id: O00170
gene_symbol: AIP
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: AIP (AH receptor-interacting protein, also known as XAP2/ARA9) is a ~37 kDa,
  330-amino acid FKBP-type immunophilin homolog that functions as a co-chaperone/scaffold
  in the HSP90-AHR (aryl hydrocarbon receptor) cytosolic complex and as a cytosolic factor
  mediating mitochondrial preprotein import via interaction with the import receptor TOMM20.
  It contains an N-terminal FKBP-type PPIase-like domain that is catalytically inactive
  (lacking PPIase enzymatic activity and FK506/rapamycin binding) and C-terminal TPR
  repeats (three TPR motifs plus a terminal alpha-7 helix) that mediate interactions with
  HSP90 and TOMM20. Cryo-EM structural analysis of the human agonist-bound AHR cytosolic
  complex (DOI:10.1038/s41467-022-34773-w) reveals AIP/XAP2 acting as a structural brace
  associated with the HSP90 dimer and the AHR client, with the HSP90 C-terminal MEEVD
  motif docked into the TPR domain of AIP. AIP exhibits chaperone-like (holdase) activity,
  suppressing thermal aggregation of substrate proteins. Beyond the AHR complex, AIP also
  interacts with phosphodiesterases PDE4A5 and PDE2A3, linking it to localized cAMP
  regulation and modulation of AHR nuclear translocation. Proteomic studies show AIP
  co-localizes with HSPA9 in the mitochondrial chaperone network, consistent with broader
  chaperone-network functions beyond the AHR complex
  (DOI:10.18632/oncotarget.24183). Germline loss-of-function AIP variants predispose to
  pituitary neuroendocrine tumors (PitNETs) with incomplete penetrance (~12-30%), behaving
  as a tumor suppressor with a two-hit model (loss of heterozygosity in tumors). AIP
  mutations account for ~29% of childhood-onset GH-secreting pituitary tumors presenting
  as gigantism and ~9% of macroprolactinomas presenting before age 20
  (DOI:10.1038/s41574-023-00948-8).
existing_annotations:
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: This IEA annotation was inferred by logical inference from AIP having
      transcription coactivator activity (GO:0003713). AIP/XAP2 was shown by Meyer et al.
      (PMID:9447995) to enhance AhR-driven transcription from a dioxin-responsive element
      by about twofold. This is an indirect consequence of AIP stabilizing the AHR-HSP90
      complex in the cytosol, not a direct transcriptional activation function. The
      annotation is logically consistent with the coactivator annotation but represents
      a secondary downstream effect rather than a core function of AIP.
    action: KEEP_AS_NON_CORE
    reason: AIP does enhance AhR-driven transcription, but this is an indirect effect
      of its co-chaperone function in stabilizing the AHR-HSP90 complex, not a direct
      transcriptional regulatory activity. The annotation is technically correct as an
      inference from the coactivator annotation, but represents a downstream biological
      consequence rather than core function.
    supported_by:
    - reference_id: PMID:9447995
      supporting_text: XAP2 enhanced the ability of endogenous murine and human AhR
        complexes to activate a dioxin-responsive element-luciferase reporter twofold,
        following transient expression of XAP2 in Hepa 1c1c7 and HeLa cells.
- term:
    id: GO:0003755
    label: peptidyl-prolyl cis-trans isomerase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: This IEA annotation was automatically assigned based on InterPro domain
      IPR001179 (FKBP-type PPIase domain). While AIP does contain an FKBP-type PPIase-like
      domain, multiple studies have shown this domain is catalytically inactive. Laenger
      et al. (PMID:19375531) explicitly demonstrated that the PPIase-like region of XAP2
      is enzymatically inactive. The domain has diverged from catalytically active FKBP
      family members and lacks key residues for PPIase catalysis.
    action: REMOVE
    reason: AIP contains an FKBP-type PPIase-like domain that is catalytically inactive
      (PMID:19375531). The InterPro domain match is structurally correct but the functional
      annotation of PPIase activity is incorrect for this protein. This is a well-documented
      case of a domain homolog that has lost enzymatic activity.
    supported_by:
    - reference_id: PMID:19375531
      supporting_text: The PPIase-like region turned out to be enzymatically inactive.
        Thus, PPIase activity is not essential for the action of XAP2 on GR, similarly
        to FKBP51 and FKBP52.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: This IEA annotation is based on UniProtKB/Swiss-Prot Subcellular Location
      mapping. AIP is well-established as a cytoplasmic protein. Kuzhandaivelu et al.
      (PMID:8972861) showed by immunofluorescence that XAP2 is a cytoplasmic protein.
      UniProt CC line states Subcellular location as Cytoplasm. This is consistent with
      AIP functioning as a cytosolic co-chaperone in the AHR-HSP90 complex and as a
      cytosolic factor in mitochondrial preprotein import.
    action: ACCEPT
    reason: AIP is well-established as a cytoplasmic protein across multiple studies.
      This is consistent with its function as a cytosolic co-chaperone.
    supported_by:
    - reference_id: PMID:8972861
      supporting_text: Antiserum raised against XAP2 recognizes a cytoplasmic protein
        with an apparent molecular mass of 36 kDa.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: This IEA annotation of GO:0051082 (unfolded protein binding) was assigned
      by ARBA machine learning models. GO:0051082 is being obsoleted (go-ontology issue
      30962). While AIP does have experimentally demonstrated chaperone-like activity
      that prevents thermal aggregation of substrate proteins (PMID:14557246), the
      appropriate replacement term is GO:0044183 (protein folding chaperone), which
      better captures the holdase/chaperone function rather than implying simple binding
      to unfolded proteins. The IEA annotation here is redundant with the IDA annotation
      from the same gene also annotated to GO:0051082 based on PMID:14557246.
    action: MODIFY
    reason: GO:0051082 is being obsoleted. The experimental data from PMID:14557246
      demonstrates genuine chaperone-like (holdase) activity for AIP, including suppression
      of thermal aggregation of rhodanese and citrate synthase in vitro. The replacement
      term GO:0044183 (protein folding chaperone) accurately captures this function.
