Affinage

AIP

Small ribosomal subunit protein bS22, mitochondrial · UniProt Q9NWT8

Length
199 aa
Mass
22.4 kDa
Annotated
2026-06-09
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AIP (XAP2/ARA9) is a TPR-domain co-chaperone that controls the cytoplasmic maturation, stability, and signaling output of client proteins assembled on the Hsp90 chaperone machine (PMID:9837941, PMID:10413464, PMID:36385050). Its best-characterized client is the aryl hydrocarbon receptor (AHR): AIP is a constituent of the unliganded AHR–Hsp90 complex, where its three C-terminal TPR motifs bind the C-terminal acceptor site of Hsp90 while its N-terminal region stabilizes the ternary receptor–Hsp90–AIP assembly (PMID:9837941, PMID:10413464, PMID:11805120), and cryo-EM resolves AIP acting as a structural brace bracing AHR threaded through a closed Hsp90 dimer (PMID:36385050). Through this association AIP raises cytosolic AHR levels by protecting the receptor from CHIP-mediated ubiquitination and proteasomal degradation, retains unliganded AHR in the cytoplasm by hindering importin-β access to the receptor NLS, and represses AHR transactivation (PMID:11013261, PMID:12431985, PMID:12837759); in mouse liver AIP is required to maintain functional cytosolic AHR and for dioxin-induced hepatotoxicity and a subset of AHR target genes (PMID:20829355). AIP also engages other nuclear receptors (TRβ1, ERα, GR), in each case acting on receptor stability or transcriptional output via its TPR/Hsp90 interface (PMID:16936638, PMID:19375531, PMID:21984905). Beyond chaperone clients, AIP binds and reversibly inhibits the cAMP-specific phosphodiesterase PDE4A5 through TPR residue Arg271, linking it to cAMP control (PMID:12810716), and it mediates Tom20-dependent mitochondrial import of preproteins including survivin, with chaperone-like anti-aggregation activity essential for embryonic erythropoietic survival (PMID:14557246, PMID:21454573). In pituitary somatotrophs AIP is a tumor suppressor: heterozygous loss drives GH-secreting adenomas, and AIP deficiency elevates cAMP through defective Gαi-2/Gαi-3 signaling and interaction with PKA subunits, blunts somatostatin-analog responses partly via ZAC1, and disables a membrane RET/caspase-3/PKCδ complex that normally triggers a PIT1/ARF/p53 apoptotic program (PMID:20709796, PMID:23702468, PMID:24662816, PMID:29726992, PMID:34588620). Disease-associated TPR mutations selectively abolish client binding at the C-terminal α-7 helix while sparing chaperone binding (PMID:23300914), and missense AIP variants are rapidly degraded by the SCF–FBXO3 E3 ubiquitin ligase, with variant half-life correlating with age at acromegaly diagnosis (PMID:27253664).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1996 Medium

    AIP was first isolated as a viral X-associated protein, establishing it as a protein-interaction module before any cellular chaperone role was known.

    Evidence Yeast two-hybrid with hepatitis B virus X protein, confirmed by in vitro binding and reporter assays

    PMID:8972861

    Open questions at the time
    • Physiological relevance of the viral X-protein interaction to endogenous AIP function not established
    • No domain mapping of the interaction surface
  2. 1999 High

    Identifying AIP as a TPR-mediated component of the unliganded AHR–Hsp90 complex defined its core biochemical role and the architecture of binding.

    Evidence Reciprocal Co-IP, domain mapping, in vitro binding, and yeast functional assays defining the 9S tetrameric core complex

    PMID:10413464 PMID:9837941

    Open questions at the time
    • Stoichiometry and conformational detail not resolved at this stage
    • Functional consequence for receptor turnover only inferred
  3. 2003 High

    AIP was shown to determine AHR fate by protecting the receptor from CHIP-mediated ubiquitination and by blocking importin-β access to the NLS, explaining both its stabilizing and cytoplasmic-retention effects.

    Evidence Ubiquitination assays, nuclear translocation and importin-β binding assays, siRNA depletion, and CHIP identification

    PMID:11013261 PMID:12431985 PMID:12837759

    Open questions at the time
    • Species-specific differences between mouse and human AHR handling not yet reconciled
    • Quantitative competition with CHIP at the Hsp90 acceptor site not measured directly
  4. 2003 High

    Discovery of TPR-mediated inhibition of PDE4A5 and Tom20-dependent mitochondrial preprotein import established that AIP has chaperone clients beyond AHR.

    Evidence In vitro enzyme assays with TPR mutagenesis (PDE4A5); in vitro import reconstitution, ternary complex formation, and RNAi (mitochondrial import)

    PMID:12810716 PMID:14557246

    Open questions at the time
    • Physiological substrate range of the mitochondrial import function incompletely defined
    • Whether PDE inhibition and AHR chaperoning are coordinated in the same cellular context unknown
  5. 2006 Medium

    Extension of AIP binding to TRβ1, ERα, and GR showed it acts broadly on nuclear-receptor stability and transcriptional output, with receptor-isoform selectivity.

    Evidence Yeast two-hybrid, Co-IP, ChIP, siRNA, and reporter/in vivo functional assays across TRβ1, ERα and GR

    PMID:16936638 PMID:19375531 PMID:21984905

    Open questions at the time
    • Mechanistic basis for receptor-isoform selectivity not resolved
    • Most receptor studies confined to single labs and overexpression systems
  6. 2010 High

    Genetic mouse models established AIP as required for hepatic AHR function and as a haploinsufficient pituitary tumor suppressor, anchoring its physiological roles.

