FE65-centred actin regulation pathways (Arf6/ELMO1/DOCK1/Rac1; Mena/profilin) underlying dendritic spine dynamics and plasticity, integrating membrane trafficking and nuclear signaling. Cells, Jun 2021; https://doi.org/10.3390/cells10071599. (augustin2021fe65ascaffolding pages 11-13, augustin2021fe65ascaffoldinga pages 11-13)

8) Statistics and specific data points
- Secretase dependence: Quantitative subcellular fractionation/imaging demonstrated nuclear FE65 decreases upon γ‑secretase (DAPT) and α‑secretase (ADAM10) inhibition in SH‑SY5Y cells; deletion of PTB2 impairs membrane anchoring/nuclear translocation. PLoS ONE, Mar 21, 2017; https://doi.org/10.1371/journal.pone.0173888. (koistinen2017nuclearlocalizationof pages 7-10, koistinen2017nuclearlocalizationof pages 11-13)
- ALK phosphorylation mapping: In-cell and in‑vitro kinase assays identified multiple APBB1 tyrosine sites phosphorylated by ALK, with Y269 a major target; proximity-labeling identified 43 candidate interactors, with APBB1 prioritized and shown to affect NB‑1 cell viability. Journal of Biochemistry, Aug 2024; https://doi.org/10.1093/jb/mvae055. (suzuki2024identificationofapbb1 pages 9-9)

Functional annotation summary
- Molecular function: FE65 is a multidomain adaptor/scaffold. It binds APP/AICD (PTB2), recruits/associates with Tip60/KAT5 in AFT complexes for nuclear transcriptional signaling, and scaffolds actin regulators and trafficking receptors at membranes/synapses. It is not an enzyme or transporter; activity derives from modular protein–protein interactions and regulated localization/post‑translational modification. (augustin2021fe65ascaffoldinga pages 13-14, augustin2021fe65ascaffolding pages 11-13, chow2015fe65rolesbeyond pages 13-16)
- Biological processes: APP processing–coupled nuclear signaling; regulation of gene transcription; endocytic trafficking and receptor-coupled APP processing; synaptic plasticity and actin cytoskeleton remodeling; potentially autophagy control and degradative trafficking (emerging). (koistinen2017nuclearlocalizationof pages 7-10, augustin2021fe65ascaffolding pages 11-13, chan2025beclin1mediatedautophagy pages 14-16)
- Cellular localization: cytosol/plasma membrane/endosomes (via APP and receptors), synaptic compartments, and nucleus; nuclear entry depends on APP proteolysis (α/γ secretases) and FE65 domain integrity and phosphorylation state. (koistinen2017nuclearlocalizationof pages 7-10, augustin2021fe65ascaffolding pages 11-13)

Notes on scope and evidence
- Where 2023–2024 items are limited, we have emphasized the 2024 ALK–APBB1 phosphorylation study and retained foundational mechanistic studies and reviews. Some 2025 reports (autophagy) are noted as emergent but should be corroborated by additional independent studies. (suzuki2024identificationofapbb1 pages 9-9, chan2025beclin1mediatedautophagy pages 14-16, chan2025beclin1mediatedautophagy pages 1-2)

Key sources with URLs and dates
- Suzuki et al., Identification of APBB1 as a substrate for anaplastic lymphoma kinase. Journal of Biochemistry, 176:395–403 (Aug 2024). https://doi.org/10.1093/jb/mvae055 (published 2024-08). (suzuki2024identificationofapbb1 pages 9-9)
- Koistinen et al., Nuclear localization of FE65 is dependent on regulated intramembrane proteolysis. PLoS ONE, 12:e0173888 (Mar 21, 2017). https://doi.org/10.1371/journal.pone.0173888 (published 2017-03-21). (koistinen2017nuclearlocalizationof pages 11-13, koistinen2017nuclearlocalizationof pages 7-10)
- Augustin & Kins, Fe65: A Scaffolding Protein of Actin Regulators. Cells, 10:1599 (Jun 2021). https://doi.org/10.3390/cells10071599 (published 2021-06-26). (augustin2021fe65ascaffolding pages 11-13, augustin2021fe65ascaffoldinga pages 11-13, augustin2021fe65ascaffoldinga pages 13-14)
- Chow et al., FE65: Roles beyond amyloid precursor protein processing. Cellular and Molecular Biology Letters, 20:66–87 (Mar 2015). https://doi.org/10.1515/cmble-2015-0002 (published 2015-03-01). (chow2015fe65rolesbeyond pages 1-3, chow2015fe65rolesbeyond pages 3-6, chow2015fe65rolesbeyond pages 13-16)
- Chan et al., Beclin 1-mediated autophagy is potentiated by an interaction with FE65. Biology, 14:97 (Jan 2025). https://doi.org/10.3390/biology14010097 (published 2025-01). (chan2025beclin1mediatedautophagy pages 14-16, chan2025beclin1mediatedautophagy pages 1-2)

Conclusion
APBB1/FE65 is a human neuronal adaptor with WW, PTB1, PTB2 domains that scaffold APP/AICD to nuclear co-regulators (Tip60/KAT5) and to membrane/cytoskeletal machineries. FE65’s nuclear localization and transcriptional effects are tightly coupled to APP proteolysis by α/γ secretases; its synaptic/membrane roles integrate actin remodeling and receptor-dependent APP trafficking. Recent work identifies FE65 as an ALK substrate (Y269 as a major site), expanding its integration with RTK signaling; emerging reports suggest FE65 may also modulate autophagy initiation via Beclin 1, highlighting ongoing diversification of FE65’s functional repertoire in neuronal homeostasis and disease mechanisms. (koistinen2017nuclearlocalizationof pages 7-10, augustin2021fe65ascaffoldinga pages 13-14, augustin2021fe65ascaffolding pages 11-13, suzuki2024identificationofapbb1 pages 9-9, chan2025beclin1mediatedautophagy pages 14-16)