      Additionally, this IEA annotation is redundant with the experimentally supported
      IDA annotation from PMID:14557246 on the same gene.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - PMID:14557246
    supported_by:
    - reference_id: PMID:14557246
      supporting_text: An aggregation suppression assay indicated that AIP has a chaperone-like
        activity to prevent substrate proteins from aggregation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17329248
  review:
    summary: This IPI annotation records the interaction between AIP (XAP2) and PDE2A
      (UniProtKB:O00408). De Oliveira et al. (PMID:17329248) identified XAP2 as a major
      PDE2A-interacting protein via yeast two-hybrid screening and mapped the binding
      site to the GAF-B domain of PDE2A. This is a functionally significant interaction
      as PDE2A binding to XAP2 inhibits TCDD- and cAMP-induced nuclear translocation of
      AhR in hepatocytes. The interaction is relevant to AIP function in cAMP signaling
      regulation. However, protein binding is uninformative; the more specific annotation
      GO:0036004 (GAF domain binding) already captures this interaction.
    action: ACCEPT
    reason: The interaction between AIP and PDE2A is well-documented by yeast two-hybrid
      and co-immunoprecipitation (PMID:17329248). While protein binding is a generic term,
      the IPI evidence with specific interactor is standard practice and the more specific
      GAF domain binding annotation is also present. Duplicates with different evidence
      lines are acceptable.
    supported_by:
    - reference_id: PMID:17329248
      supporting_text: In a yeast two-hybrid screening we identified XAP2, a crucial
        component of the aryl hydrocarbon receptor (AhR) complex, as a major
        PDE2A-interacting protein. We mapped the XAP2 binding site to the GAF-B domain
        of PDE2A.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19375531
  review:
    summary: This IPI annotation records the interaction between AIP (XAP2) and HSP90AB1
      (UniProtKB:P08238). Laenger et al. (PMID:19375531) showed that XAP2 interacts with
      Hsp90 through its TPR motif and that this interaction is required for XAP2 to
      inhibit glucocorticoid receptor activity. The AIP-HSP90 interaction is one of the
      most well-characterized interactions for this protein, mediated by the TPR domain
      binding to the MEEVD motif at the C-terminus of HSP90. This is a core interaction
      of AIP.
    action: ACCEPT
    reason: The AIP-HSP90 interaction is a core functional interaction, extensively
      validated. This IPI evidence from PMID:19375531 provides additional confirmation
      that the TPR domain mediates the HSP90 binding. Multiple independent studies
      confirm this interaction.
    supported_by:
    - reference_id: PMID:19375531
      supporting_text: The effect of XAP2 on GR requires its interaction with Hsp90
        through the TPR motif.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20029029
  review:
    summary: This IPI annotation records the interaction between AIP and EGFR
      (UniProtKB:P00533) from a study on HDAC6 regulation of EGFR trafficking
      (PMID:20029029). AIP was not the focus of this study. The interaction between AIP
      and EGFR is likely detected in a high-throughput context and may represent an
      indirect interaction mediated through the HSP90 chaperone machinery, since EGFR
      is a known HSP90 client. Without more specific evidence for a direct, functional
      AIP-EGFR interaction, this should be considered with caution.
    action: ACCEPT
    reason: The interaction was detected by physical interaction evidence (IPI) and is
      plausible given that AIP is part of the HSP90 co-chaperone system and EGFR is an
      HSP90 client. While likely indirect, the IPI evidence is valid as recorded.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21170051
  review:
    summary: This IPI annotation records the interaction between AIP and HSP90AB1
      (UniProtKB:P08238) from a study on mixed Hsp90-cochaperone complexes
      (PMID:21170051). This study demonstrates that AIP forms part of mixed HSP90
      co-chaperone complexes important for the chaperone reaction cycle. This is
      consistent with AIP being a bona fide HSP90 co-chaperone via its TPR domain.
    action: ACCEPT
    reason: This confirms the well-established AIP-HSP90 co-chaperone interaction in
      the context of functional chaperone cycle complexes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21903422
  review:
    summary: This IPI annotation records the interaction between AIP and IRF7
      (UniProtKB:Q92985) from a study mapping innate immunity protein interaction networks
      (PMID:21903422). AIP was detected interacting with IRF7 in a high-throughput
      innate immunity interaction mapping study. AIP is not known to have a role in
      interferon signaling. This interaction may be indirect (mediated through HSP90
      which is known to interact with various signaling proteins) or may represent a
      non-physiological interaction from the high-throughput screen.
    action: ACCEPT
    reason: The interaction was detected by IPI evidence in a systematic study. While
      the biological relevance to AIP function is unclear, the physical evidence is
      valid as recorded. It may reflect AIP participating in HSP90-mediated regulation
      of signaling proteins.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22113938
  review:
    summary: This IPI annotation records the interaction between AIP and CSNK2A1/CK2alpha
      (UniProtKB:P68400) from a large-scale kinase substrate identification study
      (PMID:22113938). The interaction is from a high-throughput bead-based screen. CK2
      is a ubiquitous kinase and the interaction may or may not be physiologically
      significant for AIP function. AIP has a phosphoserine at position 43
      (ECO:0007744|PubMed:23186163), which could be a CK2 substrate site.
    action: ACCEPT
    reason: The interaction was detected by IPI evidence and is plausible given that
      AIP is known to be phosphorylated. The evidence stands as a valid physical
      interaction record.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  review:
    summary: This IPI annotation records the interaction between AIP and HSP90AB1
      (UniProtKB:P08238) from a quantitative chaperone interaction network study
      (PMID:25036637). This study systematically mapped the chaperone-cochaperone
      interaction network and places AIP firmly within the HSP90 co-chaperone system.
      This is one of the core interactions of AIP.
    action: ACCEPT
    reason: This further validates the well-established AIP-HSP90 co-chaperone
      interaction in a comprehensive chaperone interactome study.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  review:
    summary: This IPI annotation records the interaction between AIP and PRAMEF10
      (UniProtKB:O60809) from a large-scale interactome mapping study (PMID:28514442).
