Affinage

AIP

AH receptor-interacting protein · UniProt O00170

Length
330 aa
Mass
37.7 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AIP is a TPR-domain co-chaperone that functions as a molecular scaffold stabilizing cytosolic client proteins — most prominently the aryl hydrocarbon receptor (AhR) — within Hsp90-containing complexes, while simultaneously suppressing cAMP/PKA signaling and facilitating mitochondrial preprotein import. In the AhR pathway, AIP assembles into a tetrameric complex with AhR and an Hsp90 dimer, where it protects AhR from ubiquitin-mediated degradation by competing with the E3 ligase CHIP for the Hsp90 TPR acceptor site and retains unliganded AhR in the cytoplasm by blocking importin-β access to the AhR nuclear localization signal (PMID:11013261, PMID:12837759, PMID:12431985, PMID:36385050). AIP suppresses cAMP signaling through multiple mechanisms — direct inhibition of PDE4A5 catalytic activity, recruitment of PDE2A to the AhR complex to lower local cAMP, physical interaction with Gαi-2/Gαi-3 subunits and PKA regulatory/catalytic subunits, and maintenance of Gαi-2 expression partly by restraining miR-34a — and loss-of-function AIP mutations cause accelerated proteasomal degradation of the mutant protein (via the SCF-FBXO3 E3 ligase), cAMP derepression, and failure of RET/caspase-3-mediated somatotroph apoptosis, resulting in young-onset growth-hormone-secreting pituitary adenomas (PMID:12810716, PMID:17329248, PMID:24662816, PMID:29726992, PMID:27253664, PMID:34588620, PMID:32856736). AIP also mediates mitochondrial import of preproteins including survivin via the Tom20 receptor, a function essential for embryonic viability (PMID:14557246, PMID:21454573).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1996 Medium

    Discovery of AIP as a novel TPR protein: identified through its interaction with hepatitis B virus X protein, establishing AIP as a cellular factor capable of modulating viral transactivation, but leaving its endogenous function unknown.

    Evidence Yeast two-hybrid screen with HBV X protein, confirmed by in vitro binding and reporter assay

    PMID:8972861

    Open questions at the time
    • No endogenous cellular partner or pathway identified
    • Physiological relevance of HBV X interaction unclear
    • Single lab without independent replication
  2. 1999 High

    Defining AIP as a core subunit of the cytosolic AhR chaperone complex: multiple groups demonstrated that AIP assembles with AhR and Hsp90 into a tetrameric complex via its TPR domain, stabilizes AhR protein levels, and retains it in the cytoplasm, establishing AIP's primary known function as an AhR co-chaperone.

    Evidence Co-immunoprecipitation, domain deletion mapping, yeast and mammalian expression, biochemical fractionation across multiple labs

    PMID:10413464 PMID:10692406 PMID:11005382 PMID:9837941

    Open questions at the time
    • Mechanism of AhR stabilization (ubiquitination vs. other turnover) not yet defined
    • Molecular basis of cytoplasmic retention unknown
  3. 2002 High

    Revealing the dual mechanisms of AhR regulation: AIP protects AhR from ubiquitination and retains it cytoplasmically by specifically blocking importin-β access to the AhR bipartite NLS, explaining how AIP coordinates receptor stability and localization.

    Evidence Ubiquitination assays, importin-β binding assays, leptomycin B treatment, subcellular fractionation

    PMID:11013261 PMID:11805120 PMID:12431985

    Open questions at the time
    • Identity of E3 ubiquitin ligase targeting AhR not yet known
    • Species-specific differences in cytoplasmic retention not addressed
  4. 2003 High

    Three new mechanistic dimensions emerged simultaneously: AIP competes with the E3 ligase CHIP for Hsp90's TPR site to protect AhR; AIP inhibits PDE4A5 enzymatic activity revealing a cAMP-regulatory role; and AIP mediates mitochondrial preprotein import via Tom20, establishing AIP as a multifunctional scaffold beyond AhR biology.

    Evidence CHIP competition/knockdown studies; PDE4A5 activity assays with IC50 measurement and co-IP from brain; reconstituted in vitro mitochondrial import with Tom20 ternary complex

    PMID:12810716 PMID:12837759 PMID:14557246

    Open questions at the time
    • Whether PDE4A5 and Tom20 functions operate independently of AhR not fully resolved
    • Physiological substrates of Tom20-mediated import via AIP not catalogued
    • In vivo relevance of cAMP modulation unclear
  5. 2007 High

    AIP recruits PDE2A to the AhR complex where it hydrolyzes local cAMP, attenuating both ligand-dependent and cAMP-induced AhR nuclear translocation — demonstrating that AIP integrates cAMP and AhR signaling through phosphodiesterase scaffolding.

