id: Q9H8T0
gene_symbol: AKTIP
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  AKTIP (also known as FTS/Ft1) is a UEV-domain scaffold protein that lacks the catalytic
  cysteine
  required for E2 ubiquitin-conjugating enzyme activity. Its core functions include:
  (1) telomere
  replication support through interactions with shelterin components (TRF1/TRF2) and
  replication
  factors (PCNA/RPA70), facilitating replication through difficult telomeric DNA structures;
  (2) ESCRT-I adaptor function at the midbody during cytokinesis, where it interacts
  with VPS28
  and collaborates with TSG101 to recruit ESCRT-III components (CHMP4B, IST1) for
  abscission;
  (3) core component of the FTS-Hook-FHIP (FHF) complex that links cytoplasmic dynein-1
  to
  various cargos for microtubule-based transport. AKTIP also interacts with A- and
  B-type lamins
  and localizes to the nuclear rim, linking telomere maintenance to nuclear architecture.
  Despite its name (AKT-interacting protein), the AKT interaction represents a minor
  aspect
  of its biology compared to its telomere and ESCRT functions.
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      AKTIP localizes to the nucleus with enrichment at the nuclear rim in interphase,
      showing
      partial colocalization with lamins. In S phase, it transiently associates
      with telomeres
      (5-25% colocalization with TRF1 in asynchronous cells) (file:human/AKTIP/AKTIP-deep-research-falcon.md).
    action: ACCEPT
    reason: >-
      Nuclear localization is well-supported by multiple primary studies demonstrating
      nuclear rim
      enrichment, lamin interactions, and telomeric associations. The IBA annotation
      is consistent
      with the literature.
    additional_reference_ids:
    - file:human/AKTIP/AKTIP-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/AKTIP/AKTIP-deep-research-falcon.md
      supporting_text: "Interphase: nuclear rim enrichment in puncta; intranuclear
        foci partially overlapping lamins; detergent-resistant nuclear signals"

- term:
    id: GO:0061631
    label: ubiquitin conjugating enzyme activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      AKTIP contains a UBC-like (UEV) domain but critically LACKS the conserved
      catalytic cysteine
      residue necessary for E2 ubiquitin-conjugating activity (file:human/AKTIP/AKTIP-deep-research-falcon.md).
    action: REMOVE
    reason: >-
      This annotation is incorrect. While AKTIP has UEV-domain homology, it lacks
      the catalytic
      cysteine required for E2 activity. The IBA annotation likely propagated from
      sequence
      similarity without considering the critical absence of the catalytic residue.
      There is
      even a NOT annotation (NAS) for GO:0019787 (ubiquitin-like protein transferase
      activity)
      confirming this is NOT a function of AKTIP.
    additional_reference_ids:
    - file:human/AKTIP/AKTIP-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:18799622
      supporting_text: "Fused Toes (FTS) is a member of a small group of inactive
        variant E2 ubiquitin-conjugating enzyme domain-containing proteins of unknown
        function"

- term:
    id: GO:0070534
    label: protein K63-linked ubiquitination
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      This annotation suggests AKTIP is involved in K63-linked ubiquitination. However,
      AKTIP
      lacks the catalytic cysteine for E2 activity. While K63-linked ubiquitination
      is associated
      with UEV/UBC13 complexes (which AKTIP's yeast homolog participates in), there
      is no direct
      evidence that human AKTIP participates in K63-linked ubiquitination.
    action: UNDECIDED
    reason: >-
      The IBA annotation is based on phylogenetic inference, but AKTIP lacks the
      catalytic cysteine.
      In yeast, related UEV proteins (like MMS2) work with UBC13 for K63 ubiquitination,
      but there
      is no direct evidence AKTIP participates in this process. The deep research
      focuses on AKTIP's
      roles in telomere replication, ESCRT function, and FHF complex - not ubiquitination.
      Requires more investigation to determine if AKTIP has a scaffold role in K63
      ubiquitination.