      PRAMEF10 is a PRAME family member. This is from a high-throughput study and the
      biological significance of AIP interacting with PRAMEF10 is unclear. PRAMEF10
      is poorly characterized.
    action: ACCEPT
    reason: The interaction was detected by IPI evidence in a systematic interactome
      study. The biological relevance is uncertain, but the physical interaction evidence
      is valid as recorded.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28634279
  review:
    summary: This IPI annotation records the interaction between AIP and HSP90AB1
      (UniProtKB:P08238) from Salvatori et al. (PMID:28634279), which studied the
      c.805_825dup AIP mutation. The study demonstrated by co-immunoprecipitation that
      wild-type AIP interacts with HSP90, and that the p.F269_H275dup mutation in TPR3
      disrupts this interaction. This provides important functional validation that the
      AIP-HSP90 interaction is mediated through the TPR domain and is disrupted by
      disease-causing mutations.
    action: ACCEPT
    reason: This co-immunoprecipitation study confirms the AIP-HSP90 interaction and
      demonstrates its functional importance, as disease-causing AIP mutations disrupt
      the HSP90 binding. This is directly relevant to the tumor suppressor function of
      AIP.
    supported_by:
    - reference_id: PMID:28634279
      supporting_text: The results of a co-immunoprecipitation experiment with mutant
        AIP and HSP90 were consistent with lack of interaction between the two proteins
        (Fig
    - reference_id: PMID:28634279
      supporting_text: The mutation results in the duplication of seven amino-acids in
        third TPR domain of AIP, leading to the disruption of protein-protein interactions
        and markedly reduced protein stability.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31980649
  review:
    summary: This IPI annotation records the interaction between AIP and EGFR
      (UniProtKB:P00533) from a study on EGFR network rewiring in KRAS-mutant colorectal
      cancer cells (PMID:31980649). AIP was not the focus of this study. The interaction
      with EGFR is likely indirect, mediated through the HSP90 chaperone machinery.
    action: ACCEPT
    reason: The interaction was detected by IPI evidence. While likely reflecting
      indirect interaction through the HSP90 system, the physical evidence is valid
      as recorded.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: This IPI annotation records interactions between AIP and PRAMEF10
      (UniProtKB:O60809) and/or SYCN (UniProtKB:Q0VAF6) from a dual proteome-scale
      network study (PMID:33961781). These are from a high-throughput interactome
      study. The biological significance of these interactions for AIP function is
      unclear.
    action: ACCEPT
    reason: The interactions were detected by IPI evidence in a systematic
      proteome-scale interactome study. While biological relevance to AIP function is
      uncertain, the physical evidence is valid as recorded.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  review:
    summary: This IPI annotation records the interaction between AIP and CSNK2A1/CK2alpha
      (UniProtKB:P68400) from the OpenCell study (PMID:35271311), a large-scale
      endogenous tagging and imaging study. This is a second independent confirmation
      of the AIP-CK2alpha interaction after PMID:22113938.
    action: ACCEPT
    reason: The interaction was detected by IPI evidence in an independent large-scale
      study, providing a second line of evidence for the AIP-CK2alpha interaction.
- term:
    id: GO:0003712
    label: transcription coregulator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This IEA annotation was transferred from the mouse ortholog via Ensembl
      Compara. AIP/XAP2 was shown to enhance AhR-mediated transcription (PMID:9447995),
      which is the basis for the mouse ortholog annotation. The term GO:0003712
      (transcription coregulator activity) is broader than the TAS annotation
      GO:0003713 (transcription coactivator activity) also present for this gene. AIP
      enhances AhR transcription indirectly by stabilizing the cytosolic AHR-HSP90
      complex, not by acting as a direct transcriptional coregulator in the nucleus.
      This is a secondary consequence of its co-chaperone function.
    action: KEEP_AS_NON_CORE
    reason: AIP does enhance AhR-dependent transcription, but this is an indirect
      effect of its co-chaperone role in stabilizing the AHR complex. The broader IEA
      term is acceptable as a non-core annotation consistent with the TAS coactivator
      annotation.
    supported_by:
    - reference_id: PMID:9447995
      supporting_text: XAP2 enhanced the ability of endogenous murine and human AhR
        complexes to activate a dioxin-responsive element-luciferase reporter twofold,
        following transient expression of XAP2 in Hepa 1c1c7 and HeLa cells.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This IEA annotation was transferred from the mouse ortholog via Ensembl
      Compara. AIP is established as a cytosolic protein by multiple lines of evidence
      including IDA annotations based on immunofluorescence (GO_REF:0000052) and direct
      experimental evidence (PMID:17329248). This IEA is consistent with and redundant
      with the experimental evidence.
    action: ACCEPT
    reason: Cytosolic localization of AIP is well-established by multiple experimental
      methods. This IEA is consistent with experimental evidence.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This IEA annotation was transferred from the mouse ortholog via Ensembl
      Compara. AIP is primarily a cytosolic protein. The membrane annotation may reflect
      AIP association with the outer mitochondrial membrane via its interaction with
      TOMM20 (PMID:14557246), or its reported colocalization with the plasma membrane
      via PDE2A interaction (PMID:17329248). AIP itself is not a membrane protein and
      does not have a transmembrane domain. The term GO:0016020 (membrane) is very
      broad and not very informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: AIP is not an integral membrane protein. While it may associate with
      membranes through protein-protein interactions (TOMM20 at the mitochondrial
      outer membrane, or PDE2A at the plasma membrane), the broad term "membrane" is
      uninformative and potentially misleading for a primarily cytosolic co-chaperone
      protein. More specific localization terms (cytosol, plasma membrane
      colocalization) are already captured by other annotations.