References

(chow2015fe65rolesbeyond pages 1-3): Wan Ning Vanessa Chow, Hei Nga Maggie Cheung, Wen Li, and Kwok-Fai Lau. Fe65: roles beyond amyloid precursor protein processing. Cellular and Molecular Biology Letters, 20:66-87, Mar 2015. URL: https://doi.org/10.1515/cmble-2015-0002, doi:10.1515/cmble-2015-0002. This article has 26 citations and is from a peer-reviewed journal.
(augustin2021fe65ascaffolding pages 11-13): Vanessa Augustin and Stefan Kins. Fe65: a scaffolding protein of actin regulators. Cells, 10:1599, Jun 2021. URL: https://doi.org/10.3390/cells10071599, doi:10.3390/cells10071599. This article has 17 citations and is from a poor quality or predatory journal.
(koistinen2017nuclearlocalizationof pages 7-10): Niina A. Koistinen, Anna K. Edlund, Preeti K. Menon, Elena V. Ivanova, Smaranda Bacanu, and Kerstin Iverfeldt. Nuclear localization of amyloid-β precursor protein-binding protein fe65 is dependent on regulated intramembrane proteolysis. PLoS ONE, 12:e0173888, Mar 2017. URL: https://doi.org/10.1371/journal.pone.0173888, doi:10.1371/journal.pone.0173888. This article has 11 citations and is from a peer-reviewed journal.
(augustin2021fe65ascaffoldinga pages 13-14): V Augustin and S Kins. Fe65: a scaffolding protein of actin regulators. cells 2021, 10, 1599. Unknown journal, 2021.
(chow2015fe65rolesbeyond pages 13-16): Wan Ning Vanessa Chow, Hei Nga Maggie Cheung, Wen Li, and Kwok-Fai Lau. Fe65: roles beyond amyloid precursor protein processing. Cellular and Molecular Biology Letters, 20:66-87, Mar 2015. URL: https://doi.org/10.1515/cmble-2015-0002, doi:10.1515/cmble-2015-0002. This article has 26 citations and is from a peer-reviewed journal.
(koistinen2017nuclearlocalizationof pages 11-13): Niina A. Koistinen, Anna K. Edlund, Preeti K. Menon, Elena V. Ivanova, Smaranda Bacanu, and Kerstin Iverfeldt. Nuclear localization of amyloid-β precursor protein-binding protein fe65 is dependent on regulated intramembrane proteolysis. PLoS ONE, 12:e0173888, Mar 2017. URL: https://doi.org/10.1371/journal.pone.0173888, doi:10.1371/journal.pone.0173888. This article has 11 citations and is from a peer-reviewed journal.
(suzuki2024identificationofapbb1 pages 9-9): Yuji Suzuki, Shoma Tsubota, Kenji Kadomatsu, and Kazuma Sakamoto. Identification of apbb1 as a substrate for anaplastic lymphoma kinase. Journal of Biochemistry, 176:395-403, Aug 2024. URL: https://doi.org/10.1093/jb/mvae055, doi:10.1093/jb/mvae055. This article has 0 citations and is from a peer-reviewed journal.
(chan2025beclin1mediatedautophagy pages 14-16): Wai Wa Ray Chan, Jessica Chow, Dennis Dik-Long Chau, Yuqi Zhai, and Kwok-Fai Lau. Beclin 1-mediated autophagy is potentiated by an interaction with the neuronal adaptor fe65. Biology, 14:97, Jan 2025. URL: https://doi.org/10.3390/biology14010097, doi:10.3390/biology14010097. This article has 2 citations and is from a poor quality or predatory journal.
(chan2025beclin1mediatedautophagy pages 1-2): Wai Wa Ray Chan, Jessica Chow, Dennis Dik-Long Chau, Yuqi Zhai, and Kwok-Fai Lau. Beclin 1-mediated autophagy is potentiated by an interaction with the neuronal adaptor fe65. Biology, 14:97, Jan 2025. URL: https://doi.org/10.3390/biology14010097, doi:10.3390/biology14010097. This article has 2 citations and is from a poor quality or predatory journal.
(chow2015fe65rolesbeyond pages 3-6): Wan Ning Vanessa Chow, Hei Nga Maggie Cheung, Wen Li, and Kwok-Fai Lau. Fe65: roles beyond amyloid precursor protein processing. Cellular and Molecular Biology Letters, 20:66-87, Mar 2015. URL: https://doi.org/10.1515/cmble-2015-0002, doi:10.1515/cmble-2015-0002. This article has 26 citations and is from a peer-reviewed journal.
(augustin2021fe65ascaffoldinga pages 11-13): V Augustin and S Kins. Fe65: a scaffolding protein of actin regulators. cells 2021, 10, 1599. Unknown journal, 2021.

Citations

koistinen2017nuclearlocalizationof pages 7-10
koistinen2017nuclearlocalizationof pages 11-13
https://doi.org/10.1093/jb/mvae055.
https://doi.org/10.3390/biology14010097.
https://doi.org/10.1371/journal.pone.0173888.
https://doi.org/10.1515/cmble-2015-0002.
https://doi.org/10.3390/cells10071599.
https://doi.org/10.1093/jb/mvae055
https://doi.org/10.1371/journal.pone.0173888
https://doi.org/10.3390/cells10071599
https://doi.org/10.1515/cmble-2015-0002
https://doi.org/10.3390/biology14010097
https://doi.org/10.1515/cmble-2015-0002,
https://doi.org/10.3390/cells10071599,
https://doi.org/10.1371/journal.pone.0173888,
https://doi.org/10.1093/jb/mvae055,
https://doi.org/10.3390/biology14010097,