- term:
    id: GO:0006301
    label: DNA damage tolerance
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      DNA damage tolerance (postreplication repair) is associated with UEV/UBC13
      complexes in yeast.
      AKTIP depletion causes S-phase arrest and activation of intra-S checkpoint,
      telomere dysfunction-
      induced foci (TIFs), and fragile telomere phenotypes (file:human/AKTIP/AKTIP-deep-research-falcon.md).
    action: KEEP_AS_NON_CORE
    reason: >-
      While AKTIP's telomere replication support function does relate to handling
      replication stress
      at difficult DNA sequences (G4 structures), this is not its core function.
      The annotation is
      based on phylogenetic inference from yeast homologs involved in post-replication
      repair. AKTIP's
      primary function is more accurately described as telomere replication support
      rather than
      general DNA damage tolerance.
    additional_reference_ids:
    - file:human/AKTIP/AKTIP-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/AKTIP/AKTIP-deep-research-falcon.md
      supporting_text: "AKTIP depletion in human primary fibroblasts causes reduced
        chromatin-bound PCNA, activation of intra-S checkpoint, S-phase arrest, and
        telomere dysfunction-induced foci (TIFs)"

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      AKTIP has cytoplasmic localization in addition to nuclear localization. It
      is found in
      the cytosol (IDA from HPA) and at the plasma membrane, and forms part of the
      cytoplasmic
      FHF complex involved in vesicle trafficking.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is supported by multiple lines of evidence including
      UniProt
      subcellular location annotation and functional studies showing AKTIP in the
      FHF complex
      involved in cytoplasmic vesicle trafficking.
    supported_by:
    - reference_id: PMID:18799622
      supporting_text: "The approximately 500-kDa FHF complex contained all three
        Hook proteins"

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      AKTIP localizes to the plasma membrane as a peripheral membrane protein, as
      shown in
      Remy & Michnick 2004 (PMID:14749367) studying AKT interaction.
    action: ACCEPT
    reason: >-
      Plasma membrane localization is supported by experimental evidence in PMID:14749367
      which
      showed AKTIP at the plasma membrane in context of AKT signaling. Also confirmed
      by IDA
      annotations from MGI and HPA.
    supported_by:
    - reference_id: PMID:14749367
      supporting_text: "The wide distribution of Ft1 in adult tissues suggests that
        it could be a general regulator of PKB activity"

- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      This annotation comes from UniProtKB/Swiss-Prot keyword mapping (KW-0053 Apoptosis).
      The
      original 2004 paper by Remy & Michnick reported that AKTIP modulates apoptosis
      susceptibility
      in T lymphocytes via the AKT/GSK3/NFAT signaling cascade. However, subsequent
      extensive
      characterization has revealed AKTIP's core functions are telomere replication
      support and
      ESCRT-mediated cytokinesis - not apoptosis (file:human/AKTIP/AKTIP-deep-research-falcon.md).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The apoptosis annotation derives from a single early study (PMID:14749367)
      that identified
      AKTIP as an AKT-interacting protein affecting apoptosis susceptibility. However,
      comprehensive
      subsequent research (2015-2022) establishes AKTIP's core functions as: (1)
      telomere replication
      support through shelterin/PCNA interactions, (2) ESCRT-I adaptor for cytokinetic
      abscission,
      (3) FHF complex component for dynein cargo transport. Any effect on apoptosis
      is a downstream
      pleiotropic consequence, not a direct core function. The deep research review
      found no
      significant role for AKTIP in apoptosis pathways.
    additional_reference_ids:
    - file:human/AKTIP/AKTIP-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/AKTIP/AKTIP-deep-research-falcon.md
      supporting_text: "Primary cellular roles: (1) Telomere replication support through
        interactions with shelterin (TRF1/TRF2) and replication factors (PCNA/RPA70);
        (2) Nuclear lamina/lamin-associated processes and senescence regulation; (3)
        ESCRT-associated function at the midbody during cytokinetic abscission"

- term:
    id: GO:0015031
    label: protein transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      AKTIP is a core component of the FHF (FTS-Hook-FHIP) complex that links cytoplasmic
      dynein-1
      to various cargos for microtubule-based transport. The FHF complex promotes
      vesicle trafficking
      via the HOPS complex and mediates perinuclear distribution of AP-4 and its
      cargo ATG9A.
    action: ACCEPT
    reason: >-
      Protein transport is a genuine core function of AKTIP through its role in
      the FHF complex.
      Multiple studies demonstrate AKTIP's involvement in dynein-mediated cargo
      transport.
    supported_by:
    - reference_id: PMID:18799622
      supporting_text: "These data suggest that the FTS/Hook/FHIP complex functions
        to promote vesicle trafficking and/or fusion via the HOPS complex"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  review:
    summary: >-
      High-throughput protein-protein interaction study. The interactor is HOOK2
      (Q96ED9).
      AKTIP does bind HOOK2 as part of the FHF complex.
    action: REMOVE
    reason: >-
      Generic protein binding annotation is uninformative. The specific interaction
      with HOOK2
      is meaningful and should be captured through the FHF complex annotation (GO:0070695)
      and
      more specific MF terms if available. HOOK2 interaction is validated in multiple
      studies.