- term:
    id: GO:0017162
    label: aryl hydrocarbon receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This IEA annotation was transferred from the mouse ortholog via Ensembl
      Compara. AIP/XAP2 was originally identified as a component of the AhR core
      complex (PMID:9447995). Meyer et al. showed that XAP2 coprecipitates with
      FLAG-tagged AhR and is present in the unliganded AhR 9S complex. AIP binding
      to AhR is well-established as a core function of this protein and is the basis
      for its name.
    action: ACCEPT
    reason: AIP binding to the aryl hydrocarbon receptor is one of its best-characterized
      functions. This was demonstrated by coprecipitation and is the basis for the
      protein name. The IEA transfer from mouse ortholog is appropriate.
    supported_by:
    - reference_id: PMID:9447995
      supporting_text: Here we report the purification of an approximately 38-kDa protein
        (p38) from COS-1 cell cytosol that is a member of this complex by
        coprecipitation with a FLAG-tagged AhR.
- term:
    id: GO:0034751
    label: aryl hydrocarbon receptor complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This IEA annotation was transferred from the mouse ortholog via Ensembl
      Compara. AIP/XAP2 is an established subunit of the unliganded AhR core complex
      (PMID:9447995). Meyer et al. demonstrated that XAP2 is part of the heterotetrameric
      9S AhR complex consisting of AhR, two HSP90 molecules, and XAP2. Reactome entries
      (R-HSA-8936849, R-HSA-8937169) also model AIP as part of the AHR:2xHSP90:AIP:PTGES3
      complex. This is a core localization for AIP.
    action: ACCEPT
    reason: AIP is a bona fide subunit of the aryl hydrocarbon receptor complex. This
      is one of the defining characteristics of this protein and is supported by
      multiple independent studies and Reactome pathway models.
    supported_by:
    - reference_id: PMID:9447995
      supporting_text: Prior to ligand activation, the unactivated aryl hydrocarbon
        receptor (AhR) exists in a heterotetrameric 9S core complex consisting of the
        AhR ligand-binding subunit, a dimer of hsp90, and an unknown subunit.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: This IDA annotation is based on curation of immunofluorescence data (HPA).
      Cytosolic localization of AIP is well-established and consistent with its function
      as a cytosolic co-chaperone. Multiple studies confirm AIP is primarily cytosolic
      (PMID:8972861, PMID:14557246, PMID:17329248).
    action: ACCEPT
    reason: Immunofluorescence-based evidence for cytosolic localization of AIP is
      consistent with extensive other evidence for cytosolic localization.
- term:
    id: GO:0003755
    label: peptidyl-prolyl cis-trans isomerase activity
  evidence_type: IDA
  original_reference_id: PMID:14557246
  review:
    summary: This IDA annotation citing PMID:14557246 (Yano et al. 2003) claims PPIase
      activity for AIP. However, Yano et al. 2003 does NOT demonstrate PPIase enzymatic
      activity for AIP. The paper focuses on AIP as a mitochondrial import mediator with
      chaperone-like holdase activity. AIP belongs to the FKBP PPIase family structurally
      but its PPIase domain is catalytically inactive. Laenger et al. (PMID:19375531)
      explicitly showed the PPIase-like region is enzymatically inactive. This IDA
      annotation appears to be an error in the original curation, conflating structural
      homology to PPIases with actual catalytic activity.
    action: REMOVE
    reason: AIP does not have PPIase catalytic activity. PMID:14557246 does not
      demonstrate PPIase activity; it describes chaperone-like holdase activity and
      mitochondrial import function. PMID:19375531 explicitly demonstrated that the
      PPIase-like region of AIP is enzymatically inactive. The IDA annotation based on
      PMID:14557246 for PPIase activity is an error.
    supported_by:
    - reference_id: PMID:19375531
      supporting_text: The PPIase-like region turned out to be enzymatically inactive.
    - reference_id: PMID:14557246
      supporting_text: AIP belongs to a family of peptidyl-prolyl cis/trans isomerases
        (PPIases) that are ubiquitous in prokaryotes and eukaryotes (Galat and Metcalfe,
        1995).
- term:
    id: GO:0051604
    label: protein maturation
  evidence_type: IDA
  original_reference_id: PMID:14557246
  review:
    summary: This IDA annotation to GO:0051604 (protein maturation) cites Yano et al.
      (PMID:14557246). The paper demonstrates that AIP functions as a cytosolic factor
      mediating mitochondrial preprotein import. AIP maintains preproteins in an
      import-competent conformation and facilitates their import into mitochondria via
      interaction with TOMM20. Overexpression of AIP enhanced mature OTC production
      (processing of pOTC to mature OTC by mitochondrial import and cleavage), and
      depletion reduced it. While the end result is maturation of mitochondrial
      preproteins (signal peptide cleavage), AIP does not directly participate in the
      proteolytic processing. A more accurate annotation would be GO:0070585 (protein
      localization to mitochondrion), which is already annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: AIP facilitates mitochondrial import but does not directly participate in
      protein maturation (proteolytic processing). The observed effect on pOTC maturation
      is an indirect consequence of enhanced mitochondrial import. The more appropriate
      annotation GO:0070585 (protein localization to mitochondrion) is already present
      for this gene and this reference. GO:0051604 is too broad and somewhat misleading
      for what AIP actually does.
    supported_by:
    - reference_id: PMID:14557246
      supporting_text: AIP can enhance the mitochondrial import of pOTC.