    Evidence Yeast two-hybrid, purified protein pull-down, PDE activity assay, nuclear translocation and reporter assays

    PMID:17329248

    Open questions at the time
    • Relative contribution of PDE4A5 inhibition vs. PDE2A recruitment to net cAMP regulation unclear
    • Whether PDE2A-AhR crosstalk operates in vivo not tested
  6. 2010 High

    In vivo validation that AIP loss causes pituitary tumorigenesis: hepatocyte-specific Aip knockout confirmed AIP is essential for maintaining cytosolic AhR and dioxin toxicity, while whole-body Aip heterozygous knockout mice developed GH-secreting pituitary adenomas with complete penetrance, establishing AIP as a pituitary tumor suppressor.

    Evidence Conditional hepatocyte-specific and heterozygous whole-body Aip knockout mice, immunohistochemistry, gene expression analysis

    PMID:20709796 PMID:20829355

    Open questions at the time
    • Mechanism linking AIP loss to somatotroph-specific proliferation not defined
    • Role of AhR pathway vs. cAMP pathway in tumorigenesis not distinguished
  7. 2011 High

    AIP mediates survivin import to mitochondria via Tom20, directly linking AIP to apoptosis control; homozygous Aip deletion causes embryonic lethality with increased apoptosis, demonstrating that AIP's mitochondrial import function is essential for viability.

    Evidence Aip-/- mice, reconstituted in vitro mitochondrial import with survivin-AIP-Tom20, shRNA knockdown

    PMID:21454573

    Open questions at the time
    • Full repertoire of AIP-dependent mitochondrial import substrates unknown
    • Whether survivin import contributes to pituitary tumor suppression not tested
  8. 2012 High

    Crystal structure of AIP's TPR domain revealed how disease-associated mutations in the C-terminal α-7 helix selectively abolish client binding (AhR, PDE4A5) while preserving chaperone/Tom20 interactions, providing a structural framework for genotype-phenotype correlations.

    Evidence X-ray crystallography with mutagenesis and binding assays

    PMID:23300914

    Open questions at the time
    • Full-length AIP structure not resolved
    • How N-terminal FKBP-like domain contributes to client recognition structurally undetermined
  9. 2014 Medium

    AIP's tumor suppressor mechanism was linked to Gαi signaling: AIP deficiency reduces Gαi-2/Gαi-3 protein levels, derepressing adenylyl cyclase and elevating cAMP in somatotrophs — a mechanism distinct from PDE scaffolding and directly connecting AIP loss to proliferative cAMP signaling.

    Evidence cAMP measurement, Gαi knockdown, immunostaining of human and mouse somatotropinomas

    PMID:24662816

    Open questions at the time
    • Whether AIP directly binds Gαi proteins or acts indirectly not established
    • Relative contributions of Gαi loss vs. PDE dysfunction to elevated cAMP not quantified
  10. 2016 High

    AIP protein turnover was shown to be governed by the SCF-FBXO3 E3 ubiquitin ligase; disease-causing missense mutations accelerate AIP degradation, and mutant protein half-life correlates with clinical severity (age at diagnosis), providing a unifying explanation for loss-of-function across diverse AIP mutations.

    Evidence Cycloheximide chase of 15 variants, quantitative mass spectrometry identification of FBXO3, co-IP, knockdown, clinical correlation

    PMID:27253664

    Open questions at the time
    • Degron motif within AIP recognized by FBXO3 not mapped
    • Whether stabilizing mutant AIP protein can rescue tumor suppressor function not tested
  11. 2018 Medium

    AIP physically interacts with both regulatory (R1α) and catalytic (Cα) subunits of PKA, and AIP reduction increases PKA activity, revealing a third node (beyond PDE and Gαi) through which AIP restrains cAMP/PKA signaling.

    Evidence Co-immunoprecipitation, siRNA knockdown, PKA activity assay

    PMID:29726992

    Open questions at the time
    • Structural basis of AIP-PKA interaction not determined
    • Whether AIP sequesters PKA subunits or alters holoenzyme assembly unclear
    • Single-lab finding
  12. 2020 High

    A miR-34a → Gαi2 suppression axis was identified downstream of mutant AIP: AIP mutations upregulate miR-34a, which directly targets Gnai2 mRNA, amplifying cAMP elevation and conferring resistance to somatostatin analog therapy.

    Evidence miRNA array, ectopic mutant AIP in Aip-/- MEFs, luciferase validation of direct Gnai2 targeting, GH inhibition and proliferation assays, patient tumor confirmation

    PMID:32856736

    Open questions at the time
    • How AIP mutations upregulate miR-34a transcription mechanistically not defined
    • Whether miR-34a inhibition can restore octreotide sensitivity in vivo not tested
  13. 2021 High

    AIP was shown to scaffold a plasma-membrane RET/caspase-3/PKCδ apoptotic complex in somatotrophs, activating a PIT1/p19ARF/p53 pathway; AIP deficiency blocks this apoptotic checkpoint, directly explaining somatotroph-specific tumor susceptibility.