📄 View Raw YAML

id: O00213
gene_symbol: APBB1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'APBB1 (Fe65) is a multidomain adaptor protein that functions primarily
  as a scaffold linking APP (amyloid precursor protein) to nuclear signaling pathways
  and DNA damage responses. It contains a WW domain and two PTB (phosphotyrosine-binding)
  domains. The PTB2 domain binds the APP intracellular domain (AICD), while PTB1 interacts
  with transcription factors like KAT5/TIP60. Fe65 is normally tethered to the plasma
  membrane via APP, but under cellular stress translocates to the nucleus where it
  participates in DNA damage response by binding phosphorylated H2AX (Y142) and recruiting
  pro-apoptotic factors like JNK1. Fe65 also functions as a transcription coregulator
  forming complexes with AICD and Tip60 to regulate gene expression. Additionally,
  Fe65 promotes neurite outgrowth through activation of ARF6-Rac1 signaling upon insulin
  stimulation.'
alternative_products:
  - name: '1'
    id: O00213-1
  - name: '2'
    id: O00213-2
    sequence_note: VSP_011658
  - name: '3'
    id: O00213-3
    sequence_note: VSP_045326, VSP_045327, VSP_011658
  - name: 4 (p60Fe65)
    id: O00213-4
    sequence_note: VSP_047459
  - name: '5'
    id: O00213-5
    sequence_note: VSP_045326, VSP_045327
  - name: '6'
    id: O00213-6
    sequence_note: VSP_054709
existing_annotations:
  - term:
      id: GO:0006974
      label: DNA damage response
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Fe65 plays a well-documented role in DNA damage response. Under 
        cellular stress, Fe65 is released from APP at the plasma membrane and 
        translocates to the nucleus where it accumulates in the nuclear matrix 
        (PMID:18468999). Fe65 induces gammaH2AX formation and binds specifically
        to H2AX phosphorylated on tyrosine 142 via its PTB2 domain 
        (PMID:19234442). This binding is critical for recruiting pro-apoptotic 
        factors like JNK1 to sites of DNA damage.
      action: ACCEPT
      reason: This IBA annotation is strongly supported by experimental evidence
        from multiple studies. PMID:18468999 showed Fe65 translocates to nucleus
        under stress and induces gammaH2AX formation. PMID:19234442 demonstrated
        direct binding of Fe65 PTB2 domain to phosphorylated H2AX Y142 and its 
        role in the DNA damage-apoptosis signaling axis.
      supported_by:
        - reference_id: PMID:18468999
          supporting_text: In the nucleus, FE65 induced gammaH2AX, which plays 
            an important role in DNA repair as a cellular response by 
            stress-damaged cells.
        - reference_id: PMID:19234442
          supporting_text: Fe65 protein interacted with endogenous JNK1 by 
            co-immunoprecipitation in 293T cells treated with the DNA-damage 
            agent etoposide
        - reference_id: file:human/APBB1/APBB1-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0060090
      label: molecular adaptor activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Fe65 is a canonical adaptor protein with WW and PTB domains that 
        scaffolds multiple protein interactions. It adapts APP to nuclear 
        signaling, links phosphorylated H2AX to JNK1, and connects insulin 
        signaling to ARF6-Rac1 for neurite outgrowth.
      action: ACCEPT
      reason: Molecular adaptor activity is the core molecular function of Fe65.
        The protein contains well-characterized WW and PTB domains that mediate 
        protein-protein interactions. PMID:36250347 explicitly describes Fe65 as
        a neuronal adaptor and demonstrates its adaptor function in linking 
        insulin signaling to ARF6-Rac1-mediated neurite outgrowth.
      additional_reference_ids:
        - PMID:36250347
        - PMID:19234442
      supported_by:
        - reference_id: PMID:36250347
          supporting_text: Insulin stimulates atypical protein kinase C-mediated
            phosphorylation of the neuronal adaptor FE65 to potentiate neurite 
            outgrowth by activating ARF6-Rac1 signaling.
        - reference_id: PMID:19234442
          supporting_text: Tyrosine dephosphorylation of H2AX modulates 
            apoptosis and survival decisions.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Fe65 translocates to the nucleus under stress conditions where it
        accumulates in the nuclear matrix and participates in DNA damage 
        response and transcriptional regulation.
      action: ACCEPT
      reason: Nuclear localization is well-documented for Fe65. PMID:18468999 
        demonstrated that Fe65 translocates to nucleus under osmotic stress, 
        accumulating in the nuclear matrix. PMID:19343227 showed Fe65 
        colocalizes with TSHZ3 in the nucleus and functions as a transcriptional
        repressor.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Under normal conditions, Fe65 is predominantly cytoplasmic with a
        population tethered to the membrane via APP binding.
      action: ACCEPT
      reason: Cytoplasmic localization is well-supported. PMID:18468999 showed 
        that under normal conditions Fe65 mainly localizes to the cytoplasm, 
        with a fraction tethered to the cell membrane via APP interaction.
  - term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Fe65 functions as a transcription coregulator with both 
        coactivator and corepressor activities depending on context.
      action: ACCEPT
      reason: Fe65 forms transcriptionally active complexes with the APP 
        intracellular domain (AICD) and interacts with KAT5/TIP60. PMID:19343227
        showed Fe65 associates with TSHZ3, SET, and HDAC1 to repress CASP4 
        expression. Fe65 also binds chromatin at CASP4 transcription start 
        sites. UniProt summarizes both activation and repression functions.
  - term:
      id: GO:0001540
      label: amyloid-beta binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Fe65 binds the intracellular domain of APP (the amyloid-beta 
        precursor protein) via its PTB2 domain. This is a core function 
        conserved across the Fe65 family.
      action: ACCEPT
      reason: Binding to APP is a defining characteristic of Fe65. The PTB2 
        domain specifically recognizes the YENPTY motif in the APP cytoplasmic 
        tail. Multiple structural and biochemical studies confirm this 
        interaction (PMID:8887653, PMID:18833287). Note that Fe65 binds APP 
        itself, not the cleaved amyloid-beta peptide, but this term captures the
        functional relationship to APP/amyloid biology.
  - term:
      id: GO:0001540
      label: amyloid-beta binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: Duplicate IEA annotation for amyloid-beta binding based on 
        InterPro domain mapping.
      action: ACCEPT
      reason: This IEA annotation correctly captures the APP-binding function of
        Fe65 based on InterPro domain analysis. The PTB domains in Fe65 are 
        recognized as APP-binding domains. Consistent with the IBA annotation.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: IEA annotation for nuclear localization from UniProt subcellular 
        location vocabulary.
      action: ACCEPT
      reason: Consistent with IBA and IDA annotations. Fe65 nuclear localization
        is well-documented experimentally.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: IEA annotation for cytoplasmic localization from combined 
        automated methods.
      action: ACCEPT
      reason: Consistent with IBA and IDA annotations. Cytoplasmic localization 
        is the default state for Fe65 under non-stressed conditions.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: IEA annotation for plasma membrane localization from UniProt 
        subcellular location vocabulary.
      action: ACCEPT
      reason: Consistent with IDA annotation. Fe65 is tethered to the plasma 
        membrane via its interaction with APP in normal conditions. 
        PMID:18468999 demonstrated this membrane-tethered pool.