    - reference_id: PMID:14557246
      supporting_text: All these results suggest strongly that AIP stabilizes pOTC in
        the cytosol and facilitates its import into mitochondria.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8937169
  review:
    summary: This TAS annotation is based on Reactome pathway R-HSA-8937169
      (AHR:TCDD:2xHSP90AB1:AIP:PTGES3 translocates from cytosol to nucleoplasm). In
      the Reactome model, the entire AHR complex including AIP translocates to the
      nucleus upon ligand binding. AIP is primarily cytosolic and its presence in the
      nucleoplasm is transient as part of the ligand-bound AHR complex before the
      complex dissociates. This is a non-core localization.
    action: KEEP_AS_NON_CORE
    reason: AIP transiently enters the nucleoplasm as part of the ligand-activated
      AHR-HSP90 complex, but this is not its primary localization. The Reactome
      pathway model is accurate for the transient translocation event.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8937191
  review:
    summary: This TAS annotation is based on Reactome pathway R-HSA-8937191
      (AHR:TCDD:2xHSP90AB1:AIP:PTGES3 dissociates). This represents the dissociation
      of the AHR complex in the nucleoplasm after translocation. AIP is released from
      the complex in the nucleus. This is consistent with the transient nuclear
      localization of AIP during AHR signaling.
    action: KEEP_AS_NON_CORE
    reason: This represents transient nuclear localization of AIP during AHR signaling,
      consistent with the Reactome pathway model. Not the primary localization.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8936849
  review:
    summary: This TAS annotation is based on Reactome pathway R-HSA-8936849
      (AHR:2xHSP90:AIP:PTGES3 binds TCDD). AIP is part of the cytosolic AHR complex
      that binds the TCDD ligand. Cytosolic localization of AIP is well-established.
    action: ACCEPT
    reason: Cytosolic localization of AIP as part of the AHR complex is well-supported
      by multiple lines of evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8937169
  review:
    summary: This TAS annotation is based on Reactome pathway R-HSA-8937169
      (AHR:TCDD:2xHSP90AB1:AIP:PTGES3 translocates from cytosol to nucleoplasm).
      AIP starts in the cytosol as part of the AHR complex. Cytosol is the primary
      localization.
    action: ACCEPT
    reason: Cytosolic localization is the primary and well-established localization
      for AIP.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8950201
  review:
    summary: This TAS annotation is based on Reactome pathway R-HSA-8950201
      (Expression of Aryl Hydrocarbon receptor-interacting protein). AIP is expressed
      and localized in the cytosol. This is consistent with all other evidence.
    action: ACCEPT
    reason: Cytosolic localization of AIP is the primary and well-established
      localization, supported by all available evidence.
- term:
    id: GO:0036004
    label: GAF domain binding
  evidence_type: IDA
  original_reference_id: PMID:17329248
  review:
    summary: This IDA annotation to GO:0036004 (GAF domain binding) is based on de
      Oliveira et al. (PMID:17329248), which showed that XAP2 binds to the GAF-B
      domain of PDE2A. The binding was identified by yeast two-hybrid and confirmed
      by immunoprecipitation. The GAF-B domain was specifically mapped as the XAP2
      binding site. This is a well-characterized, specific molecular interaction.
    action: ACCEPT
    reason: The interaction between AIP/XAP2 and the GAF-B domain of PDE2A was
      specifically mapped and validated by multiple methods (yeast two-hybrid and
      co-immunoprecipitation). This is a specific and informative MF annotation.
    supported_by:
    - reference_id: PMID:17329248
      supporting_text: We mapped the XAP2 binding site to the GAF-B domain of PDE2A.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:17329248
  review:
    summary: This IDA annotation for cytosol localization is based on de Oliveira et al.
      (PMID:17329248), which performed immunofluorescence showing XAP2 in the cytosol.
      The study also showed that PDE2A colocalizes with XAP2 in the cytosol and at the
      plasma membrane.
    action: ACCEPT
    reason: Cytosolic localization demonstrated by immunofluorescence is consistent
      with all other evidence for AIP being primarily a cytosolic protein.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:17329248
  review:
    summary: This IDA annotation with qualifier colocalizes_with records that AIP/XAP2
      colocalizes with the plasma membrane, based on de Oliveira et al. (PMID:17329248).
      The study showed XAP2 and PDE2A colocalize at the plasma membrane in addition to
      the cytosol. This likely reflects AIP being recruited to the plasma membrane
      through its interaction with PDE2A, which has membrane association. This is a
      secondary, non-core localization dependent on the PDE2A interaction.
    action: KEEP_AS_NON_CORE
    reason: Plasma membrane colocalization is a secondary localization dependent on
      the interaction with PDE2A. AIP is primarily a cytosolic protein and does not
      have intrinsic membrane targeting. The colocalizes_with qualifier appropriately
      indicates indirect association.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14557246
  review:
    summary: This IPI annotation records AIP interactions with Hsc70 (UniProtKB:P11142),
      TOMM20 (UniProtKB:Q15388), and/or TOMM20L (UniProtKB:Q9NS69) from Yano et al.
      (PMID:14557246). The paper demonstrated by two-hybrid and in vitro binding that
      AIP interacts with TOMM20 via its TPR domain and with Hsc70. AIP forms a ternary
      complex with preproteins and TOMM20. These are core, functionally important
      interactions for AIP's role in mitochondrial preprotein import.
    action: ACCEPT
    reason: The interactions of AIP with TOMM20 and Hsc70 demonstrated in PMID:14557246
      are core to its mitochondrial import mediator function. The binding was validated
      by multiple methods including two-hybrid, in vitro binding, and co-precipitation.
    supported_by:
    - reference_id: PMID:14557246
      supporting_text: Using two-hybrid screening, we identified arylhydrocarbon
        receptor-interacting protein (AIP), an FK506-binding protein homologue,
        interacting with Tom20.
    - reference_id: PMID:14557246
      supporting_text: Hsc70 was also found to bind to AIP.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: PMID:14557246
  review:
    summary: This TAS annotation for cytosol localization cites Yano et al.