    supported_by:
    - reference_id: PMID:16189514
      supporting_text: Towards a proteome-scale map of the human protein-protein
        interaction network.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17353931
  review:
    summary: >-
      Mass spectrometry-based protein interaction mapping. The interactor is HOOK1
      (Q9UJC3).
      AKTIP does bind HOOK1 as part of the FHF complex.
    action: REMOVE
    reason: >-
      Generic protein binding annotation is uninformative. The specific HOOK1 interaction
      is
      meaningful and captured through FHF complex membership. Remove in favor of
      more specific
      annotations.

    supported_by:
    - reference_id: PMID:17353931
      supporting_text: Large-scale mapping of human protein-protein interactions
        by mass spectrometry.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23414517
  review:
    summary: >-
      Skeletal muscle interactome study. Interactors include TRIM32 (Q13049) and
      HOOK3 (Q86VS8).
    action: REMOVE
    reason: >-
      Generic protein binding is uninformative. The HOOK3 interaction is part of
      AKTIP's core
      FHF complex function. TRIM32 interaction significance is unclear.

    supported_by:
    - reference_id: PMID:23414517
      supporting_text: 'A human skeletal muscle interactome centered on proteins involved
        in muscular dystrophies: LGMD interactome.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  review:
    summary: >-
      Proteome-scale interactome study. Interactor is HOOK1 (Q9UJC3).
    action: REMOVE
    reason: >-
      Redundant generic protein binding annotation. HOOK1 interaction is captured
      via FHF complex.

    supported_by:
    - reference_id: PMID:25416956
      supporting_text: A proteome-scale map of the human interactome network.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  review:
    summary: >-
      Study of genetic variant effects on protein interactions. Interactor is HOOK2
      (Q96ED9).
    action: REMOVE
    reason: >-
      Generic protein binding is uninformative. HOOK2 interaction captured via FHF
      complex.

    supported_by:
    - reference_id: PMID:31515488
      supporting_text: Extensive disruption of protein interactions by genetic 
        variants across the allele frequency spectrum in human populations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32073997
  review:
    summary: >-
      This is a focused mechanistic study demonstrating AKTIP/FTS interactions with
      HOOK1,
      HOOK2, HOOK3, FHIP1A, and FHIP1B as part of the FHF complex. Shows the WF->AA
      mutation
      impairs these interactions.
    action: REMOVE
    reason: >-
      While this study provides excellent mechanistic detail, the generic GO:0005515
      term
      does not capture the biological significance. The interactions are better
      represented
      by the FHF complex annotation (GO:0070695). The specific interactions documented
      here
      are: FHIP1A (Q05DH4), HOOK3 (Q86VS8), HOOK2 (Q96ED9), HOOK1 (Q9UJC3).

    supported_by:
    - reference_id: PMID:32073997
      supporting_text: 2020 Feb 19. The FTS-Hook-FHIP (FHF) complex interacts 
        with AP-4 to mediate perinuclear distribution of AP-4 and its cargo 
        ATG9A.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: >-
      Binary protein interactome reference map. Interactors are HOOK2 isoform (Q96ED9-2)
      and HOOK1.
    action: REMOVE
    reason: >-
      Generic protein binding is uninformative. Hook interactions captured via FHF
      complex.

    supported_by:
    - reference_id: PMID:32296183
      supporting_text: Apr 8. A reference map of the human binary protein 
        interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: >-
      Dual proteome-scale network study. Multiple interactors identified.
    action: REMOVE
    reason: >-
      Generic protein binding is uninformative. Biologically meaningful interactions
      should
      be captured through specific complex or pathway annotations.