  - term:
      id: GO:0006325
      label: chromatin organization
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: IEA annotation for chromatin organization based on UniProt 
        keyword mapping.
      action: ACCEPT
      reason: Fe65 has documented chromatin binding activity (PMID:19343227 
        shows IDA for chromatin binding) and interacts with histone modifying 
        enzymes (HDAC1, KAT5/TIP60). Fe65 binds phosphorylated H2AX at 
        chromatin. The chromatin regulator UniProt keyword is justified.
  - term:
      id: GO:0006915
      label: apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: This IEA annotation from UniProt keyword mapping is an 
        over-annotation. Fe65 does not directly execute apoptosis; rather, it 
        REGULATES apoptosis by serving as an adaptor that recruits the 
        pro-apoptotic factor JNK1 to phosphorylated H2AX at DNA damage sites.
      action: MARK_AS_OVER_ANNOTATED
      reason: Fe65 is not an executioner of apoptosis but rather a regulator. 
        The IDA annotation GO:0043065 (positive regulation of apoptotic process)
        from PMID:18468999 correctly captures Fe65's role. PMID:19234442 clearly
        demonstrates that Fe65 functions as an adaptor protein that binds 
        phosphorylated H2AX Y142 and recruits JNK1, thereby promoting the 
        apoptotic response - this is a regulatory role, not direct execution of 
        apoptosis. The parent term GO:0006915 implies direct participation in 
        the apoptotic process, which is misleading.
      proposed_replacement_terms:
        - id: GO:0043065
          label: positive regulation of apoptotic process
      additional_reference_ids:
        - PMID:18468999
        - PMID:19234442
      supported_by:
        - reference_id: PMID:18468999
          supporting_text: 2008 May 9. Regulation of FE65 nuclear translocation 
            and function by amyloid beta-protein precursor in osmotically 
            stressed cells.
        - reference_id: PMID:19234442
          supporting_text: Tyrosine dephosphorylation of H2AX modulates 
            apoptosis and survival decisions.
  - term:
      id: GO:0006974
      label: DNA damage response
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: IEA annotation for DNA damage response based on UniProt keyword 
        mapping.
      action: ACCEPT
      reason: Consistent with IBA and IDA annotations for this term. Fe65's role
        in DNA damage response is well-documented experimentally.
  - term:
      id: GO:0016607
      label: nuclear speck
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: IEA annotation for nuclear speck localization from UniProt 
        subcellular location vocabulary.
      action: ACCEPT
      reason: UniProt notes that Fe65 colocalizes with NEK6 at nuclear speckles 
        (PMID:17512906). This is a minor localization site but supported.
  - term:
      id: GO:0030426
      label: growth cone
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: IEA annotation for growth cone localization from UniProt 
        subcellular location vocabulary.
      action: ACCEPT
      reason: Consistent with IDA annotation from PMID:12843239 which showed 
        Fe65 localizes to growth cones in neurons.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16049941
    review:
      summary: Non-informative protein binding annotation from APP interactome 
        study.
      action: REMOVE
      reason: Protein binding is too generic to be informative. Fe65's specific 
        binding activities are better captured by more specific MF terms like 
        molecular adaptor activity, amyloid-beta binding, histone binding, and 
        chromatin binding.
      supported_by:
        - reference_id: PMID:16049941
          supporting_text: A pilot proteomic study of amyloid precursor 
            interactors in Alzheimer's disease.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16273093
    review:
      summary: Non-informative protein binding annotation from ErbB receptor 
        interactome study (binds EGFR, ERBB2).
      action: REMOVE
      reason: Protein binding is too generic. The interaction with ErbB 
        receptors is not a core function of Fe65 and is better captured by more 
        specific terms if relevant.
      supported_by:
        - reference_id: PMID:16273093
          supporting_text: A quantitative protein interaction network for the 
            ErbB receptors using protein microarrays.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21968187
    review:
      summary: Non-informative protein binding annotation showing interaction 
        with LRP1 and APP isoform 4.
      action: REMOVE
      reason: Protein binding is too generic. LRP1 binding is captured by the 
        low-density lipoprotein particle receptor binding term.
      supported_by:
        - reference_id: PMID:21968187
          supporting_text: Epub 2011 Sep 29. Phosphorylation of LRP1 regulates 
            the interaction with Fe65.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24056087
    review:
      summary: Non-informative protein binding annotation showing interaction 
        with ARF6.
      action: REMOVE
      reason: Protein binding is too generic. The ARF6 interaction is 
        functionally important for neurite outgrowth (PMID:36250347) but 
        molecular adaptor activity better captures this scaffolding function.
      supported_by:
        - reference_id: PMID:24056087
          supporting_text: FE65 interacts with ADP-ribosylation factor 6 to 
            promote neurite outgrowth.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24284412
    review:
      summary: Non-informative protein binding annotation from Fe65 
        interactomics study identifying SV2A and SERCA2 as interactors.
      action: REMOVE
      reason: Protein binding is too generic to be informative for annotation 
        purposes.
      supported_by:
        - reference_id: PMID:24284412
          supporting_text: 2013 Nov 27. Amyloid beta a4 precursor 
            protein-binding family B member 1 (FE65) interactomics revealed 
            synaptic vesicle glycoprotein 2A (SV2A) and sarcoplasmic/endoplasmic
            reticulum calcium ATPase 2 (SERCA2) as new binding proteins in the 
            human brain.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26045787
    review:
      summary: Non-informative protein binding annotation from APP interaction 
        screen.
      action: REMOVE
      reason: Protein binding is too generic. Fe65-APP interaction is captured 
        by amyloid-beta binding term.
      supported_by:
        - reference_id: PMID:26045787
          supporting_text: Screening of APP interaction proteins by DUALmembrane
            yeast two-hybrid system.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:30664241
    review:
      summary: Non-informative protein binding annotation from quantitative APP 
        isoform interactome study.
      action: REMOVE
      reason: Protein binding is too generic. The APP interaction is captured by
        amyloid-beta binding.
      supported_by:
        - reference_id: PMID:30664241
          supporting_text: Quantitative interaction proteomics reveals 
            differences in the interactomes of amyloid precursor protein 
            isoforms.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31413325
    review:
      summary: Non-informative protein binding annotation from Alzheimer's 
        disease network dataset.
      action: REMOVE
      reason: Protein binding is too generic to be informative.
      supported_by:
        - reference_id: PMID:31413325
          supporting_text: HENA, heterogeneous network-based data set for 
            Alzheimer's disease.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: Non-informative protein binding annotation from dual 
        proteome-scale interactome study showing APP and APLP2 interactions.
      action: REMOVE