      (PMID:14557246). The paper demonstrates AIP functions as a cytosolic factor
      mediating preprotein import into mitochondria. AIP was detected in cytosolic
      fractions of HeLa, HepG2, COS-7, and Hepa1c1c7 cells by immunoblot.
    action: ACCEPT
    reason: Cytosolic localization of AIP is well-documented by immunoblot analysis
      in multiple cell lines in this paper and is consistent with all other evidence.
    supported_by:
    - reference_id: PMID:14557246
      supporting_text: When immunoblot analysis was done using anti-human AIP, AIP
        polypeptides were readily detected in the lysates of HeLa (human), HepG2
        (human), COS-7 (monkey), and Hepa1c1c7 (mouse) cells.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:14557246
  review:
    summary: This IDA annotation to GO:0051082 (unfolded protein binding) is based on
      Yano et al. 2003 (PMID:14557246), which demonstrated that AIP has genuine
      chaperone-like (holdase) activity. The key evidence is from thermal aggregation
      suppression assays (Figure 6 of the paper). AIP suppressed thermal aggregation
      of rhodanese at 55C and citrate synthase at 43C in a dose-dependent manner. At
      equimolar concentrations, GST-AIP suppressed rhodanese aggregation at early time
      points, and completely suppressed citrate synthase aggregation. This activity was
      additive or synergistic with Hsc70. The paper also showed AIP binds specifically
      to mitochondrial preproteins via their presequences, maintaining them in an
      import-competent (unfolded) conformation. The chaperone activity is mechanistically
      linked to AIP's role in mitochondrial import, keeping preproteins unfolded for
      translocation through the TOM complex. GO:0051082 is being obsoleted
      (go-ontology issue 30962), and the activity described is better captured by
      GO:0044183 (protein folding chaperone), which describes binding to proteins to
      assist the folding process, encompassing holdase activity that prevents
      aggregation of unfolded substrates.
    action: MODIFY
    reason: GO:0051082 is being obsoleted. The experimental evidence from PMID:14557246
      clearly demonstrates a chaperone-like holdase activity for AIP, not merely passive
      binding to unfolded proteins. AIP actively prevents thermal aggregation of model
      substrates (rhodanese and citrate synthase) and maintains mitochondrial preproteins
      in import-competent conformations. The replacement term GO:0044183 (protein folding
      chaperone) is the appropriate successor, capturing the active nature of this
      chaperone function. The evidence is robust -- the aggregation suppression assays
      used purified GST-AIP protein with proper GST-only controls, showed dose-dependent
      effects, and the physiological relevance was confirmed by in vivo import assays
      showing AIP maintains preprotein import competency.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    supported_by:
    - reference_id: PMID:14557246
      supporting_text: AIP exhibited a chaperone-like activity to suppress the aggregation
        of substrate proteins.
    - reference_id: PMID:14557246
      supporting_text: When GST-AIP was added instead of GST, the aggregation of
        rhodanese was partially suppressed, and that of citrate synthase was completely
        suppressed. These results reconfirmed that AIP has chaperone-like activity.
    - reference_id: PMID:14557246
      supporting_text: AIP was found to function as a chaperone to suppress thermal
        aggregation of rhodanese and citrate synthase (Fig. 6). AIP may function as
        a chaperone to maintain mitochondria-targeted preproteins unfolded and to
        suppress their aggregation.
- term:
    id: GO:0070585
    label: protein localization to mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:14557246
  review:
    summary: This IDA annotation to GO:0070585 (protein localization to mitochondrion)
      is based on Yano et al. (PMID:14557246), which provides extensive evidence that
      AIP mediates mitochondrial preprotein import. Key evidence includes in vitro
      import assays showing AIP maintains pOTC import competency, cell-based assays
      showing AIP overexpression enhances pOTC import by ~3-fold, siRNA depletion of
      AIP impairing pOTC import to ~40% of control, AIP binding specifically to
      mitochondrial preproteins via their presequences, AIP forming ternary complexes
      with preproteins and TOMM20, and AIP having chaperone-like activity to prevent
      preprotein aggregation. This is a well-supported core function of AIP.
    action: ACCEPT
    reason: The evidence for AIP mediating protein localization to mitochondria is
      extensive and robust, including in vitro import assays, overexpression and
      depletion experiments in cells, specific binding to preproteins and TOMM20,
      and ternary complex formation. This represents a core function of AIP alongside
      its role in the AHR-HSP90 complex.
    supported_by:
    - reference_id: PMID:14557246
      supporting_text: These results suggest that AIP functions as a cytosolic factor
        that mediates preprotein import into mitochondria.
    - reference_id: PMID:14557246
      supporting_text: Thus, depletion of AIP reduced the mitochondrial import of pOTC,
        which means that endogenous AIP facilitates pOTC import into mitochondria.
    - reference_id: PMID:14557246
      supporting_text: Formation of a ternary complex of Tom20, AIP, and preprotein
        was observed.
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: TAS
  original_reference_id: PMID:9447995
  review:
    summary: This TAS annotation to GO:0003713 (transcription coactivator activity) is
      based on Meyer et al. (PMID:9447995), which showed that XAP2 enhanced AhR-driven
      transcription of a dioxin-responsive element reporter by about twofold when
      transiently expressed in Hepa 1c1c7 and HeLa cells. However, AIP does not function
      as a classical transcription coactivator. AIP enhances AhR signaling indirectly by
      stabilizing the cytosolic AHR-HSP90 complex, improving AhR receptivity for ligand
      and/or nuclear targeting. AIP does not directly contact DNA or recruit
      transcriptional machinery. The term "transcription coactivator activity" implies
      direct participation in transcriptional activation, which overstates AIP's role.
      A more accurate description would be that AIP modulates AhR signaling through its
      co-chaperone function.
    action: MARK_AS_OVER_ANNOTATED
    reason: AIP enhances AhR-driven transcription indirectly through its co-chaperone
      function in the AHR-HSP90 complex, not by acting as a direct transcription
      coactivator. The twofold enhancement of reporter activity (PMID:9447995) reflects
      improved AhR complex stability and signaling, not direct transcriptional
      coactivation. Calling AIP a transcription coactivator overstates its molecular
      role and is misleading about its mechanism of action.
    supported_by:
    - reference_id: PMID:9447995
      supporting_text: XAP2 enhanced the ability of endogenous murine and human AhR
        complexes to activate a dioxin-responsive element-luciferase reporter twofold,
        following transient expression of XAP2 in Hepa 1c1c7 and HeLa cells.
