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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006974 DNA damage response | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:18468999 In the nucleus, FE65 induced gammaH2AX, which plays an important role in DNA repair as a cellular response by stress-damaged cells. PMID:19234442 Fe65 protein interacted with endogenous JNK1 by co-immunoprecipitation in 293T cells treated with the DNA-damage agent etoposide file:human/APBB1/APBB1-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0060090 molecular adaptor activity | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: 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:19234442 Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | 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. 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. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Under normal conditions, Fe65 is predominantly cytoplasmic with a population tethered to the membrane via APP binding. 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. |
| GO:0006355 regulation of DNA-templated transcription | IBA GO_REF:0000033 | ACCEPT | Summary: Fe65 functions as a transcription coregulator with both coactivator and corepressor activities depending on context. 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. |
| GO:0001540 amyloid-beta binding | IBA GO_REF:0000033 | ACCEPT | 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. 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. |
| GO:0001540 amyloid-beta binding | IEA GO_REF:0000002 | ACCEPT | Summary: Duplicate IEA annotation for amyloid-beta binding based on InterPro domain mapping. 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. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation for nuclear localization from UniProt subcellular location vocabulary. Reason: Consistent with IBA and IDA annotations. Fe65 nuclear localization is well-documented experimentally. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for cytoplasmic localization from combined automated methods. Reason: Consistent with IBA and IDA annotations. Cytoplasmic localization is the default state for Fe65 under non-stressed conditions. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation for plasma membrane localization from UniProt subcellular location vocabulary. 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. |
| GO:0006325 chromatin organization | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation for chromatin organization based on UniProt keyword mapping. 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. |
| GO:0006915 apoptotic process | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | 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. 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 replacements: positive regulation of apoptotic process Supporting Evidence: PMID:18468999 2008 May 9. 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. |
| GO:0006974 DNA damage response | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation for DNA damage response based on UniProt keyword mapping. Reason: Consistent with IBA and IDA annotations for this term. Fe65's role in DNA damage response is well-documented experimentally. |
| GO:0016607 nuclear speck | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation for nuclear speck localization from UniProt subcellular location vocabulary. Reason: UniProt notes that Fe65 colocalizes with NEK6 at nuclear speckles (PMID:17512906). This is a minor localization site but supported. |
| GO:0030426 growth cone | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation for growth cone localization from UniProt subcellular location vocabulary. Reason: Consistent with IDA annotation from PMID:12843239 which showed Fe65 localizes to growth cones in neurons. |
| GO:0005515 protein binding | IPI PMID:16049941 A pilot proteomic study of amyloid precursor interactors in ... | REMOVE | Summary: Non-informative protein binding annotation from APP interactome study. 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. Supporting Evidence: PMID:16049941 A pilot proteomic study of amyloid precursor interactors in Alzheimer's disease. |
| GO:0005515 protein binding | IPI PMID:16273093 A quantitative protein interaction network for the ErbB rece... | REMOVE | Summary: Non-informative protein binding annotation from ErbB receptor interactome study (binds EGFR, ERBB2). 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. Supporting Evidence: PMID:16273093 A quantitative protein interaction network for the ErbB receptors using protein microarrays. |