    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:34882091
  review:
    summary: >-
      Comprehensive study of FHF complex assembly showing how different combinations
      of Hook
      and FHIP proteins form distinct FHF complexes for cargo specificity. Demonstrates
      AKTIP
      (FTS) as the invariant core component.
    action: REMOVE
    reason: >-
      While this is an excellent mechanistic study, generic protein binding does
      not capture
      the functional significance. The FHF complex annotation (GO:0070695) and protein
      transport
      annotations better represent AKTIP's role.

    supported_by:
    - reference_id: PMID:34882091
      supporting_text: Cytoplasmic dynein-1 cargo diversity is mediated by the 
        combinatorial assembly of FTS-Hook-FHIP complexes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  review:
    summary: >-
      Multimodal cell maps study. Interactor is HOOK3 (Q86VS8).
    action: REMOVE
    reason: >-
      Generic protein binding is uninformative. HOOK3 interaction captured via FHF
      complex.

    supported_by:
    - reference_id: PMID:40205054
      supporting_text: Apr 9. Multimodal cell maps as a foundation for 
        structural and functional genomics.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      AKTIP localizes to the cytosol based on immunofluorescence data from the Human
      Protein Atlas.
    action: ACCEPT
    reason: >-
      Cytosolic localization is consistent with AKTIP's role in the cytoplasmic
      FHF complex
      for vesicle trafficking.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      AKTIP localizes to the plasma membrane based on immunofluorescence data from
      HPA.
    action: ACCEPT
    reason: >-
      Consistent with experimental data from Remy & Michnick 2004 and UniProt annotation.

- term:
    id: GO:0098840
    label: protein transport along microtubule
  evidence_type: NAS
  original_reference_id: PMID:34882091
  review:
    summary: >-
      The FHF complex (containing AKTIP/FTS) links cargo to cytoplasmic dynein-1
      for
      microtubule-based retrograde transport. AKTIP is the invariant core component
      of all
      FHF complexes identified (file:human/AKTIP/AKTIP-deep-research-falcon.md).
    action: ACCEPT
    reason: >-
      This annotation accurately captures AKTIP's role in the FHF complex linking
      dynein to
      cargos for microtubule-based transport.
    additional_reference_ids:
    - file:human/AKTIP/AKTIP-deep-research-falcon.md

    supported_by:
    - reference_id: PMID:34882091
      supporting_text: Cytoplasmic dynein-1 cargo diversity is mediated by the 
        combinatorial assembly of FTS-Hook-FHIP complexes.
- term:
    id: GO:0070695
    label: FHF complex
  evidence_type: IDA
  original_reference_id: PMID:32073997
  review:
    summary: >-
      AKTIP is a core component of the FHF (FTS-Hook-FHIP) complex. This study demonstrates
      AKTIP interacts directly with Hook proteins (HOOK1, HOOK2, HOOK3) and FHIP
      proteins,
      forming the complex that mediates perinuclear distribution of AP-4 and ATG9A
      cargo.
    action: ACCEPT
    reason: >-
      FHF complex membership is a core function of AKTIP. This is well-documented
      with
      direct experimental evidence including co-IP, mutagenesis (WF->AA disrupts
      interactions),
      and functional assays.

    supported_by:
    - reference_id: PMID:32073997
      supporting_text: 2020 Feb 19. The FTS-Hook-FHIP (FHF) complex interacts 
        with AP-4 to mediate perinuclear distribution of AP-4 and its cargo 
        ATG9A.
- term:
    id: GO:1905719
    label: protein localization to perinuclear region of cytoplasm
  evidence_type: IMP
  original_reference_id: PMID:32073997
  review:
    summary: >-
      AKTIP knockdown (as part of FHF complex) results in dispersal of AP-4 and
      ATG9A from
      the perinuclear region, demonstrating its role in perinuclear protein localization.
    action: ACCEPT
    reason: >-
      This is a well-supported functional consequence of AKTIP's role in the FHF
      complex.
      The phenotype upon knockdown directly demonstrates involvement in perinuclear
      localization.

    supported_by:
    - reference_id: PMID:32073997
      supporting_text: 2020 Feb 19. The FTS-Hook-FHIP (FHF) complex interacts 
        with AP-4 to mediate perinuclear distribution of AP-4 and its cargo 
        ATG9A.
- term:
    id: GO:0001934
    label: positive regulation of protein phosphorylation
  evidence_type: IDA
  original_reference_id: PMID:14749367
  review:
    summary: >-
      Remy & Michnick 2004 reported that AKTIP enhances AKT1 phosphorylation by
      promoting
      its interaction with PDK1. This affects apoptosis susceptibility via the AKT/GSK3/NFAT
      cascade.
    action: KEEP_AS_NON_CORE
    reason: >-
      While experimentally supported, this is not a core function of AKTIP. Extensive
      subsequent
      research (2015-2022) has established AKTIP's primary roles in telomere replication
      and
      ESCRT function. The AKT interaction that gave AKTIP its name represents a
      minor aspect
      of its biology.
    supported_by:
    - reference_id: PMID:14749367
      supporting_text: "the Ft1 protein interacts directly with PKB, enhancing the
        phosphorylation of both of its regulatory sites by promoting its interaction
        with the upstream kinase PDK1"