    Evidence Conditional liver-specific and heterozygous Aip knockout mice with gene-expression, toxicity, and tumor-penetrance readouts

    PMID:20709796 PMID:20829355

    Open questions at the time
    • Why somatotrophs are uniquely sensitive to AIP loss not explained by AHR biology alone
    • Link between reduced ARNT and tumorigenesis correlative
  7. 2011 High

    AIP-directed mitochondrial import of survivin was shown to be essential for embryonic erythropoietic survival, giving the import function a developmental phenotype.

    Evidence Homozygous Aip knockout (embryonic lethal), in vitro import reconstitution with recombinant proteins, and Tom20/Tom70 shRNA dissection

    PMID:21454573

    Open questions at the time
    • Full repertoire of physiological mitochondrial import substrates unknown
    • Relationship of import function to pituitary tumor suppression unclear
  8. 2014 High

    AIP deficiency was mechanistically tied to elevated cAMP through defective Gαi-2/Gαi-3 signaling, providing a signaling basis for somatotroph tumorigenesis.

    Evidence Microarray, cAMP assays, Gαi knockdown epistasis, and immunostaining in mouse and human tumors

    PMID:23702468 PMID:24662816

    Open questions at the time
    • How AIP physically regulates Gαi proteins not defined
    • Relative contributions of PDE, Gαi, and PKA inputs to cAMP not quantified
  9. 2016 High

    Defining SCF–FBXO3 as the E3 ligase for AIP and linking variant half-life to disease age explained how missense mutations cause loss of function.

    Evidence Cycloheximide chase, proteasome rescue, GST pull-down with mass spectrometry, and patient genotype–phenotype correlation

    PMID:27080473 PMID:27253664

    Open questions at the time
    • Signals triggering SCF-FBXO3 recognition of mutant AIP not defined
    • Whether wild-type AIP turnover is physiologically regulated unknown
  10. 2018 Medium

    AIP was shown to bind both PKA subunits and a wider chaperone/cytoskeletal interactome, broadening the cAMP/PKA regulatory model and identifying mutation-sensitive partners.

    Evidence Co-IP, PKA activity assays, and quantitative mass spectrometry from somatotropinoma lysates

    PMID:29507682 PMID:29726992

    Open questions at the time
    • Functional consequence of novel partners (NME1, SOD1, tubulins) not established
    • Direct vs Hsp90-bridged nature of PKA interactions unclear
  11. 2021 High

    A membrane RET/caspase-3/PKCδ complex requiring AIP to drive a PIT1/ARF/p53 apoptotic pathway provided a somatotroph-specific tumor-suppressor mechanism distinct from the chaperone role.

    Evidence Complex-formation and caspase activation assays, in vivo virogenomics in rats, Aip-KO mouse and human tumor analysis

    PMID:30867568 PMID:32856736 PMID:34588620

    Open questions at the time
    • Molecular detail of how AIP assembles the RET complex at the membrane unknown
    • Integration of the apoptotic pathway with cAMP/Gαi defects not resolved
  12. 2022 High

    The cryo-EM structure of the AHR–Hsp90–XAP2 complex resolved decades of biochemistry, showing AIP as a structural brace on a closed Hsp90 dimer with AHR threaded through its lumen.

    Evidence 2.85 Å cryo-EM structure of the indirubin-bound human ternary complex

    PMID:36385050

    Open questions at the time
    • Structures of AIP with non-AHR clients (PDE4A5, Tom20, nuclear receptors) not available
    • Conformational basis of ligand-triggered AIP release not captured

Open questions

Synthesis pass · forward-looking unresolved questions
  • How AIP's distinct activities — Hsp90-client chaperoning, mitochondrial import, cAMP/PKA/Gαi regulation, and the RET apoptotic pathway — are coordinated within a single cell, and which is most relevant to somatotroph tumor suppression, remains unresolved.
  • No unified model linking the multiple AIP functions
  • Tissue specificity of pituitary phenotype unexplained at the molecular level