| GO:0005515 protein binding | IPI PMID:21968187 Phosphorylation of LRP1 regulates the interaction with Fe65. | REMOVE | Summary: Non-informative protein binding annotation showing interaction with LRP1 and APP isoform 4. Reason: Protein binding is too generic. LRP1 binding is captured by the low-density lipoprotein particle receptor binding term. Supporting Evidence: PMID:21968187 Epub 2011 Sep 29. Phosphorylation of LRP1 regulates the interaction with Fe65. |
| GO:0005515 protein binding | IPI PMID:24056087 FE65 interacts with ADP-ribosylation factor 6 to promote neu... | REMOVE | Summary: Non-informative protein binding annotation showing interaction with ARF6. 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. Supporting Evidence: PMID:24056087 FE65 interacts with ADP-ribosylation factor 6 to promote neurite outgrowth. |
| GO:0005515 protein binding | IPI PMID:24284412 Amyloid beta a4 precursor protein-binding family B member 1 ... | REMOVE | Summary: Non-informative protein binding annotation from Fe65 interactomics study identifying SV2A and SERCA2 as interactors. Reason: Protein binding is too generic to be informative for annotation purposes. Supporting Evidence: PMID:24284412 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. |
| GO:0005515 protein binding | IPI PMID:26045787 Screening of APP interaction proteins by DUALmembrane yeast ... | REMOVE | Summary: Non-informative protein binding annotation from APP interaction screen. Reason: Protein binding is too generic. Fe65-APP interaction is captured by amyloid-beta binding term. Supporting Evidence: PMID:26045787 Screening of APP interaction proteins by DUALmembrane yeast two-hybrid system. |
| GO:0005515 protein binding | IPI PMID:30664241 Quantitative interaction proteomics reveals differences in t... | REMOVE | Summary: Non-informative protein binding annotation from quantitative APP isoform interactome study. Reason: Protein binding is too generic. The APP interaction is captured by amyloid-beta binding. Supporting Evidence: PMID:30664241 Quantitative interaction proteomics reveals differences in the interactomes of amyloid precursor protein isoforms. |
| GO:0005515 protein binding | IPI PMID:31413325 HENA, heterogeneous network-based data set for Alzheimer's d... | REMOVE | Summary: Non-informative protein binding annotation from Alzheimer's disease network dataset. Reason: Protein binding is too generic to be informative. Supporting Evidence: PMID:31413325 HENA, heterogeneous network-based data set for Alzheimer's disease. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Non-informative protein binding annotation from dual proteome-scale interactome study showing APP and APLP2 interactions. Reason: Protein binding is too generic. APP/APLP2 interactions captured by amyloid-beta binding. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0005515 protein binding | IPI PMID:35914814 Chr21 protein-protein interactions: enrichment in proteins i... | REMOVE | Summary: Non-informative protein binding annotation from chromosome 21 protein interaction study. Reason: Protein binding is too generic to be informative. Supporting Evidence: PMID:35914814 Chr21 protein-protein interactions: enrichment in proteins involved in intellectual disability, autism, and late-onset Alzheimer's disease. |
| GO:0005515 protein binding | IPI PMID:8887653 The phosphotyrosine interaction domains of X11 and FE65 bind... | REMOVE | Summary: Non-informative protein binding annotation showing Fe65 PTB domain binds APP YENPTY motif. Reason: Protein binding is too generic. This specific interaction is better captured by amyloid-beta binding term which describes Fe65's binding to APP. Supporting Evidence: PMID:8887653 The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein. |
| GO:0005515 protein binding | IPI PMID:9461550 Fe65L2: a new member of the Fe65 protein family interacting ... | REMOVE | Summary: Non-informative protein binding annotation showing Fe65L2 family member interactions with APP and APLP2. Reason: Protein binding is too generic. APP family interactions are captured by amyloid-beta binding. Supporting Evidence: PMID:9461550 Fe65L2: a new member of the Fe65 protein family interacting with the intracellular domain of the Alzheimer's beta-amyloid precursor protein. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Plasma membrane localization from HPA immunofluorescence curation. Reason: Consistent with other annotations. Fe65 is tethered to plasma membrane via APP binding under normal conditions. |