      reason: Protein binding is too generic. APP/APLP2 interactions captured by
        amyloid-beta binding.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: 2021 May 6. Dual proteome-scale networks reveal 
            cell-specific remodeling of the human interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35914814
    review:
      summary: Non-informative protein binding annotation from chromosome 21 
        protein interaction study.
      action: REMOVE
      reason: Protein binding is too generic to be informative.
      supported_by:
        - reference_id: PMID:35914814
          supporting_text: "Chr21 protein-protein interactions: enrichment in proteins
            involved in intellectual disability, autism, and late-onset Alzheimer's
            disease."
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:8887653
    review:
      summary: Non-informative protein binding annotation showing Fe65 PTB 
        domain binds APP YENPTY motif.
      action: REMOVE
      reason: Protein binding is too generic. This specific interaction is 
        better captured by amyloid-beta binding term which describes Fe65's 
        binding to APP.
      supported_by:
        - reference_id: PMID:8887653
          supporting_text: The phosphotyrosine interaction domains of X11 and 
            FE65 bind to distinct sites on the YENPTY motif of amyloid precursor
            protein.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9461550
    review:
      summary: Non-informative protein binding annotation showing Fe65L2 family 
        member interactions with APP and APLP2.
      action: REMOVE
      reason: Protein binding is too generic. APP family interactions are 
        captured by amyloid-beta binding.
      supported_by:
        - reference_id: PMID:9461550
          supporting_text: "Fe65L2: a new member of the Fe65 protein family interacting
            with the intracellular domain of the Alzheimer's beta-amyloid precursor
            protein."
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: Plasma membrane localization from HPA immunofluorescence 
        curation.
      action: ACCEPT
      reason: Consistent with other annotations. Fe65 is tethered to plasma 
        membrane via APP binding under normal conditions.
  - term:
      id: GO:0010976
      label: positive regulation of neuron projection development
    evidence_type: IDA
    original_reference_id: PMID:36250347
    review:
      summary: Fe65 promotes neurite outgrowth through PKC-mediated 
        phosphorylation that activates ARF6-Rac1 signaling upon insulin 
        stimulation.
      action: ACCEPT
      reason: PMID:36250347 demonstrated that Fe65 potentiates neurite outgrowth
        by activating the ARF6-Rac1 axis. PKC phosphorylates Fe65 at S459, 
        enhancing the Fe65-ARF6 interaction. This is a legitimate developmental 
        function of Fe65 in neurons.
      supported_by:
        - reference_id: PMID:36250347
          supporting_text: Insulin stimulates atypical protein kinase C-mediated
            phosphorylation of the neuronal adaptor FE65 to potentiate neurite 
            outgrowth by activating ARF6-Rac1 signaling.
  - term:
      id: GO:0060090
      label: molecular adaptor activity
    evidence_type: IDA
    original_reference_id: PMID:36250347
    review:
      summary: Direct experimental evidence for Fe65 molecular adaptor activity 
        in linking insulin signaling to ARF6-Rac1-mediated neurite outgrowth.
      action: ACCEPT
      reason: PMID:36250347 explicitly identifies Fe65 as a neuronal adaptor and
        demonstrates its scaffolding function between PKC-mediated 
        phosphorylation and ARF6-Rac1 activation. This is a core molecular 
        function.
      supported_by:
        - reference_id: PMID:36250347
          supporting_text: Insulin stimulates atypical protein kinase C-mediated
            phosphorylation of the neuronal adaptor FE65 to potentiate neurite 
            outgrowth by activating ARF6-Rac1 signaling.
  - term:
      id: GO:0006939
      label: smooth muscle contraction
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ISS annotation transferred from mouse ortholog. Fe65 may play a 
        role in muscle function through maintenance of neuromuscular junction.
      action: KEEP_AS_NON_CORE
      reason: This annotation is based on sequence similarity to mouse Fe65. 
        UniProt notes Fe65 may play a role in muscle cell strength. However, 
        this is not a core function of Fe65 and is peripheral to its main roles 
        as adaptor and transcription coregulator.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ISS annotation for nuclear localization transferred from rat 
        ortholog.
      action: ACCEPT
      reason: Consistent with multiple other annotations (IBA, IDA, IEA) for 
        nuclear localization.
  - term:
      id: GO:1902807
      label: negative regulation of cell cycle G1/S phase transition
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ISS annotation transferred from rat ortholog for cell cycle 
        regulation.
      action: KEEP_AS_NON_CORE
      reason: This annotation is based on sequence similarity to rat Fe65. While
        Fe65 may participate in cell cycle regulation through its interactions 
        with transcription factors, this is not a well-established core function
        and requires further experimental validation in human cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18468999
    review:
      summary: Non-informative protein binding annotation showing Fe65-APP 
        interaction.
      action: REMOVE
      reason: Protein binding is too generic. The Fe65-APP interaction is 
        captured by amyloid-beta binding term.
      supported_by:
        - reference_id: PMID:18468999
          supporting_text: 2008 May 9. Regulation of FE65 nuclear translocation 
            and function by amyloid beta-protein precursor in osmotically 
            stressed cells.
  - term:
      id: GO:0003713
      label: transcription coactivator activity
    evidence_type: TAS
    original_reference_id: PMID:12153398
    review:
      summary: Fe65 functions as a transcription coactivator when in complex 
        with APP intracellular domain and KAT5/TIP60.
      action: ACCEPT
      reason: Fe65 is well-documented as a transcription coregulator. It forms 
        transcriptionally active complexes with the gamma-secretase-derived APP 
        intracellular domain (AICD). UniProt explicitly describes coactivator 
        function. Note that Fe65 also has corepressor activity in other 
        contexts.
      supported_by:
        - reference_id: PMID:12153398
          supporting_text: Characterization of an amyloid precursor 
            protein-binding protein Fe65L2 and its novel isoforms lacking 
            phosphotyrosine-interaction domains.
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: TAS
    original_reference_id: PMID:12153398
    review:
      summary: Fe65 positively regulates transcription through its coactivator 
        function with AICD complex.
      action: ACCEPT
      reason: Consistent with Fe65's documented transcription coactivator 
        activity. The AICD-Fe65 complex activates transcription of target genes.
      supported_by:
        - reference_id: PMID:12153398
          supporting_text: Characterization of an amyloid precursor 
            protein-binding protein Fe65L2 and its novel isoforms lacking 
            phosphotyrosine-interaction domains.
  - term:
      id: GO:0050714
      label: positive regulation of protein secretion
    evidence_type: TAS
    original_reference_id: PMID:12153398
    review:
      summary: Fe65 regulates secretion of beta-amyloid peptides (Abeta40, 
        Abeta42) through its interaction with APP.
      action: KEEP_AS_NON_CORE
      reason: PMID:12153398 showed Fe65L2 overexpression increased Abeta40 and 
        Abeta42 secretion. While this is an experimentally supported effect, it 
        is downstream of Fe65's core adaptor function in APP processing rather 