    Evidence Co-immunoprecipitation, apoptosis assays with pathogenic AIP variant panel, virogenomics in neonatal rats, Aip-knockout mouse and patient tumor analysis

    PMID:34588620

    Open questions at the time
    • How AIP is recruited to the plasma membrane and RET complex not determined
    • Whether the RET-apoptotic and cAMP-proliferative mechanisms act independently or synergistically in tumorigenesis unknown
  14. 2022 High

    Cryo-EM at 2.85 Å resolved the intact AhR–Hsp90–AIP ternary complex, showing AhR threaded through the lumen of a closed Hsp90 dimer with AIP acting as a structural brace, providing the definitive architecture of AIP's founding client complex.

    Evidence Cryo-EM structure of the human complex

    PMID:36385050

    Open questions at the time
    • Dynamic conformational changes upon ligand binding not captured
    • How AIP dissociates during AhR nuclear translocation structurally unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how AIP selectively suppresses pituitary somatotroph proliferation despite ubiquitous expression; the structural basis of AIP interactions with Gαi, PKA, and RET; whether the AhR, cAMP, and apoptotic functions of AIP converge on a common tumorigenic mechanism or represent parallel pathways; and whether pharmacological stabilization of mutant AIP protein or pathway-targeted therapy can prevent pituitary adenoma formation.
  • Cell-type specificity of AIP tumor suppression unexplained
  • No integrated model unifying AhR, cAMP, and RET pathways
  • No therapeutic rescue strategy validated in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0044183 protein folding chaperone 4 GO:0060090 molecular adaptor activity 3
Localization
GO:0005829 cytosol 4 GO:0005634 nucleus 2 GO:0005739 mitochondrion 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 4 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9609507 Protein localization 2
Partners
AHRHSP90AA1PDE2APDE4A5PRKACAPRKAR1ARETTOMM20
Complex memberships
AhR-Hsp90-XAP2 complexRET-caspase-3-PKCδ complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 AIP (XAP2) was identified as a novel cellular protein that interacts with the hepatitis B virus X protein; overexpression of XAP2 abolishes transactivation by the X protein, acting as a negative regulator of X protein transcriptional activity. Yeast two-hybrid, in vitro interaction assay, transfection reporter assay Nucleic acids research Medium 8972861
1998 AIP (ARA9) forms a complex with the unliganded aryl hydrocarbon receptor (AHR) and Hsp90; the three tetratricopeptide repeats (TPR) at the C-terminus of ARA9 are necessary and sufficient for interaction with the AHR complex, while the AHR's repressor/Hsp90-binding domain is required for interaction with ARA9. ARA9 specifically associates with AHR-Hsp90 but not glucocorticoid receptor-Hsp90 complexes, and ARA9 expression enhances AHR agonist response in yeast. Co-immunoprecipitation, domain deletion mapping, yeast expression assay The Journal of biological chemistry High 9837941
1999 AIP (XAP2) exists in 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 directly interact with AhR in the absence of Hsp90. XAP2 binds the C-terminal TPR acceptor site of Hsp90, while AhR binds the middle of Hsp90. Transient expression of XAP2 increases cytosolic AhR levels, suggesting a role in regulating AhR turnover. Biochemical fractionation, co-immunoprecipitation, domain mapping, transient transfection Biochemistry High 10413464
2000 XAP2 (AIP) protects the unliganded dioxin (AhR) receptor against ubiquitination, increasing receptor protein levels. Upon ligand exposure, XAP2 markedly delays nuclear translocation of the dioxin receptor by a mechanism of cytoplasmic retention. These effects require stable association of XAP2 with the Hsp90-p23 chaperone complex. Transfection, ubiquitination assay, subcellular localization/nuclear translocation assay, immunoprecipitation The Journal of biological chemistry High 11013261
2000 AIP (ARA9) enhances AhR signaling by increasing the available AhR binding sites within the cytosolic compartment; it increases the fraction of AhR in the cytosol and stabilizes the receptor under heat stress, acting as a cellular chaperone. Coexpression in yeast and mammalian cells, receptor photoaffinity labeling, subcellular fractionation The Journal of biological chemistry High 10692406
2000 AIP (XAP2) TPR domain mediates binding to both AhR and Hsp90; single-point mutations in the TPR region disrupt association with both. Cotransfection of AhR and XAP2 increases AhR levels in a TPR-dependent manner unique among Hsp90-binding proteins. YFP-XAP2 localizes to both nucleus and cytoplasm. Site-directed mutagenesis, co-transfection, co-immunoprecipitation, fluorescence microscopy Cell stress & chaperones High 11005382