| GO:0010976 positive regulation of neuron projection development | IDA PMID:36250347 Insulin stimulates atypical protein kinase C-mediated phosph... | ACCEPT | Summary: Fe65 promotes neurite outgrowth through PKC-mediated phosphorylation that activates ARF6-Rac1 signaling upon insulin stimulation. 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. Supporting Evidence: PMID:36250347 Insulin stimulates atypical protein kinase C-mediated phosphorylation of the neuronal adaptor FE65 to potentiate neurite outgrowth by activating ARF6-Rac1 signaling. |
| GO:0060090 molecular adaptor activity | IDA PMID:36250347 Insulin stimulates atypical protein kinase C-mediated phosph... | ACCEPT | Summary: Direct experimental evidence for Fe65 molecular adaptor activity in linking insulin signaling to ARF6-Rac1-mediated neurite outgrowth. 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. Supporting Evidence: PMID:36250347 Insulin stimulates atypical protein kinase C-mediated phosphorylation of the neuronal adaptor FE65 to potentiate neurite outgrowth by activating ARF6-Rac1 signaling. |
| GO:0006939 smooth muscle contraction | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation transferred from mouse ortholog. Fe65 may play a role in muscle function through maintenance of neuromuscular junction. 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. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for nuclear localization transferred from rat ortholog. Reason: Consistent with multiple other annotations (IBA, IDA, IEA) for nuclear localization. |
| GO:1902807 negative regulation of cell cycle G1/S phase transition | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation transferred from rat ortholog for cell cycle regulation. 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. |
| GO:0005515 protein binding | IPI PMID:18468999 Regulation of FE65 nuclear translocation and function by amy... | REMOVE | Summary: Non-informative protein binding annotation showing Fe65-APP interaction. Reason: Protein binding is too generic. The Fe65-APP interaction is captured by amyloid-beta binding term. Supporting Evidence: PMID:18468999 2008 May 9. Regulation of FE65 nuclear translocation and function by amyloid beta-protein precursor in osmotically stressed cells. |
| GO:0003713 transcription coactivator activity | TAS PMID:12153398 Characterization of an amyloid precursor protein-binding pro... | ACCEPT | Summary: Fe65 functions as a transcription coactivator when in complex with APP intracellular domain and KAT5/TIP60. 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. Supporting Evidence: PMID:12153398 Characterization of an amyloid precursor protein-binding protein Fe65L2 and its novel isoforms lacking phosphotyrosine-interaction domains. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | TAS PMID:12153398 Characterization of an amyloid precursor protein-binding pro... | ACCEPT | Summary: Fe65 positively regulates transcription through its coactivator function with AICD complex. Reason: Consistent with Fe65's documented transcription coactivator activity. The AICD-Fe65 complex activates transcription of target genes. Supporting Evidence: PMID:12153398 Characterization of an amyloid precursor protein-binding protein Fe65L2 and its novel isoforms lacking phosphotyrosine-interaction domains. |
| GO:0050714 positive regulation of protein secretion | TAS PMID:12153398 Characterization of an amyloid precursor protein-binding pro... | KEEP AS NON CORE | Summary: Fe65 regulates secretion of beta-amyloid peptides (Abeta40, Abeta42) through its interaction with APP. 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. Supporting Evidence: PMID:12153398 Characterization of an amyloid precursor protein-binding protein Fe65L2 and its novel isoforms lacking phosphotyrosine-interaction domains. |
| GO:0050750 low-density lipoprotein particle receptor binding | TAS PMID:12153398 Characterization of an amyloid precursor protein-binding pro... | ACCEPT | Summary: Fe65 binds LRP1 (LDL receptor-related protein 1) via its PTB domains. 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. Supporting Evidence: PMID:12153398 Characterization of an amyloid precursor protein-binding protein Fe65L2 and its novel isoforms lacking phosphotyrosine-interaction domains. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:25342469 Regulation of neuronal survival and morphology by the E3 ubi... | ACCEPT | Summary: Fe65 interacts with the E3 ubiquitin ligase RNF157 and is a substrate for ubiquitination. 