    - reference_id: PMID:9447995
      supporting_text: It was not required for the assembly of an AhR-hsp90 complex in
        vitro. Additionally, XAP2 did not directly associate with hsp90 upon in vitro
        translation, but was present in a 9S form when cotranslated in vitro with murine
        AhR.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: TAS
  original_reference_id: PMID:8972861
  review:
    summary: This TAS annotation for cytoplasm is based on Kuzhandaivelu et al.
      (PMID:8972861), the original paper identifying XAP2 as a hepatitis B virus
      X-associated protein. The paper showed by immunostaining with anti-XAP2 antiserum
      that XAP2 is a cytoplasmic protein with apparent molecular mass of 36 kDa.
    action: ACCEPT
    reason: Cytoplasmic localization of AIP/XAP2 was directly demonstrated by
      immunostaining in the original characterization paper and is consistent with
      all subsequent evidence.
    supported_by:
    - reference_id: PMID:8972861
      supporting_text: Antiserum raised against XAP2 recognizes a cytoplasmic protein
        with an apparent molecular mass of 36 kDa.
- term:
    id: GO:0051879
    label: Hsp90 protein binding
  evidence_type: IDA
  original_reference_id: PMID:19375531
  review:
    summary: AIP/XAP2 binds HSP90 through its TPR motif, as demonstrated in multiple
      studies. Laenger et al. (PMID:19375531) showed that XAP2 inhibits GR through
      its interaction with Hsp90 via the TPR motif. The crystal structure of the AIP
      TPR domain bound to the HSP90 MEEVD peptide (PDB:4APO, PMID:23300914) confirms
      this interaction at atomic resolution. Salvatori et al. (PMID:28634279) showed
      disease-causing TPR mutations disrupt HSP90 binding. This is a core molecular
      function of AIP not currently captured by a specific GO annotation in the
      existing set.
    action: NEW
    reason: AIP binding to HSP90 via its TPR domain is the most well-characterized
      core molecular function of AIP. While multiple IPI protein binding annotations
      record AIP-HSP90 interactions, the specific term GO:0051879 (Hsp90 protein binding)
      would more accurately capture this core function. This is supported by extensive
      experimental evidence including co-immunoprecipitation, structural data, and
      functional studies.
    supported_by:
    - reference_id: PMID:19375531
      supporting_text: The effect of XAP2 on GR requires its interaction with Hsp90
        through the TPR motif.
    - reference_id: PMID:28634279
      supporting_text: The mutation results in the duplication of seven amino-acids in
        third TPR domain of AIP, leading to the disruption of protein-protein interactions
        and markedly reduced protein stability.
core_functions:
- molecular_function:
    id: GO:0051879
    label: Hsp90 protein binding
  description: >-
    AIP/XAP2 binds HSP90 via its C-terminal TPR domain (three TPR motifs plus a
    terminal alpha-7 helix), serving as a co-chaperone/scaffold in the AHR-HSP90
    complex. The TPR domain engages the MEEVD motif at the HSP90 C-terminus
    (PDB:4APO). Cryo-EM structure of the human agonist-bound HSP90-XAP2-AHR
    cytosolic complex (DOI:10.1038/s41467-022-34773-w) reveals AIP acting as a
    structural brace associated with the HSP90 dimer and the AHR client, with the
    MEEVD motif docked into the TPR domain of AIP, consistent with canonical
    TPR-mediated recruitment of HSP90 co-chaperones. Disease-causing mutations in
    the TPR domain disrupt HSP90 binding and are associated with pituitary
    neuroendocrine tumor predisposition (PitNET/PITA1), consistent with a two-hit
    tumor suppressor model (loss of heterozygosity in tumors).
  directly_involved_in:
    - id: GO:0006457
      label: protein folding
  locations:
    - id: GO:0005829
      label: cytosol
  in_complex:
    id: GO:0034751
    label: aryl hydrocarbon receptor complex
  supported_by:
    - reference_id: PMID:19375531
      supporting_text: >-
        The effect of XAP2 on GR requires its interaction with Hsp90 through the
        TPR motif.
    - reference_id: PMID:28634279
      supporting_text: >-
        The mutation results in the duplication of seven amino-acids in third TPR
        domain of AIP, leading to the disruption of protein-protein interactions
        and markedly reduced protein stability.
- molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  description: >-
    AIP exhibits chaperone-like holdase activity, suppressing thermal aggregation of
    model substrates (rhodanese, citrate synthase) in vitro. This chaperone activity
    is linked to its role in maintaining mitochondrial preproteins in an
    import-competent conformation for translocation through the TOM complex.
  directly_involved_in:
    - id: GO:0070585
      label: protein localization to mitochondrion
  locations:
    - id: GO:0005829
      label: cytosol
  supported_by:
    - reference_id: PMID:14557246
      supporting_text: >-
        AIP exhibited a chaperone-like activity to suppress the aggregation of
        substrate proteins.
    - reference_id: PMID:14557246
      supporting_text: >-
        AIP may function as a chaperone to maintain mitochondria-targeted
        preproteins unfolded and to suppress their aggregation.
- molecular_function:
    id: GO:0017162
    label: aryl hydrocarbon receptor binding
  description: >-
    AIP/XAP2 is a stoichiometric component of the unliganded AHR 9S core complex
    (AHR:2xHSP90:AIP:PTGES3), binding directly to the aryl hydrocarbon receptor.
    It stabilizes the cytosolic AHR-HSP90 complex, enhancing AhR receptivity for
    ligand and subsequent transcriptional activation. Cryo-EM structural analysis
    (DOI:10.1038/s41467-022-34773-w) confirms the architectural arrangement of AIP
    as a brace spanning the HSP90 dimer and AHR client within this complex.
  directly_involved_in:
    - id: GO:0045893
      label: positive regulation of DNA-templated transcription
  locations:
    - id: GO:0005829
      label: cytosol
  in_complex:
    id: GO:0034751
    label: aryl hydrocarbon receptor complex
  supported_by:
    - reference_id: PMID:9447995
      supporting_text: >-
        Here we report the purification of an approximately 38-kDa protein (p38)
        from COS-1 cell cytosol that is a member of this complex by
        coprecipitation with a FLAG-tagged AhR.