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0044183 protein folding chaperone 2 GO:0140104 molecular carrier activity 2
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 2 GO:0005739 mitochondrion 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9609507 Protein localization 2
Partners
AHRHSP90AB1PDE4A5PRKACAPRKAR1ARETTHRBTOMM20
Complex memberships
AHR–Hsp90–AIP (9S) complexTom20–AIP–preprotein import complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 XAP2 (AIP) was identified as a novel hepatitis B virus X-associated protein that inhibits X protein-mediated transcriptional transactivation; the interaction requires amino acids 13-26 of the X protein and overexpression of XAP2 abolishes X protein transactivation in transfection assays. Yeast two-hybrid, in vitro interaction assay, transfection/reporter assay Nucleic acids research Medium 8972861
1998 AIP (ARA9) was identified as a component of the unliganded AHR-Hsp90 complex; the three tetratricopeptide repeats (TPR) in the C-terminus of ARA9 are necessary and sufficient for interaction with the AHR complex, whereas the AHR's Hsp90-binding domain is required for interaction with ARA9. ARA9 specifically associates with AHR-Hsp90 but not GR-Hsp90 complexes. In a yeast expression system, ARA9 expression enhanced AHR agonist response by decreasing EC50 >5-fold and increasing maximal response 2.5-fold. Co-immunoprecipitation, domain mapping, yeast expression system functional assay The Journal of biological chemistry High 9837941
1999 XAP2 (AIP) forms part of a tetrameric 9S core complex with the AHR, a dimer of Hsp90, and itself. XAP2 requires the PAS, Hsp90, and ligand-binding domains of AHR for binding and can interact directly with AHR in the absence of Hsp90. XAP2 binds to the C-terminal end of Hsp90 (TPR acceptor site), distinct from where AHR binds (middle of Hsp90). XAP2 is not associated with the AHR-ARNT heterocomplex. Transient expression of XAP2 in COS-1 cells enhanced cytosolic AHR levels, suggesting a role in regulating AHR turnover. Biochemical mapping, co-immunoprecipitation, transient transfection/cotransfection, in vitro binding Biochemistry High 10413464
2000 XAP2 (AIP) protected the ligand-free AHR against ubiquitination, resulting in increased AHR protein levels. Upon ligand exposure, nuclear translocation of the AHR was markedly delayed by XAP2, indicating a role in cytoplasmic retention. These effects required stable association of XAP2 with the Hsp90-p23 chaperone complex. Ubiquitination assay, nuclear translocation assay, immunoprecipitation The Journal of biological chemistry High 11013261
2000 AIP (ARA9) enhances AHR signal transduction by increasing available AHR binding sites within the cytosolic compartment; co-expression of ARA9 increases the fraction of AHR in the cytosol and stabilizes the receptor under heat stress. This effect is not due to inhibition of a membrane pump or modification of transactivation properties. Photoaffinity labeling, coexpression experiments in yeast and mammalian cells The Journal of biological chemistry High 10692406
2000 XAP2 TPR domain mediates binding to both AHR and Hsp90; single-point mutations in the TPR region disrupt association of XAP2 with both AHR and Hsp90 in cells. Co-transfection of AHR with XAP2 (but not FKBP52, PP5, or TPR-mutant XAP2) increases AHR levels. XAP2-YFP localizes to both nucleus and cytoplasm. Cotransfection, Co-immunoprecipitation, site-directed mutagenesis, fluorescence microscopy Cell stress & chaperones High 11005382
2002 XAP2 (AIP) inhibits ligand-independent nucleocytoplasmic shuttling of the AHR and hinders importin-β binding to the AHR complex, suggesting that XAP2 alters the conformation of the bipartite NLS of AHR. XAP2 also represses the transactivation potential of AHR and does not physically tether the complex in the cytoplasm. Leptomycin B nuclear export inhibition assay, cytoskeletal disruption, NLS antibody studies, importin-β binding assay, fluorescence imaging The Journal of biological chemistry High 12431985
2002 Two distinct regions of XAP2 (AIP) modulate dioxin receptor function: the C-terminal part (TPR motifs plus adjacent region) directly contacts Hsp90, while the N-terminal part is required for stability of the ternary dioxin receptor-Hsp90-XAP2 complex and for XAP2-mediated regulation of receptor intracellular localization. Co-immunoprecipitation of XAP2 deletion mutants, functional localization assay The Journal of biological chemistry Medium 11805120
2003 XAP2 (AIP) interacts specifically with the cAMP-specific phosphodiesterase PDE4A5 (but not with closely related AIPL1, FKBP51, FKBP52, or other PDE4 isoforms). XAP2 reversibly inhibits PDE4A5 enzymatic activity (~60% maximal inhibition, IC50 ~120 nM), increases sensitivity to rolipram, and attenuates PKA-mediated phosphorylation of PDE4A5. The XAP2 TPR domain (aa 170-330) mediates these effects; Arg271→Ala mutation in the TPR abrogates both interaction and inhibition. Specific regions of PDE4A5 (N-terminal and UCR2 domains) are required for XAP2-mediated inhibition. Yeast two-hybrid, biochemical pull-down, in vitro enzyme activity assay, co-immunoprecipitation in COS7 and brain tissue, site-directed mutagenesis, PKA phosphorylation assay The Journal of biological chemistry High 12810716
2003 XAP2 (AIP) reduced levels destabilize the dioxin receptor (AHR). XAP2 protects AHR from CHIP (C-terminal Hsp70-interacting protein)-mediated ubiquitin ligase degradation, dependent on the XAP2 TPR domain. This suggests that competition for the C-terminal TPR acceptor site of Hsp90 determines whether AHR undergoes chaperone-mediated maturation or ubiquitin-proteasome degradation. siRNA/RNAi depletion, overexpression, co-immunoprecipitation, proteasome inhibitor experiments The Journal of biological chemistry High 12837759