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:14749367
  review:
    summary: >-
      AKTIP localizes to plasma membrane as peripheral membrane protein in context
      of AKT signaling.
    action: ACCEPT
    reason: >-
      Duplicate localization annotation from same reference as IEA. Experimental
      support is valid.

    supported_by:
    - reference_id: PMID:14749367
      supporting_text: Regulation of apoptosis by the Ft1 protein, a new 
        modulator of protein kinase B/Akt.
- term:
    id: GO:0032092
    label: positive regulation of protein binding
  evidence_type: IDA
  original_reference_id: PMID:14749367
  review:
    summary: >-
      AKTIP promotes the interaction between AKT1 and PDK1, thereby enhancing AKT
      phosphorylation.
    action: KEEP_AS_NON_CORE
    reason: >-
      While experimentally supported, this relates to the AKT interaction which
      is not AKTIP's
      core function. Subsequent research has established telomere and ESCRT roles
      as primary.
    supported_by:
    - reference_id: PMID:14749367
      supporting_text: "enhancing the phosphorylation of both of its regulatory sites
        by promoting its interaction with the upstream kinase PDK1"

- term:
    id: GO:0070695
    label: FHF complex
  evidence_type: IDA
  original_reference_id: PMID:18799622
  review:
    summary: >-
      Original identification of the FHF (FTS/Hook/FHIP) complex by proteomic analysis.
      AKTIP (FTS) identified as core component along with Hook proteins and FHIP.
    action: ACCEPT
    reason: >-
      This is the seminal paper identifying the FHF complex. AKTIP's role as a core
      component
      is fundamental to its cellular function.
    supported_by:
    - reference_id: PMID:18799622
      supporting_text: "we identified a new multiprotein complex, the FHF complex,
        containing FTS, members of the microtubule-binding Hook family of coiled-coil
        proteins"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18799622
  review:
    summary: >-
      Demonstrates AKTIP interactions with HOOK3, FHIP1B, HOOK2, HOOK1 in the FHF
      complex.
    action: REMOVE
    reason: >-
      Generic protein binding is uninformative. These meaningful interactions are
      captured
      through the FHF complex annotation.

    supported_by:
    - reference_id: PMID:18799622
      supporting_text: 2008 Sep 17. An FTS/Hook/p107(FHIP) complex interacts 
        with and promotes endosomal clustering by the homotypic vacuolar protein
        sorting complex.
- term:
    id: GO:0007032
    label: endosome organization
  evidence_type: IMP
  original_reference_id: PMID:18799622
  review:
    summary: >-
      AKTIP depletion affects endosomal organization through its role in the FHF
      complex
      which associates with the HOPS complex for endosome clustering.
    action: ACCEPT
    reason: >-
      This is a core function of AKTIP through its FHF complex role. The HOPS complex
      interaction and effects on endosome/lysosome organization are well-documented.
    supported_by:
    - reference_id: PMID:18799622
      supporting_text: "the efficiency by which overexpression of the HOPS component
        Vps18 promotes clustering of lysosomal-associated membrane protein 1-positive
        endosome/lysosomes"

- term:
    id: GO:0007040
    label: lysosome organization
  evidence_type: IMP
  original_reference_id: PMID:18799622
  review:
    summary: >-
      AKTIP depletion affects lysosome organization through FHF/HOPS complex interaction.
    action: ACCEPT
    reason: >-
      Part of AKTIP's core function in vesicle trafficking via FHF/HOPS complex
      interaction.
    supported_by:
    - reference_id: PMID:18799622
      supporting_text: "promotes clustering of lysosomal-associated membrane protein
        1-positive endosome/lysosomes"