        than a direct secretory function.
      supported_by:
        - reference_id: PMID:12153398
          supporting_text: Characterization of an amyloid precursor 
            protein-binding protein Fe65L2 and its novel isoforms lacking 
            phosphotyrosine-interaction domains.
  - term:
      id: GO:0050750
      label: low-density lipoprotein particle receptor binding
    evidence_type: TAS
    original_reference_id: PMID:12153398
    review:
      summary: Fe65 binds LRP1 (LDL receptor-related protein 1) via its PTB 
        domains.
      action: ACCEPT
      reason: Fe65 interacts with LRP1 as documented in UniProt (PMID:21968187).
        The PTB domains of Fe65 can bind multiple receptors including APP and 
        LRP1. This is a documented binding activity.
      supported_by:
        - reference_id: PMID:12153398
          supporting_text: Characterization of an amyloid precursor 
            protein-binding protein Fe65L2 and its novel isoforms lacking 
            phosphotyrosine-interaction domains.
  - term:
      id: GO:0031625
      label: ubiquitin protein ligase binding
    evidence_type: IPI
    original_reference_id: PMID:25342469
    review:
      summary: Fe65 interacts with the E3 ubiquitin ligase RNF157 and is a 
        substrate for ubiquitination.
      action: ACCEPT
      reason: PMID:25342469 demonstrated that Fe65 interacts with RNF157 and is 
        polyubiquitinated by RNF157, leading to proteasomal degradation. This 
        regulates Fe65 levels and neuronal survival.
      supported_by:
        - reference_id: PMID:25342469
          supporting_text: Oct 24. Regulation of neuronal survival and 
            morphology by the E3 ubiquitin ligase RNF157.
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IGI
    original_reference_id: PMID:21803450
    review:
      summary: Fe65 functions as a transcriptional corepressor in complex with 
        AICD to negatively regulate transcription.
      action: ACCEPT
      reason: Fe65 has documented corepressor as well as coactivator functions. 
        PMID:19343227 showed Fe65 associates with TSHZ3, SET, and HDAC1 to 
        repress CASP4 expression. This annotation captures the corepressor 
        function.
      supported_by:
        - reference_id: PMID:21803450
          supporting_text: The APP intracellular domain (AICD) potentiates ER 
            stress-induced apoptosis.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5683986
    review:
      summary: Reactome annotation for nucleoplasm localization in the context 
        of H2AX binding pathway.
      action: ACCEPT
      reason: Fe65 localizes to the nucleoplasm where it binds phosphorylated 
        H2AX. The Reactome pathway R-HSA-5683986 describes the APBB1 and MAPK8 
        binding to diphosphorylated H2AFX.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12972431
    review:
      summary: Non-informative protein binding annotation showing Fe65 
        interaction with Alcadein proteins.
      action: REMOVE
      reason: Protein binding is too generic. The Alcadein interaction relates 
        to APP metabolism but is captured by molecular adaptor activity.
      supported_by:
        - reference_id: PMID:12972431
          supporting_text: 2003 Sep 12. Novel cadherin-related membrane 
            proteins, Alcadeins, enhance the X11-like protein-mediated 
            stabilization of amyloid beta-protein precursor metabolism.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17332754
    review:
      summary: Non-informative protein binding annotation showing Fe65 
        interaction with Alcadein in kinesin transport.
      action: REMOVE
      reason: Protein binding is too generic.
      supported_by:
        - reference_id: PMID:17332754
          supporting_text: Mar 1. The novel cargo Alcadein induces vesicle 
            association of kinesin-1 motor components and activates axonal 
            transport.
  - term:
      id: GO:0003682
      label: chromatin binding
    evidence_type: IDA
    original_reference_id: PMID:19343227
    review:
      summary: Fe65 binds chromatin at the CASP4 transcription start site region
        as part of its transcriptional repressor function.
      action: ACCEPT
      reason: PMID:19343227 demonstrated Fe65 associates with chromatin in a 
        region surrounding the CASP4 transcriptional start site(s). This is 
        direct experimental evidence for chromatin binding activity.
      supported_by:
        - reference_id: PMID:19343227
          supporting_text: FE65 binds Teashirt, inhibiting expression of the 
            primate-specific caspase-4.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19343227
    review:
      summary: Non-informative protein binding annotation showing Fe65 
        interaction with SET and TSHZ3.
      action: REMOVE
      reason: Protein binding is too generic. The TSHZ3 and SET interactions are
        functionally relevant for transcriptional repression but molecular 
        adaptor activity captures this scaffolding function.
      supported_by:
        - reference_id: PMID:19343227
          supporting_text: FE65 binds Teashirt, inhibiting expression of the 
            primate-specific caspase-4.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:19343227
    review:
      summary: Direct experimental evidence for Fe65 nuclear localization where 
        it colocalizes with TSHZ3 and functions in transcriptional repression.
      action: ACCEPT
      reason: PMID:19343227 showed Fe65 colocalizes with TSHZ3 in the nucleus. 
        This IDA annotation provides direct experimental support for nuclear 
        localization.
      supported_by:
        - reference_id: PMID:19343227
          supporting_text: FE65 binds Teashirt, inhibiting expression of the 
            primate-specific caspase-4.
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:19343227
    review:
      summary: Fe65 positively regulates transcription in certain contexts while
        repressing it in others (e.g., CASP4).
      action: ACCEPT
      reason: Fe65 has documented dual transcriptional regulatory activities. 
        PMID:19343227 showed both positive and negative regulatory functions. 
        This annotation captures the coactivator function.
      supported_by:
        - reference_id: PMID:19343227
          supporting_text: FE65 binds Teashirt, inhibiting expression of the 
            primate-specific caspase-4.
  - term:
      id: GO:0070064
      label: proline-rich region binding
    evidence_type: IPI
    original_reference_id: PMID:17686488
    review:
      summary: The Fe65 WW domain binds proline-rich regions of interaction 
        partners including ENAH.
      action: ACCEPT
      reason: PMID:17686488 determined the structural basis for Fe65 WW domain 
        recognition of polyproline sequences. X-ray crystallography showed Fe65 
        WW domain in complex with ENAH proline-rich peptide. This is a 
        well-characterized binding activity.
      supported_by:
        - reference_id: PMID:17686488
          supporting_text: 2007 Jun 29. Structural basis for polyproline 
            recognition by the FE65 WW domain.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19234442
    review:
      summary: Non-informative protein binding annotation from Nature paper on 
        H2AX-mediated apoptosis decisions, showing Fe65-JNK1 interaction.
      action: REMOVE
      reason: Protein binding is too generic. The functionally important 
        Fe65-JNK1 interaction is captured by the positive regulation of 
        apoptotic process annotation.
      supported_by:
        - reference_id: PMID:19234442
          supporting_text: Tyrosine dephosphorylation of H2AX modulates 
            apoptosis and survival decisions.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:18468999
    review:
      summary: Direct experimental evidence for Fe65 nuclear translocation under
        osmotic stress conditions.
      action: ACCEPT