2003 AIP was identified as a mitochondrial import mediator that binds to both the import receptor Tom20 and mitochondrial preproteins. AIP directly prevents preornithine transcarbamylase from losing import competency in vitro, overexpression enhances preprotein import, and RNAi depletion impairs import. AIP, Tom20, and preprotein form a ternary complex; Hsc70 also binds AIP. AIP has chaperone-like activity preventing substrate protein aggregation. Yeast two-hybrid, in vitro import assay, co-immunoprecipitation, RNAi knockdown, in vitro binding assay, aggregation suppression assay The Journal of cell biology High 14557246
2004 XAP2 (AIP) shows divergent roles for mouse versus human AHR: XAP2 redistributes mouse AHR-YFP from nucleus to cytoplasm and blocks nuclear translocation, but does not affect cytoplasmic localization of human AHR-YFP. For the human AHR, XAP2 remains bound during nucleocytoplasmic shuttling and enhances rate of nuclear translocation but represses transcriptional activity. Fluorescence microscopy of AHR-YFP fusions, leptomycin B nuclear export inhibition, XAP2-NLS fusion experiments, cotransfection Biochemistry Medium 14730974
2006 XAP2 (AIP) acts as a novel partner for TRβ1 (but not TRβ2) in the thyroid hormone receptor pathway; the interaction is enhanced by T3. XAP2 siRNA knockdown reduces TRβ1 stability in vitro and abrogates TRβ1-mediated (but not TRβ2-mediated) activation of hypothalamic TRH transcription in vivo. Yeast two-hybrid screening, mammalian co-immunoprecipitation, siRNA knockdown, in vivo siRNA injection with reporter gene assay EMBO reports High 16936638
2007 Phosphodiesterase 2A (PDE2A) interacts with XAP2 (AIP) via the GAF-B domain of PDE2A; XAP2 binding does not change PDE2A enzymatic activity. PDE2A binding to XAP2 inhibits TCDD- and cAMP-induced nuclear translocation of AHR in hepatocytes and attenuates TCDD-induced transcription, suggesting XAP2 targets PDE2A to the AHR complex to restrict AHR mobility via local reduction of cAMP. Yeast two-hybrid, pull-down with purified proteins, PDE activity assay, nuclear translocation assay, reporter gene assay The Journal of biological chemistry Medium 17329248
2009 XAP2 (AIP) inhibits glucocorticoid receptor (GR) activity by reducing GR responsiveness to hormone in transcriptional activation. This effect requires XAP2 interaction with Hsp90 through the TPR motif. The PPIase-like domain of XAP2 is enzymatically inactive, and PPIase activity is not essential for GR inhibition. Transcriptional reporter assay, TPR mutation analysis, PPIase activity assay FEBS letters Medium 19375531
2010 AIP expression in hepatocytes is essential for maintaining high levels of functional cytosolic AHR protein in the mammalian liver. AIP expression is required for dioxin-induced hepatotoxicity. Certain AHR-driven genes (Cyp1b1, Ahrr) require AIP for normal dioxin-induced upregulation while others (Cyp1a1, Cyp1a2) do not, demonstrating differential AIP dependence among AHR target genes. Conditional liver-specific Aip knockout mouse model, gene expression analysis, toxicity assays The Journal of biological chemistry High 20829355
2010 Heterozygous Aip knockout mice develop pituitary adenomas predominantly secreting GH with complete penetrance by 15 months; tumor cells show complete loss of AIP. AIP-deficient tumors in both mice and humans show reduced expression of ARNT/ARNT2 protein, suggesting AIP-related tumorigenesis involves aberrant ARNT function. Aip silencing in GH3 cells causes partial reduction of Arnt and increased cell proliferation. Aip knockout mouse model, immunohistochemistry, Ki-67 proliferation analysis, siRNA knockdown in GH3 cells The American journal of pathology High 20709796
2011 AIP, an immunophilin that interacts with Tom20, directly mediates the mitochondrial import of survivin. Homozygous AIP deletion causes embryonic lethality (E13.5-14) with increased apoptosis of early erythropoietic progenitors and loss of survivin from cytosolic and mitochondrial compartments. AIP-directed survivin import to mitochondria enables anti-apoptotic function; a survivin mutant (1-141) that does not bind AIP was not imported and failed to inhibit apoptosis. Import was independent of Hsp90 and transmembrane potential and required Tom20 but not Tom70. Homozygous AIP knockout mouse, in vitro mitochondrial import assay with recombinant proteins, shRNA knockdown of Tom20/Tom70, apoptosis assay The Journal of biological chemistry High 21454573
2011 XAP2 (AIP) interacts with estrogen receptor α (ERα) but not ERβ, and negatively regulates ERα-dependent transcription; XAP2 is recruited to promoters of ERα-regulated genes. XAP2 mutations that disrupt interaction with ERα lose the ability to regulate ERα target gene transcription. Knockdown of XAP2 leads to increased ERα activity. Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), siRNA knockdown, transcriptional reporter assays, mutagenesis PloS one Medium 21984905
2012 The crystal structure of the AIP TPR domain was determined at high resolution. Disease-associated C-terminal α-7 helix mutations (R304*, R304Q, Q307*, R325Q) disrupt client-protein binding to the Cα-7h while leaving chaperone (Hsp90/Tom20) binding unaffected, suggesting that failure of client-protein interaction with the Cα-7h is sufficient for pituitary adenoma predisposition. A molecular switch was identified allowing recognition of both the MEEVD (Hsp90) and EDDVE (Tom20) C-terminal motifs. X-ray crystallography, structural analysis of disease mutations PloS one High 23300914
2012 Somatostatin analogs (octreotide/lanreotide) increase AIP mRNA and protein levels in GH3 cells. Overexpression of wild-type (but not mutant) AIP increases ZAC1 mRNA expression, while AIP siRNA knockdown reduces ZAC1 mRNA. AIP siRNA knockdown increases metabolic activity and clonogenic ability of GH3 cells. Cell line treatment with somatostatin analogs, siRNA knockdown, plasmid transfection, RT-PCR, luciferase reporter, clonogenicity assay The Journal of clinical endocrinology and metabolism Medium 22659247
2013 Overexpression of wild-type Aip in GH3 cells reduces forskolin-induced cAMP signaling (total cAMP, CRE-reporter activity, target gene expression) and GH secretion. Knockdown of endogenous Aip increases cAMP signaling. The non-functional R304X mutant lacks this suppressive effect. The effect of Aip on cAMP is not fully ablated by PDE inhibition, suggesting involvement of other interacting partners beyond the AIP-PDE interaction. cAMP assay, CRE-reporter luciferase assay, RT-PCR, siRNA knockdown, overexpression in GH3 cells, GH secretion quantification Endocrine-related cancer Medium 23702468