- molecular_function:
    id: GO:0036004
    label: GAF domain binding
  description: >-
    AIP binds to the GAF-B domain of phosphodiesterase 2A (PDE2A), an interaction
    that inhibits TCDD- and cAMP-induced nuclear translocation of AhR in
    hepatocytes, providing a regulatory link between cAMP signaling and the AhR
    pathway. AIP also interacts with PDE4A5, further linking it to localized cAMP
    regulation (DOI:10.1586/eem.10.42). These phosphodiesterase interactions
    suggest AIP may modulate pituitary tumor biology through cAMP pathway effects.
  locations:
    - id: GO:0005829
      label: cytosol
  supported_by:
    - reference_id: PMID:17329248
      supporting_text: >-
        We mapped the XAP2 binding site to the GAF-B domain of PDE2A.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:14557246
  title: AIP is a mitochondrial import mediator that binds to both import receptor
    Tom20 and preproteins.
  findings: []
- id: PMID:17329248
  title: Phosphodiesterase 2A forms a complex with the co-chaperone XAP2 and regulates
    nuclear translocation of the aryl hydrocarbon receptor.
  findings: []
- id: PMID:19375531
  title: XAP2 inhibits glucocorticoid receptor activity in mammalian cells.
  findings: []
- id: PMID:20029029
  title: Regulation of epidermal growth factor receptor trafficking by lysine deacetylase
    HDAC6.
  findings: []
- id: PMID:21170051
  title: Mixed Hsp90-cochaperone complexes are important for the progression of the
    reaction cycle.
  findings: []
- id: PMID:21903422
  title: Mapping a dynamic innate immunity protein interaction network regulating
    type I interferon production.
  findings: []
- id: PMID:22113938
  title: A bead-based approach for large-scale identification of in vitro kinase substrates.
  findings: []
- id: PMID:23300914
  title: 'Structure of the TPR domain of AIP: lack of client protein interaction with
    the C-terminal α-7 helix of the TPR domain of AIP is sufficient for pituitary
    adenoma predisposition.'
  findings: []
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture of
    cellular protein homeostasis pathways.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
- id: PMID:28634279
  title: In-frame seven amino-acid duplication in AIP arose over the last 3000 years,
    disrupts protein interaction and stability and is associated with gigantism.
  findings: []
- id: PMID:31980649
  title: Extensive rewiring of the EGFR network in colorectal cancer cells expressing
    transforming levels of KRAS(G13D).
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:8972861
  title: XAP2, a novel hepatitis B virus X-associated protein that inhibits X transactivation.
  findings: []
- id: PMID:9447995
  title: Hepatitis B virus X-associated protein 2 is a subunit of the unliganded aryl
    hydrocarbon receptor core complex and exhibits transcriptional enhancer activity.
  findings: []
- id: Reactome:R-HSA-8936849
  title: AHR:2xHSP90:AIP:PTGES3 binds TCDD
  findings: []
- id: Reactome:R-HSA-8937169
  title: AHR:TCDD:2xHSP90AB1:AIP:PTGES3 translocates from cytosol to nucleoplasm
  findings: []
- id: Reactome:R-HSA-8937191
  title: AHR:TCDD:2xHSP90AB1:AIP:PTGES3 dissociates
  findings: []
- id: Reactome:R-HSA-8950201
  title: Expression of Aryl Hydrocarbon receptor-interacting protein
  findings: []
- id: DOI:10.1038/s41467-022-34773-w
  title: Cryo-EM structure of the agonist-bound Hsp90-XAP2-AHR cytosolic complex
  findings:
    - statement: >-
        High-resolution cryo-EM structure of the human agonist-bound AHR cytosolic
        complex with Hsp90 and XAP2/AIP reveals AIP acting as a structural brace
        associated with the Hsp90 dimer and the AHR client; the Hsp90 C-terminal
        MEEVD motif docks into the TPR domain of AIP, consistent with canonical
        TPR-mediated recruitment of HSP90 co-chaperones.
- id: DOI:10.18632/oncotarget.24183
  title: Multi-chaperone function modulation and association with cytoskeletal
    proteins are key features of the function of AIP in the pituitary gland
  findings:
    - statement: >-
        Proteomic analysis shows AIP co-localizes with HSPA9 in the mitochondrial
        chaperone network, consistent with broader chaperone-network associations
        beyond the AHR complex.
- id: DOI:10.1586/eem.10.42
  title: Role of the aryl hydrocarbon receptor-interacting protein in familial
    isolated pituitary adenoma
  findings:
    - statement: >-
        AIP interacts with phosphodiesterases PDE4A5 and PDE2A3, linking it to
        localized cAMP regulation and potentially to modulation of AHR nuclear
        translocation and pituitary tumor biology.
- id: DOI:10.1038/s41574-023-00948-8
  title: Consensus guideline for the diagnosis and management of pituitary
    adenomas in childhood and adolescence
  findings:
    - statement: >-
        Among childhood-onset GH-secreting pituitary tumours presenting as
        gigantism, AIP mutations account for approximately 29% of cases; for
        macroprolactinomas presenting before age 20, the genetic aetiology
        includes approximately 9% AIP and 5% MEN1.
- id: DOI:10.1093/ejendo/lvad148
  title: Genetic testing in prolactinomas - a cohort study
  findings:
    - statement: >-
        In sporadic isolated macroprolactinomas diagnosed at age 30 or younger,
        the germline pathogenic/likely pathogenic variant prevalence was 4.3%
        overall, with 1.9% AIP; sporadic macroprolactinoma diagnosed before age
        18 had approximately 9-fold higher odds of carrying a germline mutation
        than diagnosis at 18-30.
- id: DOI:10.3389/fendo.2023.1098367
  title: AIP gene germline variants in adult Polish patients with apparently
    sporadic pituitary macroadenomas
  findings:
    - statement: >-
        Penetrance among AIP variant carriers is incomplete and variable, with
        reported estimates ranging from approximately 12-30%, and some
        variants/families as low as approximately 6%.