- term:
    id: GO:0008333
    label: endosome to lysosome transport
  evidence_type: IMP
  original_reference_id: PMID:18799622
  review:
    summary: >-
      AKTIP knockdown affects EGF trafficking from early endosomes to late endosomes/lysosomes.
    action: ACCEPT
    reason: >-
      Core function of AKTIP through FHF complex. Well-supported by functional data
      showing
      trafficking defects upon AKTIP depletion.
    supported_by:
    - reference_id: PMID:18799622
      supporting_text: "Depletion of FTS by RNA interference affects both the trafficking
        of epidermal growth factor from early-to-late endosome/lysosomes"

- term:
    id: GO:0019787
    label: ubiquitin-like protein transferase activity
  evidence_type: NAS
  original_reference_id: PMID:18799622
  negated: true
  review:
    summary: >-
      This is a NOT annotation explicitly stating AKTIP does NOT have ubiquitin-like
      protein
      transferase activity, consistent with it lacking the catalytic cysteine.
    action: ACCEPT
    reason: >-
      This negative annotation is correct and important. AKTIP belongs to the inactive
      E2
      variant family and lacks the catalytic cysteine for transferase activity.
      This annotation
      helps prevent mis-annotation based on domain homology.
    supported_by:
    - reference_id: PMID:18799622
      supporting_text: "Fused Toes (FTS) is a member of a small group of inactive
        variant E2 ubiquitin-conjugating enzyme domain-containing proteins of unknown
        function"

- term:
    id: GO:0030897
    label: HOPS complex
  evidence_type: IDA
  original_reference_id: PMID:18799622
  review:
    summary: >-
      AKTIP (via FHF complex) associates with/colocalizes with the HOPS complex
      (homotypic
      fusion and protein sorting complex) involved in endosome/lysosome trafficking.
    action: ACCEPT
    reason: >-
      The FHF-HOPS interaction is a key aspect of AKTIP's role in vesicle trafficking.
      Note the qualifier is "colocalizes_with" not "part_of", which is appropriate
      since
      AKTIP is not a HOPS subunit.
    supported_by:
    - reference_id: PMID:18799622
      supporting_text: "Hook proteins as well as FTS interact with members of both
        the class B and class C components of the homotypic vesicular protein sorting
        (HOPS) complex"

- term:
    id: GO:0045022
    label: early endosome to late endosome transport
  evidence_type: IMP
  original_reference_id: PMID:18799622
  review:
    summary: >-
      AKTIP knockdown affects trafficking from early to late endosomes, demonstrated
      by
      EGF trafficking assays.
    action: ACCEPT
    reason: >-
      Core function through FHF/HOPS pathway. Well-documented phenotype upon AKTIP
      depletion.
    supported_by:
    - reference_id: PMID:18799622
      supporting_text: "Depletion of FTS by RNA interference affects both the trafficking
        of epidermal growth factor from early-to-late endosome/lysosomes"

# Suggested new annotations based on deep research
- term:
    id: GO:0000723
    label: telomere maintenance
  evidence_type: IMP
  original_reference_id: file:human/AKTIP/AKTIP-deep-research-falcon.md
  review:
    summary: >-
      AKTIP is required for telomere maintenance. Depletion causes telomere dysfunction-induced
      foci (TIFs), fragile telomeres (MTS), and sister telomere associations. AKTIP
      interacts
      with shelterin components TRF1 and TRF2 and replication factors PCNA and RPA70
      (file:human/AKTIP/AKTIP-deep-research-falcon.md).
    action: NEW
    reason: >-
      This is a core function of AKTIP not currently annotated. Extensive evidence
      from
      Burla et al. 2015 demonstrates AKTIP's essential role in telomere replication.
    supported_by:
    - reference_id: file:human/AKTIP/AKTIP-deep-research-falcon.md
      supporting_text: "Telomere phenotypes include multiple telomeric signals (MTS;
        \"fragile telomeres\") and sister telomere associations (STAs), phenocopying
        TRF1/BLM defects"

- term:
    id: GO:0030496
    label: midbody
  evidence_type: IDA
  original_reference_id: file:human/AKTIP/AKTIP-deep-research-falcon.md
  review:
    summary: >-
      AKTIP forms a ring encircling the dark zone (Flemming body) of the midbody
      during
      cytokinesis, with measured internal ring diameter ~1.05 um and external ~1.89
      um,
      similar to ESCRT-I rings (file:human/AKTIP/AKTIP-deep-research-falcon.md).
    action: NEW
    reason: >-
      Midbody localization is a core aspect of AKTIP's ESCRT function. High-resolution
      3D-SIM imaging provides definitive localization data.
    supported_by:
    - reference_id: file:human/AKTIP/AKTIP-deep-research-falcon.md
      supporting_text: "High-resolution 3D-SIM shows AKTIP forms a ring encircling
        the dark zone (Flemming body) of the intercellular bridge during cytokinesis"