2014 AIP deficiency leads to elevated intracellular cAMP concentrations through defective Gαi-2 and Gαi-3 signaling (which normally inhibit cAMP synthesis). In Aip knockout MEF and murine pituitary adenoma cell lines, AIP deficiency increases cAMP; knockdown of Gαi-2 and Gαi-3 phenocopies this. AIP-deficient somatotropinomas show reduced Gαi-2 protein expression. AIP deficiency is also associated with reduced phosphorylated ERK1/2 and CREB levels. Gene expression microarray, cAMP assay, G protein alpha subunit knockdown, immunostaining in human and mouse tumors, cell line experiments Oncogene High 24662816
2014 AIP binds CARMA1 in T cells and augments CARMA1-BCL10-MALT1 (CBM) complex formation, thereby promoting IKK/NF-κB signaling and IL-2 production in response to TCR/CD28 co-stimulation. AIP acts as a positive regulator of CBM complex assembly. Co-immunoprecipitation, reporter assay for NF-κB, IL-2 quantification, T cell stimulation assay Cell communication and signaling Medium 25245034
2016 AIP is a stable protein (half-life ~43 h in HEK293 cells) degraded via the ubiquitin-proteasome pathway. The FBXO3-containing SKP1-CUL1-F-box (SCF) protein complex was identified as the E3 ubiquitin-ligase recognizing AIP. Missense AIP mutations lead to rapid proteasomal degradation (reduced half-life) that is rescued by proteasome inhibition. The protein half-life of AIP variants significantly correlates with age at diagnosis of acromegaly/gigantism. Cycloheximide chase, proteasome inhibition, GST pull-down with quantitative mass spectrometry, co-immunoprecipitation, gene knockdown The Journal of clinical endocrinology and metabolism High 27253664
2016 AIP mutations impair AHR transcriptional signaling; fibroblasts from AIP-mutated patients show altered expression of AHR target genes CYP1B1 and AHRR both at baseline and after AHR ligand (kynurenine) stimulation. In GH3 pituitary cells, AIP knockdown attenuates Cyp1b1 induction by AHR ligand and affects kynurenine-dependent GH secretion. Gene expression analysis in patient fibroblasts and transfected GH3 cells, siRNA knockdown, AHR ligand stimulation, GH secretion assay Endocrine-related cancer Medium 27080473
2018 AIP physically interacts with both the regulatory subunit PRKAR1A (R1α) and catalytic subunit PRKACA (Cα) of PKA; this interaction is enhanced when all three components are present but maintained during PKA activation-induced Cα-R1α dissociation. The pathogenic AIP mutation p.R304* reduces interaction with R1α and Cα. Cα stabilizes both AIP and R1α protein levels. AIP reduction by siRNA increases PKA activity, disproportionately enhanced during PDE4 inhibition. Co-immunoprecipitation, PKA activity assay, siRNA knockdown, protein stability analysis Human molecular genetics Medium 29726992
2018 Pull-down/quantitative mass spectrometry from rat somatotropinoma-derived cell lysates confirmed AIP interaction with HSP90AA1, HSP90AB1, and HSPA8 (known) and identified novel interactions with HSPA5, HSPA9, TUBB, TUBB2A, NME1, and SOD1. AIP variants p.R304* and p.R304Q showed impaired interactions with HSPA8, HSP90AB1, NME1 and SOD1; p.R304* also showed reduced binding to TUBB and TUBB2A. AIP-mutated tumors showed reduced TUBB2A expression. Pull-down with quantitative mass spectrometry, co-immunoprecipitation, co-localization, RNA microarray Oncotarget Medium 29507682
2019 AIP-deficiency promotes tumor invasiveness through a CCL5/CCR5-mediated crosstalk with macrophages; AIP-mutation-positive tumors have increased macrophage infiltration and upregulated CCL5. Aip-knockdown cell-conditioned media increases macrophage migration (inhibited by the CCL5/CCR5 antagonist maraviroc). Macrophage-conditioned media induces EMT-like phenotype and enhanced migratory/invasive properties preferentially in Aip-knockdown cells. Immunohistochemistry, pituitary-specific Aip-KO mouse, conditioned media experiments, migration/invasion assays, CCL5/CCR5 inhibition Oncogene Medium 30867568
2020 AIP mutation-positive somatotropinomas overexpress miR-34a, which directly targets Gnai2 (encoding Gαi2), leading to reduced Gαi2 levels, increased intracellular cAMP, and octreotide resistance. Ectopic expression of AIP mutant (p.R271W) in Aip-/- MEFs upregulates miR-34a and miR-145. miR-34a overexpression in GH3 cells promotes proliferation, clonogenicity, migration, suppresses apoptosis, blunts octreotide-mediated GH inhibition and antiproliferative effects. miRNA array, ectopic AIP mutant expression in MEFs, GH3 cell miR-34a overexpression, cAMP assay, GH inhibition assay, Gnai2 target validation International journal of cancer Medium 32856736
2021 AIP is required at the plasma membrane to form a complex with monomeric intracellular RET receptor, caspase-3, and PKCδ, which activates the PIT1/CDKN2A-ARF/p53 apoptotic pathway in somatotrophs. AIP deficiency blocks RET/caspase-3/PKCδ activation preventing PIT1 accumulation and apoptosis. In vivo virogenomics in neonatal rats confirmed the effect of mutant AIP on the RET apoptotic pathway. AIP-mutated somatotroph adenomas overexpress GDNF (RET ligand), upregulating the survival pathway; AIP-mutated tissues show less CDKN2A-ARF expression. Complex formation assay, caspase-3/PKCδ activation assay, viral vector in vivo delivery in rats, pituitary-specific Aip-KO mouse tumor analysis, patient tumor immunostaining Oncogene High 34588620
2022 Cryo-EM structure of the human indirubin-bound AHR complex with Hsp90 and XAP2 (AIP) at 2.85 Å resolution reveals: a closed-conformation Hsp90 dimer with AHR threaded through its lumen; XAP2 serving as a structural brace. The structure resolves the AHR PAS-B ligand-binding domain and reveals the structural determinants of ligand-binding specificity and promiscuity. Cryo-EM structure determination at 2.85 Å Nature communications High 36385050