      reason: PMID:18468999 showed liberated Fe65 translocates into the nucleus 
        and accumulates in the nuclear matrix forming a patched structure. Key 
        experimental evidence for stress-induced nuclear localization.
      supported_by:
        - reference_id: PMID:18468999
          supporting_text: 2008 May 9. Regulation of FE65 nuclear translocation 
            and function by amyloid beta-protein precursor in osmotically 
            stressed cells.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:18468999
    review:
      summary: Direct experimental evidence for Fe65 cytoplasmic localization 
        under normal conditions.
      action: ACCEPT
      reason: PMID:18468999 demonstrated that under normal conditions Fe65 
        mainly localizes to the cytoplasm, with a small fraction tethered to the
        membrane via APP.
      supported_by:
        - reference_id: PMID:18468999
          supporting_text: 2008 May 9. Regulation of FE65 nuclear translocation 
            and function by amyloid beta-protein precursor in osmotically 
            stressed cells.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:18468999
    review:
      summary: Direct experimental evidence for Fe65 plasma membrane 
        localization through APP tethering.
      action: ACCEPT
      reason: PMID:18468999 showed a fixed population of cytoplasmic Fe65 is 
        tethered to membranes by binding APP. This membrane-tethered Fe65 is 
        liberated from membranes by APP phosphorylation under stress.
      supported_by:
        - reference_id: PMID:18468999
          supporting_text: 2008 May 9. Regulation of FE65 nuclear translocation 
            and function by amyloid beta-protein precursor in osmotically 
            stressed cells.
  - term:
      id: GO:0006974
      label: DNA damage response
    evidence_type: IDA
    original_reference_id: PMID:18468999
    review:
      summary: Direct experimental evidence for Fe65 role in DNA damage response
        through nuclear translocation and gammaH2AX induction.
      action: ACCEPT
      reason: PMID:18468999 showed Fe65 translocates to nucleus under stress and
        induces gammaH2AX formation. This is a core function of Fe65 with strong
        experimental support.
      supported_by:
        - reference_id: PMID:18468999
          supporting_text: In the nucleus, FE65 induced gammaH2AX, which plays 
            an important role in DNA repair as a cellular response by 
            stress-damaged cells.
  - term:
      id: GO:0042393
      label: histone binding
    evidence_type: IPI
    original_reference_id: PMID:19234442
    review:
      summary: Fe65 binds phosphorylated histone H2AX (Y142) via its PTB2 
        domain.
      action: ACCEPT
      reason: PMID:19234442 demonstrated Fe65 binds specifically to H2AX 
        phosphorylated on Y142. GST pull-down assays showed direct interaction 
        between Fe65 PTB2 domain and H2AX. This is a key molecular function in 
        the DNA damage-apoptosis signaling axis.
      supported_by:
        - reference_id: PMID:19234442
          supporting_text: GST pull-down assays using purified recombinant 
            protein of Fe65 PTB domains 1 and 2 also revealed a direct 
            interaction between PTB2 and the H2AX present in purified HeLa 
            histones
  - term:
      id: GO:0043065
      label: positive regulation of apoptotic process
    evidence_type: IDA
    original_reference_id: PMID:18468999
    review:
      summary: Fe65 positively regulates apoptosis by acting as an adaptor that 
        recruits pro-apoptotic factor JNK1 to phosphorylated H2AX at DNA damage 
        sites.
      action: ACCEPT
      reason: This is the CORRECT annotation for Fe65's role in apoptosis - it 
        REGULATES apoptosis rather than directly executing it. PMID:18468999 
        showed FE65 deregulated from APP induces apoptosis. PMID:19234442 
        demonstrated the mechanism - Fe65 binds phosphorylated H2AX Y142 and 
        recruits JNK1, promoting apoptotic response. This is the appropriate 
        term (not GO:0006915 apoptotic process).
      supported_by:
        - reference_id: PMID:18468999
          supporting_text: FE65 deregulated from APP induces apoptosis
        - reference_id: PMID:19234442
          supporting_text: knockdown of Fe65 strongly inhibited this interaction
  - term:
      id: GO:0007165
      label: signal transduction
    evidence_type: NAS
    original_reference_id: PMID:8894693
    review:
      summary: Very broad annotation for signal transduction based on early Fe65
        characterization.
      action: KEEP_AS_NON_CORE
      reason: Fe65 participates in signal transduction through its adaptor 
        function (APP signaling, insulin signaling to ARF6-Rac1). However, this 
        term is too broad to be informative. More specific BP terms (DNA damage 
        response, positive regulation of apoptotic process, positive regulation 
        of neuron projection development) better capture Fe65's signaling roles.
      supported_by:
        - reference_id: PMID:8894693
          supporting_text: 'cDNA cloning and chromosome mapping of the human Fe65
            gene: interaction of the conserved cytoplasmic domains of the human beta-amyloid
            precursor protein and its homologues with the mouse Fe65 protein.'
  - term:
      id: GO:0007409
      label: axonogenesis
    evidence_type: NAS
    original_reference_id: PMID:12843239
    review:
      summary: NAS annotation for axonogenesis based on Fe65 localization in 
        growth cones.
      action: KEEP_AS_NON_CORE
      reason: PMID:12843239 showed Fe65 localizes to growth cones and 
        lamellipodia, suggesting a role in neurite growth. However, the evidence
        is based on localization rather than direct functional demonstration. 
        The more specific GO:0010976 (positive regulation of neuron projection 
        development) with IDA evidence better captures Fe65's neurite outgrowth 
        function.
      supported_by:
        - reference_id: PMID:12843239
          supporting_text: The amyloid precursor protein and its regulatory 
            protein, FE65, in growth cones and synapses in vitro and in vivo.
  - term:
      id: GO:0030027
      label: lamellipodium
    evidence_type: IDA
    original_reference_id: PMID:12843239
    review:
      summary: Fe65 localizes to lamellipodia in neuronal growth cones.
      action: ACCEPT
      reason: PMID:12843239 demonstrated Fe65 concentrates in actin-rich 
        lamellipodia within growth cones. This is consistent with its role in 
        actin-based membrane motility and neurite extension.
      supported_by:
        - reference_id: PMID:12843239
          supporting_text: The amyloid precursor protein and its regulatory 
            protein, FE65, in growth cones and synapses in vitro and in vivo.
  - term:
      id: GO:0030426
      label: growth cone
    evidence_type: IDA
    original_reference_id: PMID:12843239
    review:
      summary: Direct experimental evidence for Fe65 localization to neuronal 
        growth cones.
      action: ACCEPT
      reason: PMID:12843239 showed Fe65 and APP localize to growth cones both in
        vitro and in vivo. This is direct experimental evidence supporting 
        growth cone localization.
      supported_by:
        - reference_id: PMID:12843239
          supporting_text: The amyloid precursor protein and its regulatory 
            protein, FE65, in growth cones and synapses in vitro and in vivo.
  - term:
      id: GO:0045202
      label: synapse
    evidence_type: IDA
    original_reference_id: PMID:12843239
    review:
      summary: Fe65 localizes to synapses where it associates with APP and 
        Rab5-containing organelles.
      action: ACCEPT
      reason: PMID:12843239 demonstrated Fe65 and APP interact in nerve 
        terminals and associate with Rab5-containing synaptic organelles. This 
        synaptic localization supports Fe65's potential role in synapse 