- term:
    id: GO:0000281
    label: mitotic cytokinesis
  evidence_type: IMP
  original_reference_id: file:human/AKTIP/AKTIP-deep-research-falcon.md
  review:
    summary: >-
      AKTIP is required for cytokinetic abscission. It interacts with ESCRT-I (VPS28)
      and
      collaborates with TSG101 to recruit ESCRT-III components (CHMP4B, IST1). AKTIP
      depletion
      causes abscission defects and multinucleation (file:human/AKTIP/AKTIP-deep-research-falcon.md).
    action: NEW
    reason: >-
      Cytokinesis/abscission is a core function of AKTIP through its ESCRT adaptor
      role.
      This is well-documented by Merigliano et al. 2021.
    supported_by:
    - reference_id: file:human/AKTIP/AKTIP-deep-research-falcon.md
      supporting_text: "AKTIP depletion impairs IST1 recruitment and causes abscission
        defects and multinucleation"

- term:
    id: GO:0060090
    label: molecular adaptor activity
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations.
    supported_by:
    - reference_id: file:human/AKTIP/AKTIP-deep-research-falcon.md
      supporting_text: "AKTIP binds ESCRT-I subunit VPS28 via its UEV-containing region;
        AKTIP recruitment to the midbody is MKLP1-dependent and CEP55-independent"
references:
- 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:
  - statement: Apoptosis keyword (KW-0053) mapped to GO:0006915, but this is an 
      over-annotation for AKTIP
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
    Location vocabulary mapping
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: PMID:14749367
  title: Regulation of apoptosis by the Ft1 protein, a new modulator of protein 
    kinase B/Akt.
  findings:
  - statement: Original identification of AKTIP as AKT-interacting protein
    supporting_text: "we report the identification of a novel PKB binding protein,
      called Ft1"
  - statement: Shows AKTIP enhances AKT phosphorylation via PDK1 interaction
    supporting_text: "the Ft1 protein interacts directly with PKB, enhancing the phosphorylation
      of both of its regulatory sites by promoting its interaction with the upstream
      kinase PDK1"
  - statement: Reports apoptosis modulation in T lymphocytes
    supporting_text: "modulation of PKB activity by Ft1 has a strong effect on the
      apoptosis susceptibility of T lymphocytes treated with glucocorticoids"
  - statement: Note - this early characterization does not reflect AKTIP's core 
      functions identified later
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction 
    network.
  findings:
  - statement: High-throughput protein interaction study
- id: PMID:17353931
  title: Large-scale mapping of human protein-protein interactions by mass 
    spectrometry.
  findings:
  - statement: High-throughput protein interaction study
- id: PMID:18799622
  title: An FTS/Hook/p107(FHIP) complex interacts with and promotes endosomal 
    clustering by the homotypic vacuolar protein sorting complex.
  findings:
  - statement: Original identification of FHF complex (FTS/Hook/FHIP)
    supporting_text: "we identified a new multiprotein complex, the FHF complex, containing
      FTS, members of the microtubule-binding Hook family of coiled-coil proteins"
  - statement: AKTIP identified as inactive E2 variant lacking catalytic 
      function
    supporting_text: "Fused Toes (FTS) is a member of a small group of inactive variant
      E2 ubiquitin-conjugating enzyme domain-containing proteins of unknown function"
  - statement: FHF associates with HOPS complex
    supporting_text: "Hook proteins as well as FTS interact with members of both the
      class B and class C components of the homotypic vesicular protein sorting (HOPS)
      complex"
  - statement: Role in endosome/lysosome trafficking demonstrated
    supporting_text: "Depletion of FTS by RNA interference affects both the trafficking
      of epidermal growth factor from early-to-late endosome/lysosomes"
- id: PMID:23414517
  title: A human skeletal muscle interactome centered on proteins involved in 
    muscular dystrophies
  findings:
  - statement: Identifies AKTIP interactions with TRIM32 and HOOK3
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings:
  - statement: Confirms AKTIP-HOOK1 interaction
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across
    the allele frequency spectrum
  findings:
  - statement: Validates AKTIP-HOOK2 interaction
- id: PMID:32073997
  title: The FTS-Hook-FHIP (FHF) complex interacts with AP-4 to mediate 
    perinuclear distribution of AP-4 and its cargo ATG9A.
  findings:
  - statement: Detailed characterization of FHF complex
  - statement: WF->AA mutation disrupts Hook interactions
  - statement: FHF-AP-4 interaction mediates ATG9A trafficking
  - statement: Documents perinuclear localization function
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: Confirms AKTIP-Hook protein interactions
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the 
    human interactome.
  findings:
  - statement: Multiple AKTIP interactions identified
- id: PMID:34882091
  title: Cytoplasmic dynein-1 cargo diversity is mediated by the combinatorial 
    assembly of FTS-Hook-FHIP complexes.
  findings:
  - statement: AKTIP (FTS) is invariant core component of all FHF complexes
  - statement: Different Hook/FHIP combinations determine cargo specificity
  - statement: Links FHF to dynein-mediated microtubule transport
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional 
    genomics.
  findings:
  - statement: Confirms AKTIP-HOOK3 interaction
- id: file:human/AKTIP/AKTIP-deep-research-falcon.md
  title: Deep research on human AKTIP function (falcon provider)
  findings:
  - statement: AKTIP functions in telomere replication support through 
      shelterin/PCNA interactions
    supporting_text: "AKTIP facilitates telomeric DNA replication in concert with
      TRF1"
  - statement: AKTIP functions as ESCRT-I adaptor at the midbody
    supporting_text: "AKTIP binds ESCRT-I subunit VPS28 via its UEV-containing region;
      AKTIP recruitment to the midbody is MKLP1-dependent and CEP55-independent"
  - statement: AKTIP is a core component of the FHF complex for vesicle 
      trafficking
    supporting_text: "we identified a new multiprotein complex, the FHF complex, containing
      FTS, members of the microtubule-binding Hook family"