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Selectivity for the shape, size, and orientation of objects for grasping in neurons of monkey parietal area AIP. Journal of neurophysiology 559 10805659
2006 Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science (New York, N.Y.) 414 16728643
2004 Paraptosis: mediation by MAP kinases and inhibition by AIP-1/Alix. Cell death and differentiation 317 15195070
2013 Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocrine reviews 238 23371967
1999 Characterization of the AhR-hsp90-XAP2 core complex and the role of the immunophilin-related protein XAP2 in AhR stabilization. Biochemistry 182 10413464
1998 Characterization of the Ah receptor-associated protein, ARA9. The Journal of biological chemistry 167 9837941
2010 The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in causing pituitary adenomas in a large cohort of children, adolescents, and patients with genetic syndromes. Clinical genetics 151 20507346
2012 Germline AIP mutations in apparently sporadic pituitary adenomas: prevalence in a prospective single-center cohort of 443 patients. The Journal of clinical endocrinology and metabolism 136 22319033
2010 Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families. Human mutation 132 20506337
2003 Attenuation of the activity of the cAMP-specific phosphodiesterase PDE4A5 by interaction with the immunophilin XAP2. The Journal of biological chemistry 132 12810716
2000 The immunophilin-like protein XAP2 regulates ubiquitination and subcellular localization of the dioxin receptor. The Journal of biological chemistry 131 11013261
2013 Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis. European journal of endocrinology 120 23321498
2011 High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas. European journal of endocrinology 120 21753072
2015 Landscape of Familial Isolated and Young-Onset Pituitary Adenomas: Prospective Diagnosis in AIP Mutation Carriers. The Journal of clinical endocrinology and metabolism 114 26186299
2012 Somatostatin analogs modulate AIP in somatotroph adenomas: the role of the ZAC1 pathway. The Journal of clinical endocrinology and metabolism 108 22659247
2011 AIP and its interacting partners. The Journal of endocrinology 105 21454441
2022 Cryo-EM structure of the agonist-bound Hsp90-XAP2-AHR cytosolic complex. Nature communications 101 36385050
2011 AIP mutation in pituitary adenomas in the 18th century and today. The New England journal of medicine 99 21208107
1996 XAP2, a novel hepatitis B virus X-associated protein that inhibits X transactivation. Nucleic acids research 92 8972861
2000 ARA9 modifies agonist signaling through an increase in cytosolic aryl hydrocarbon receptor. The Journal of biological chemistry 89 10692406
2002 The hsp90 Co-chaperone XAP2 alters importin beta recognition of the bipartite nuclear localization signal of the Ah receptor and represses transcriptional activity. The Journal of biological chemistry 83 12431985
2007 Phosphodiesterase 2A forms a complex with the co-chaperone XAP2 and regulates nuclear translocation of the aryl hydrocarbon receptor. The Journal of biological chemistry 79 17329248
2003 AIP is a mitochondrial import mediator that binds to both import receptor Tom20 and preproteins. The Journal of cell biology 78 14557246
2014 AIP inactivation leads to pituitary tumorigenesis through defective Gαi-cAMP signaling. Oncogene 77 24662816
2000 Aryl hydrocarbon (Ah) receptor levels are selectively modulated by hsp90-associated immunophilin homolog XAP2. Cell stress & chaperones 77 11005382
2019 Tumor microenvironment defines the invasive phenotype of AIP-mutation-positive pituitary tumors. Oncogene 69 30867568
2003 Defining the role for XAP2 in stabilization of the dioxin receptor. The Journal of biological chemistry 68 12837759
2012 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. PloS one 64 23300914
2018 Reprogramming Probiotic Lactobacillus reuteri as a Biosensor for Staphylococcus aureus Derived AIP-I Detection. ACS synthetic biology 63 29652493
2010 Mice with inactivation of aryl hydrocarbon receptor-interacting protein (Aip) display complete penetrance of pituitary adenomas with aberrant ARNT expression. The American journal of pathology 58 20709796
2008 Aryl hydrocarbon receptor interacting protein (AIP) gene mutation analysis in children and adolescents with sporadic pituitary adenomas. Clinical endocrinology 58 18410548
2008 Large genomic deletions in AIP in pituitary adenoma predisposition. The Journal of clinical endocrinology and metabolism 58 18628514
2012 Cyclin-dependent kinase inhibitor 1B (CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds. Endocrine-related cancer 57 22291433
1998 Critical amino acid residues of AIP, a highly specific inhibitory peptide of calmodulin-dependent protein kinase II. FEBS letters 57 9613610
2020 Significant Benefits of AIP Testing and Clinical Screening in Familial Isolated and Young-onset Pituitary Tumors. The Journal of clinical endocrinology and metabolism 54 31996917
2012 Germline mutations of AIP gene in somatotropinomas resistant to somatostatin analogues. European journal of endocrinology 54 23038625
2001 Apoptosis-inducing protein, AIP, from parasite-infected fish induces apoptosis in mammalian cells by two different molecular mechanisms. Cell death and differentiation 50 11319613