        modification.
      supported_by:
        - reference_id: PMID:12843239
          supporting_text: The amyloid precursor protein and its regulatory 
            protein, FE65, in growth cones and synapses in vitro and in vivo.
core_functions:
  - molecular_function:
      id: GO:0060090
      label: molecular adaptor activity
    description: Fe65 is a canonical adaptor protein with WW and PTB domains 
      that scaffolds multiple protein interactions. It links APP to nuclear 
      signaling, phosphorylated H2AX to JNK1, and insulin signaling to ARF6-Rac1
      for neurite outgrowth. IBA and IDA evidence (PMID:36250347).
    directly_involved_in:
      - id: GO:0006974
        label: DNA damage response
      - id: GO:0043065
        label: positive regulation of apoptotic process
      - id: GO:0010976
        label: positive regulation of neuron projection development
    locations:
      - id: GO:0005634
        label: nucleus
      - id: GO:0005737
        label: cytoplasm
      - id: GO:0005886
        label: plasma membrane
  - molecular_function:
      id: GO:0001540
      label: amyloid-beta binding
    description: Fe65 binds the intracellular domain of APP via its PTB2 domain.
      This interaction is central to Fe65's biology, tethering it to the 
      membrane under normal conditions and releasing it under stress. IBA 
      evidence supported by multiple structural studies.
    locations:
      - id: GO:0005886
        label: plasma membrane
  - molecular_function:
      id: GO:0003713
      label: transcription coactivator activity
    description: Fe65 functions as a transcription coregulator forming complexes
      with AICD and Tip60 for activation. It also has corepressor activity with 
      TSHZ3, SET, and HDAC1 for repression of targets like CASP4. IBA and TAS 
      evidence (PMID:12153398, PMID:19343227).
    directly_involved_in:
      - id: GO:0006355
        label: regulation of DNA-templated transcription
    locations:
      - id: GO:0005634
        label: nucleus
  - molecular_function:
      id: GO:0042393
      label: histone binding
    description: Fe65 binds phosphorylated histone H2AX (Y142) via its PTB2 
      domain. This binding mediates DNA damage-induced apoptosis by recruiting 
      JNK1. IPI evidence (PMID:19234442).
    directly_involved_in:
      - id: GO:0043065
        label: positive regulation of apoptotic process
    locations:
      - id: GO:0005654
        label: nucleoplasm
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data 
      to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping, accompanied by conservative changes to GO 
      terms applied by UniProt
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:12153398
    title: Characterization of an amyloid precursor protein-binding protein 
      Fe65L2 and its novel isoforms lacking phosphotyrosine-interaction domains.
    findings: []
  - id: PMID:12843239
    title: The amyloid precursor protein and its regulatory protein, FE65, in 
      growth cones and synapses in vitro and in vivo.
    findings: []
  - id: PMID:12972431
    title: Novel cadherin-related membrane proteins, Alcadeins, enhance the 
      X11-like protein-mediated stabilization of amyloid beta-protein precursor 
      metabolism.
    findings: []
  - id: PMID:16049941
    title: A pilot proteomic study of amyloid precursor interactors in 
      Alzheimer's disease.
    findings: []
  - id: PMID:16273093
    title: A quantitative protein interaction network for the ErbB receptors 
      using protein microarrays.
    findings: []
  - id: PMID:17332754
    title: The novel cargo Alcadein induces vesicle association of kinesin-1 
      motor components and activates axonal transport.
    findings: []
  - id: PMID:17686488
    title: Structural basis for polyproline recognition by the FE65 WW domain.
    findings: []
  - id: PMID:18468999
    title: Regulation of FE65 nuclear translocation and function by amyloid 
      beta-protein precursor in osmotically stressed cells.
    findings: []
  - id: PMID:19234442
    title: Tyrosine dephosphorylation of H2AX modulates apoptosis and survival 
      decisions.
    findings: []
  - id: PMID:19343227
    title: FE65 binds Teashirt, inhibiting expression of the primate-specific 
      caspase-4.
    findings: []
  - id: PMID:21803450
    title: The APP intracellular domain (AICD) potentiates ER stress-induced 
      apoptosis.
    findings: []
  - id: PMID:21968187
    title: Phosphorylation of LRP1 regulates the interaction with Fe65.
    findings: []
  - id: PMID:24056087
    title: FE65 interacts with ADP-ribosylation factor 6 to promote neurite 
      outgrowth.
    findings: []
  - id: PMID:24284412
    title: Amyloid beta a4 precursor protein-binding family B member 1 (FE65) 
      interactomics revealed synaptic vesicle glycoprotein 2A (SV2A) and 
      sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) as new 
      binding proteins in the human brain.
    findings: []
  - id: PMID:25342469
    title: Regulation of neuronal survival and morphology by the E3 ubiquitin 
      ligase RNF157.
    findings: []
  - id: PMID:26045787
    title: Screening of APP interaction proteins by DUALmembrane yeast 
      two-hybrid system.
    findings: []
  - id: PMID:30664241
    title: Quantitative interaction proteomics reveals differences in the 
      interactomes of amyloid precursor protein isoforms.
    findings: []
  - id: PMID:31413325
    title: HENA, heterogeneous network-based data set for Alzheimer's disease.
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the 
      human interactome.
    findings: []
  - id: PMID:35914814
    title: 'Chr21 protein-protein interactions: enrichment in proteins involved in
      intellectual disability, autism, and late-onset Alzheimer''s disease.'
    findings: []
  - id: PMID:36250347
    title: Insulin stimulates atypical protein kinase C-mediated phosphorylation
      of the neuronal adaptor FE65 to potentiate neurite outgrowth by activating
      ARF6-Rac1 signaling.
    findings: []
  - id: PMID:8887653
    title: The phosphotyrosine interaction domains of X11 and FE65 bind to 
      distinct sites on the YENPTY motif of amyloid precursor protein.
    findings: []
  - id: PMID:8894693
    title: 'cDNA cloning and chromosome mapping of the human Fe65 gene: interaction
      of the conserved cytoplasmic domains of the human beta-amyloid precursor protein
      and its homologues with the mouse Fe65 protein.'
    findings: []
  - id: PMID:9461550
    title: 'Fe65L2: a new member of the Fe65 protein family interacting with the intracellular
      domain of the Alzheimer''s beta-amyloid precursor protein.'
    findings: []
  - id: Reactome:R-HSA-5683986
    title: APBB1 and MAPK8 bind diphosphorylated H2AFX
    findings: []
  - id: file:human/APBB1/APBB1-deep-research-falcon.md
    title: Deep research report on APBB1
    findings: []

APBB1

Gene Description

Existing Annotations Review

Core Functions

Fe65 is a canonical adaptor protein with WW and PTB domains that scaffolds multiple protein interactions. It links APP to nuclear signaling, phosphorylated H2AX to JNK1, and insulin signaling to ARF6-Rac1 for neurite outgrowth. IBA and IDA evidence (PMID:36250347).

Fe65 binds the intracellular domain of APP via its PTB2 domain. This interaction is central to Fe65's biology, tethering it to the membrane under normal conditions and releasing it under stress. IBA evidence supported by multiple structural studies.

Fe65 functions as a transcription coregulator forming complexes with AICD and Tip60 for activation. It also has corepressor activity with TSHZ3, SET, and HDAC1 for repression of targets like CASP4. IBA and TAS evidence (PMID:12153398, PMID:19343227).

Fe65 binds phosphorylated histone H2AX (Y142) via its PTB2 domain. This binding mediates DNA damage-induced apoptosis by recruiting JNK1. IPI evidence (PMID:19234442).

References

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

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