core_functions:
- molecular_function:
    id: GO:0060090
    label: molecular adaptor activity
  directly_involved_in:
  - id: GO:0008333
    label: endosome to lysosome transport
  - id: GO:0098840
    label: protein transport along microtubule
  locations:
  - id: GO:0005829
    label: cytosol
  in_complex:
    id: GO:0070695
    label: FHF complex
  description: >-
    AKTIP is the invariant core component of FTS-Hook-FHIP (FHF) complexes that
    link
    cytoplasmic dynein-1 to various cargos for microtubule-based retrograde transport.
    Through FHF complex interactions with HOPS, AKTIP promotes endosome/lysosome
    trafficking and organization.
  supported_by:
  - reference_id: PMID:18799622
    supporting_text: "we identified a new multiprotein complex, the FHF complex, containing
      FTS, members of the microtubule-binding Hook family of coiled-coil proteins"

- molecular_function:
    id: GO:0060090
    label: molecular adaptor activity
  directly_involved_in:
  - id: GO:0000723
    label: telomere maintenance
  locations:
  - id: GO:0005634
    label: nucleus
  description: >-
    AKTIP supports telomeric DNA replication through interactions with shelterin
    components (TRF1/TRF2) and replication factors (PCNA/RPA70). This UEV-domain
    scaffold helps stabilize TRF1 engagement during replication through difficult
    telomeric DNA structures. Depletion causes fragile telomeres, TIFs, and STAs.
  supported_by:
  - reference_id: file:human/AKTIP/AKTIP-deep-research-falcon.md
    supporting_text: "AKTIP facilitates telomeric DNA replication in concert with
      TRF1"

- molecular_function:
    id: GO:0060090
    label: molecular adaptor activity
  directly_involved_in:
  - id: GO:0000281
    label: mitotic cytokinesis
  locations:
  - id: GO:0030496
    label: midbody
  description: >-
    AKTIP functions as an ESCRT-I adaptor at the midbody during cytokinetic abscission.
    It binds ESCRT-I subunit VPS28 and collaborates with TSG101 to recruit ESCRT-III
    components (CHMP4B, IST1) for membrane scission. Forms a characteristic ring
    structure at the midbody dark zone.
  supported_by:
  - reference_id: file:human/AKTIP/AKTIP-deep-research-falcon.md
    supporting_text: "AKTIP binds ESCRT-I subunit VPS28 via its UEV-containing region;
      AKTIP recruitment to the midbody is MKLP1-dependent and CEP55-independent"