2013 Somatostatin analogues increase AIP expression in somatotropinomas, irrespective of Gsp mutations. Endocrine-related cancer 49 23940012
2009 AIP-1 ameliorates beta-amyloid peptide toxicity in a Caenorhabditis elegans Alzheimer's disease model. Human molecular genetics 49 19414486
2009 The expression of AIP-related molecules in elucidation of cellular pathways in pituitary adenomas. The American journal of pathology 49 19850893
2008 Assessment of p27 (cyclin-dependent kinase inhibitor 1B) and aryl hydrocarbon receptor-interacting protein (AIP) genes in multiple endocrine neoplasia (MEN1) syndrome patients without any detectable MEN1 gene mutations. Clinical endocrinology 49 18710468
2002 Two distinct regions of the immunophilin-like protein XAP2 regulate dioxin receptor function and interaction with hsp90. The Journal of biological chemistry 48 11805120
2019 Surgery, Octreotide, Temozolomide, Bevacizumab, Radiotherapy, and Pegvisomant Treatment of an AIP Mutation‒Positive Child. The Journal of clinical endocrinology and metabolism 47 31125088
2012 Familial pituitary adenomas - who should be tested for AIP mutations? Clinical endocrinology 47 22612670
2016 Rapid Proteasomal Degradation of Mutant Proteins Is the Primary Mechanism Leading to Tumorigenesis in Patients With Missense AIP Mutations. The Journal of clinical endocrinology and metabolism 46 27253664
2019 AIP-mutated acromegaly resistant to first-generation somatostatin analogs: long-term control with pasireotide LAR in two patients. Endocrine connections 45 30851160
2010 The aryl hydrocarbon receptor-interacting protein (AIP) is required for dioxin-induced hepatotoxicity but not for the induction of the Cyp1a1 and Cyp1a2 genes. The Journal of biological chemistry 45 20829355
2007 Mutation analysis of aryl hydrocarbon receptor interacting protein (AIP) gene in colorectal, breast, and prostate cancers. British journal of cancer 45 17242703
2013 Clinical experience in the screening and management of a large kindred with familial isolated pituitary adenoma due to an aryl hydrocarbon receptor interacting protein (AIP) mutation. The Journal of clinical endocrinology and metabolism 44 24423289
2011 Developmental control of apoptosis by the immunophilin aryl hydrocarbon receptor-interacting protein (AIP) involves mitochondrial import of the survivin protein. The Journal of biological chemistry 41 21454573
2010 Concomitant deletions of tumor suppressor genes MEN1 and AIP are essential for the pathogenesis of the brown fat tumor hibernoma. Proceedings of the National Academy of Sciences of the United States of America 41 21078971
2004 Divergent roles of hepatitis B virus X-associated protein 2 (XAP2) in human versus mouse Ah receptor complexes. Biochemistry 41 14730974
2017 Simplified AIP-II Peptidomimetics Are Potent Inhibitors of Staphylococcus aureus AgrC Quorum Sensing Receptors. Chembiochem : a European journal of chemical biology 39 28006082
2013 Aip regulates cAMP signalling and GH secretion in GH3 cells. Endocrine-related cancer 39 23702468
2012 Novel mutations in MEN1, CDKN1B and AIP genes in patients with multiple endocrine neoplasia type 1 syndrome in Spain. Clinical endocrinology 39 22026581
2000 Neuroprotective effect of AIP on N-methyl-D-aspartate-induced cell death in retinal neurons. Brain research. Molecular brain research 39 11146104
2010 Prevalence of AIP mutations in a large series of sporadic Italian acromegalic patients and evaluation of CDKN1B status in acromegalic patients with multiple endocrine neoplasia. European journal of endocrinology 38 20530095
2021 Predictive Value of the Atherogenic Index of Plasma (AIP) for the Risk of Incident Ischemic Heart Disease among Non-Diabetic Koreans. Nutrients 37 34579107
2002 Aurora-A kinase interacting protein (AIP), a novel negative regulator of human Aurora-A kinase. The Journal of biological chemistry 37 12244051
2020 miR-34a is upregulated in AIP-mutated somatotropinomas and promotes octreotide resistance. International journal of cancer 36 32856736
2014 Familial isolated pituitary adenomas (FIPA) and mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocrinology and metabolism clinics of North America 35 25732638
2005 Redefining the role of the endogenous XAP2 and C-terminal hsp70-interacting protein on the endogenous Ah receptors expressed in mouse and rat cell lines. The Journal of biological chemistry 34 16085934
2014 Low rate of germline AIP mutations in patients with apparently sporadic pituitary adenomas before the age of 40: a single-centre adult cohort. European journal of endocrinology 33 25184284
2010 AIP gene and familial isolated pituitary adenomas. Molecular and cellular endocrinology 33 20457215
2009 Aggressive pituitary adenomas occurring in young patients in a large Polynesian kindred with a germline R271W mutation in the AIP gene. European journal of endocrinology 33 19684062
2018 Multi-chaperone function modulation and association with cytoskeletal proteins are key features of the function of AIP in the pituitary gland. Oncotarget 32 29507682
2000 Epstein-Barr virus encoded nuclear protein EBNA-3 binds XAP-2, a protein associated with Hepatitis B virus X antigen. Oncogene 32 10777214