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. Supporting Evidence: PMID:25342469 Oct 24. Regulation of neuronal survival and morphology by the E3 ubiquitin ligase RNF157. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IGI PMID:21803450 The APP intracellular domain (AICD) potentiates ER stress-in... | ACCEPT | Summary: Fe65 functions as a transcriptional corepressor in complex with AICD to negatively regulate transcription. 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. Supporting Evidence: PMID:21803450 The APP intracellular domain (AICD) potentiates ER stress-induced apoptosis. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5683986 | ACCEPT | Summary: Reactome annotation for nucleoplasm localization in the context of H2AX binding pathway. 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. |
| GO:0005515 protein binding | IPI PMID:12972431 Novel cadherin-related membrane proteins, Alcadeins, enhance... | REMOVE | Summary: Non-informative protein binding annotation showing Fe65 interaction with Alcadein proteins. Reason: Protein binding is too generic. The Alcadein interaction relates to APP metabolism but is captured by molecular adaptor activity. Supporting Evidence: PMID:12972431 2003 Sep 12. Novel cadherin-related membrane proteins, Alcadeins, enhance the X11-like protein-mediated stabilization of amyloid beta-protein precursor metabolism. |
| GO:0005515 protein binding | IPI PMID:17332754 The novel cargo Alcadein induces vesicle association of kine... | REMOVE | Summary: Non-informative protein binding annotation showing Fe65 interaction with Alcadein in kinesin transport. Reason: Protein binding is too generic. Supporting Evidence: PMID:17332754 Mar 1. The novel cargo Alcadein induces vesicle association of kinesin-1 motor components and activates axonal transport. |
| GO:0003682 chromatin binding | IDA PMID:19343227 FE65 binds Teashirt, inhibiting expression of the primate-sp... | ACCEPT | Summary: Fe65 binds chromatin at the CASP4 transcription start site region as part of its transcriptional repressor function. 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. Supporting Evidence: PMID:19343227 FE65 binds Teashirt, inhibiting expression of the primate-specific caspase-4. |
| GO:0005515 protein binding | IPI PMID:19343227 FE65 binds Teashirt, inhibiting expression of the primate-sp... | REMOVE | Summary: Non-informative protein binding annotation showing Fe65 interaction with SET and TSHZ3. 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. Supporting Evidence: PMID:19343227 FE65 binds Teashirt, inhibiting expression of the primate-specific caspase-4. |
| GO:0005634 nucleus | IDA PMID:19343227 FE65 binds Teashirt, inhibiting expression of the primate-sp... | ACCEPT | Summary: Direct experimental evidence for Fe65 nuclear localization where it colocalizes with TSHZ3 and functions in transcriptional repression. Reason: PMID:19343227 showed Fe65 colocalizes with TSHZ3 in the nucleus. This IDA annotation provides direct experimental support for nuclear localization. Supporting Evidence: PMID:19343227 FE65 binds Teashirt, inhibiting expression of the primate-specific caspase-4. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:19343227 FE65 binds Teashirt, inhibiting expression of the primate-sp... | ACCEPT | Summary: Fe65 positively regulates transcription in certain contexts while repressing it in others (e.g., CASP4). Reason: Fe65 has documented dual transcriptional regulatory activities. PMID:19343227 showed both positive and negative regulatory functions. This annotation captures the coactivator function. Supporting Evidence: PMID:19343227 FE65 binds Teashirt, inhibiting expression of the primate-specific caspase-4. |
| GO:0070064 proline-rich region binding | IPI PMID:17686488 Structural basis for polyproline recognition by the FE65 WW ... | ACCEPT | Summary: The Fe65 WW domain binds proline-rich regions of interaction partners including ENAH. 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. Supporting Evidence: PMID:17686488 2007 Jun 29. Structural basis for polyproline recognition by the FE65 WW domain. |
| GO:0005515 protein binding | IPI PMID:19234442 Tyrosine dephosphorylation of H2AX modulates apoptosis and s... | REMOVE | Summary: Non-informative protein binding annotation from Nature paper on H2AX-mediated apoptosis decisions, showing Fe65-JNK1 interaction. Reason: Protein binding is too generic. The functionally important Fe65-JNK1 interaction is captured by the positive regulation of apoptotic process annotation. Supporting Evidence: PMID:19234442 Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. |