2006 The co-chaperone XAP2 is required for activation of hypothalamic thyrotropin-releasing hormone transcription in vivo. EMBO reports 31 16936638
2016 Very low frequency of germline GPR101 genetic variation and no biallelic defects with AIP in a large cohort of patients with sporadic pituitary adenomas. European journal of endocrinology 30 26792934
2016 Acromegaly Is More Severe in Patients With AHR or AIP Gene Variants Living in Highly Polluted Areas. The Journal of clinical endocrinology and metabolism 30 26963951
2009 XAP2 inhibits glucocorticoid receptor activity in mammalian cells. FEBS letters 30 19375531
2018 Risk category system to identify pituitary adenoma patients with AIP mutations. Journal of medical genetics 29 29440248
2016 cAMP-specific PDE4 phosphodiesterases and AIP in the pathogenesis of pituitary tumors. Endocrine-related cancer 29 27267386
2011 Clinical features and treatment of pediatric somatotropinoma: case study of an aggressive tumor due to a new AIP mutation and extensive literature review. Hormone research in paediatrics 28 21546764
2018 Human hydroxymethylbilane synthase: Molecular dynamics of the pyrrole chain elongation identifies step-specific residues that cause AIP. Proceedings of the National Academy of Sciences of the United States of America 27 29632172
2015 Increasing AIP Macrocycle Size Reveals Key Features of agr Activation in Staphylococcus aureus. Chembiochem : a European journal of chemical biology 27 25801678
2008 Aryl hydrocarbon receptor interacting protein gene (AIP) mutations are rare in patients with hormone secreting or non-secreting pituitary adenomas. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 26 18484068
2007 Susceptibility to pituitary neoplasia related to MEN-1, CDKN1B and AIP mutations: an update. Human molecular genetics 26 17613551
2017 AIP and the somatostatin system in pituitary tumours. The Journal of endocrinology 25 28835453
2000 The ALG-2/AIP-complex, a modulator at the interface between cell proliferation and cell death? A hypothesis. Biochimica et biophysica acta 25 11108958
2021 RET signalling provides tumorigenic mechanism and tissue specificity for AIP-related somatotrophinomas. Oncogene 24 34588620
2014 Frequency of AIP gene mutations in young patients with acromegaly: a registry-based study. The Journal of clinical endocrinology and metabolism 24 25093619
2017 Impact of AIP and inhibitory G protein alpha 2 proteins on clinical features of sporadic GH-secreting pituitary adenomas. European journal of endocrinology 23 27998919
2009 Mutation analysis of MEN1, HRPT2, CASR, CDKN1B, and AIP genes in primary hyperparathyroidism patients with features of genetic predisposition. Journal of endocrinological investigation 23 19474519
2006 Role of endogenous XAP2 protein on the localization and nucleocytoplasmic shuttling of the endogenous mouse Ahb-1 receptor in the presence and absence of ligand. Molecular pharmacology 23 16835354
2013 Aryl hydrocarbon receptor interacting protein (AIP) mutations occur rarely in sporadic parathyroid adenomas. The Journal of clinical endocrinology and metabolism 22 23633209
2018 Interaction of AIP with protein kinase A (cAMP-dependent protein kinase). Human molecular genetics 21 29726992
2016 AIP mutations impair AhR signaling in pituitary adenoma patients fibroblasts and in GH3 cells. Endocrine-related cancer 21 27080473
2013 Screening for AIP gene mutations in a Han Chinese pituitary adenoma cohort followed by LOH analysis. European journal of endocrinology 21 24050928
2011 The immunophilin-like protein XAP2 is a negative regulator of estrogen signaling through interaction with estrogen receptor α. PloS one 21 21984905
2020 Updates on the diagnosis and management of the most common hereditary porphyrias: AIP and EPP. Hematology. American Society of Hematology. Education Program 20 33275677
2016 Analysis of GPR101 and AIP genes mutations in acromegaly: a multicentric study. Endocrine 20 26815903
2016 Increased Population Risk of AIP-Related Acromegaly and Gigantism in Ireland. Human mutation 19 27650164
2014 AIP augments CARMA1-BCL10-MALT1 complex formation to facilitate NF-κB signaling upon T cell activation. Cell communication and signaling : CCS 19 25245034
2012 NMR assignments of the FKBP-type PPIase domain of the human aryl-hydrocarbon receptor-interacting protein (AIP). Biomolecular NMR assignments 19 22287093
2012 Genetic analysis in a patient presenting with meningioma and familial isolated pituitary adenoma (FIPA) reveals selective involvement of the R81X mutation of the AIP gene in the pathogenesis of the pituitary tumor. Pituitary 19 22527616
2010 skn-1-Dependent and -independent regulation of aip-1 expression following metabolic stress in Caenorhabditis elegans. Molecular and cellular biology 19 20351174
2005 Induction of long-term potentiation in single nociceptive dorsal horn neurons is blocked by the CaMKII inhibitor AIP. Brain research 19 15804501
1999 Identification and expression of mutations in the hydroxymethylbilane synthase gene causing acute intermittent porphyria (AIP). Molecular medicine (Cambridge, Mass.) 19 10602775
2024 The phenylalanine ammonia-lyase inhibitor AIP induces rice defence against the root-knot nematode Meloidogyne graminicola. Molecular plant pathology 18 38279847

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