| GO:0005634 nucleus | IDA PMID:18468999 Regulation of FE65 nuclear translocation and function by amy... | ACCEPT | Summary: Direct experimental evidence for Fe65 nuclear translocation under osmotic stress conditions. 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. Supporting Evidence: PMID:18468999 2008 May 9. Regulation of FE65 nuclear translocation and function by amyloid beta-protein precursor in osmotically stressed cells. |
| GO:0005737 cytoplasm | IDA PMID:18468999 Regulation of FE65 nuclear translocation and function by amy... | ACCEPT | Summary: Direct experimental evidence for Fe65 cytoplasmic localization under normal conditions. Reason: PMID:18468999 demonstrated that under normal conditions Fe65 mainly localizes to the cytoplasm, with a small fraction tethered to the membrane via APP. Supporting Evidence: PMID:18468999 2008 May 9. Regulation of FE65 nuclear translocation and function by amyloid beta-protein precursor in osmotically stressed cells. |
| GO:0005886 plasma membrane | IDA PMID:18468999 Regulation of FE65 nuclear translocation and function by amy... | ACCEPT | Summary: Direct experimental evidence for Fe65 plasma membrane localization through APP tethering. 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. Supporting Evidence: PMID:18468999 2008 May 9. Regulation of FE65 nuclear translocation and function by amyloid beta-protein precursor in osmotically stressed cells. |
| GO:0006974 DNA damage response | IDA PMID:18468999 Regulation of FE65 nuclear translocation and function by amy... | ACCEPT | Summary: Direct experimental evidence for Fe65 role in DNA damage response through nuclear translocation and gammaH2AX induction. 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. Supporting Evidence: PMID:18468999 In the nucleus, FE65 induced gammaH2AX, which plays an important role in DNA repair as a cellular response by stress-damaged cells. |
| GO:0042393 histone binding | IPI PMID:19234442 Tyrosine dephosphorylation of H2AX modulates apoptosis and s... | ACCEPT | Summary: Fe65 binds phosphorylated histone H2AX (Y142) via its PTB2 domain. 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. Supporting Evidence: PMID:19234442 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 |
| GO:0043065 positive regulation of apoptotic process | IDA PMID:18468999 Regulation of FE65 nuclear translocation and function by amy... | ACCEPT | Summary: Fe65 positively regulates apoptosis by acting as an adaptor that recruits pro-apoptotic factor JNK1 to phosphorylated H2AX at DNA damage sites. 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). Supporting Evidence: PMID:18468999 FE65 deregulated from APP induces apoptosis PMID:19234442 knockdown of Fe65 strongly inhibited this interaction |
| GO:0007165 signal transduction | NAS PMID:8894693 cDNA cloning and chromosome mapping of the human Fe65 gene: ... | KEEP AS NON CORE | Summary: Very broad annotation for signal transduction based on early Fe65 characterization. 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. Supporting Evidence: 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. |
| GO:0007409 axonogenesis | NAS PMID:12843239 The amyloid precursor protein and its regulatory protein, FE... | KEEP AS NON CORE | Summary: NAS annotation for axonogenesis based on Fe65 localization in growth cones. 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. Supporting Evidence: PMID:12843239 The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. |
| GO:0030027 lamellipodium | IDA PMID:12843239 The amyloid precursor protein and its regulatory protein, FE... | ACCEPT | Summary: Fe65 localizes to lamellipodia in neuronal growth cones. 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. Supporting Evidence: PMID:12843239 The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. |
| GO:0030426 growth cone | IDA PMID:12843239 The amyloid precursor protein and its regulatory protein, FE... | ACCEPT | Summary: Direct experimental evidence for Fe65 localization to neuronal growth cones. 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. Supporting Evidence: PMID:12843239 The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. |
| GO:0045202 synapse | IDA PMID:12843239 The amyloid precursor protein and its regulatory protein, FE... | ACCEPT | Summary: Fe65 localizes to synapses where it associates with APP and Rab5-containing organelles. 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. Supporting Evidence: PMID:12843239 The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. |
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