2002 XAP2 (AIP) modulates AhR subcellular localization by hindering importin beta binding to the AhR complex, suggesting XAP2 alters the conformation of the bipartite nuclear localization signal of AhR, thereby inhibiting ligand-independent nucleocytoplasmic shuttling and repressing AhR transactivation potential. Nuclear export inhibitor (leptomycin B) treatment, cytoskeletal disruption, importin beta binding assay, fluorescence microscopy, transactivation assay The Journal of biological chemistry High 12431985
2002 Two distinct regions of XAP2 modulate dioxin receptor function: the C-terminal region (including TPR motifs plus flanking sequence) mediates direct contact with Hsp90, while the N-terminal region is required for stability of the ternary dioxin receptor-Hsp90-XAP2 complex and for regulation of receptor intracellular localization. XAP2 deletion mutant series, immunoprecipitation The Journal of biological chemistry Medium 11805120
2003 AIP (XAP2) interacts with the cAMP-specific phosphodiesterase PDE4A5 in a specific manner; XAP2's TPR domain (specifically Arg271) mediates this interaction. XAP2 reversibly inhibits PDE4A5 enzymatic activity (up to ~60%, IC50 ~120 nM), increases sensitivity to rolipram, and attenuates PKA-mediated phosphorylation of PDE4A5 in intact cells. Yeast two-hybrid, pull-down, co-immunoprecipitation from brain, PDE activity assay, mutagenesis, cell-based phosphorylation assay The Journal of biological chemistry High 12810716
2003 XAP2 (AIP) protects the dioxin receptor from CHIP (C-terminal Hsp70-interacting protein) E3 ubiquitin ligase-mediated degradation in a TPR-dependent manner, by competing for the TPR acceptor site of Hsp90. Reduced XAP2 levels destabilize the dioxin receptor, and constitutively nuclear receptor is also degraded independently of nuclear export. Knockdown of XAP2, overexpression, co-immunoprecipitation, proteasome inhibition, CHIP interaction studies The Journal of biological chemistry High 12837759
2003 AIP interacts with mitochondrial import receptor Tom20 via the extreme C-terminal acidic segment of Tom20 and the TPR repeats of AIP. AIP binds mitochondrial preproteins, forms a ternary complex with Tom20 and preprotein, has chaperone-like activity (preventing aggregation), and facilitates mitochondrial import of preornithine transcarbamylase in vitro and in cultured cells. Yeast two-hybrid, in vitro import assay, in vitro binding assay, RNA interference, overexpression, aggregation suppression assay The Journal of cell biology High 14557246
2004 Human AhR (hAhR) differs from mouse AhR (mAhR) in its interaction with XAP2: XAP2 does not retain hAhR-YFP in the cytoplasm or block its nuclear accumulation in the absence of ligand (unlike mAhR), but XAP2 enhances the rate of nuclear translocation of ligand-bound hAhR while repressing its transcriptional activity. YFP fusion proteins, nuclear export inhibitor (leptomycin B), XAP2-NLS fusion, fluorescence microscopy, transactivation assay Biochemistry Medium 14730974
2006 AIP (XAP2) interacts specifically with thyroid hormone receptor beta 1 (TRbeta1) but not TRbeta2; this interaction is enhanced by T3 and XAP2 knockdown affects TRbeta1 stability. In vivo, siRNA-mediated knockdown of XAP2 abrogates TRbeta1-mediated (but not TRbeta2) activation of hypothalamic TRH transcription. Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown in vitro and in vivo, TRH transcription assay EMBO reports High 16936638
2007 PDE2A (phosphodiesterase type 2A) interacts with XAP2 (AIP) via the GAF-B domain of PDE2A and the TPR domain of XAP2. XAP2 binding does not change PDE2A enzymatic activity, but PDE2A binding to XAP2 inhibits TCDD- and cAMP-induced nuclear translocation of AhR and attenuates AhR-driven transcription in reporter assays, suggesting PDE2A is targeted to the AhR complex by XAP2 where it reduces local cAMP levels. Yeast two-hybrid, pull-down with purified proteins, PDE activity assay, nuclear translocation assay, reporter gene assay The Journal of biological chemistry High 17329248
2009 XAP2 (AIP) inhibits glucocorticoid receptor (GR) transcriptional responsiveness to hormone. This inhibitory effect requires XAP2's interaction with Hsp90 through the TPR motif; the PPIase-like domain of XAP2 is enzymatically inactive and PPIase activity is not required for GR inhibition. Transcriptional activation assay, co-immunoprecipitation, PPIase activity assay, mutant analysis FEBS letters Medium 19375531
2010 AIP is required in hepatocytes to maintain high levels of functional cytosolic AhR protein. AIP expression is also essential for dioxin-induced hepatotoxicity. AIP shows differential effects on AhR-responsive genes: Cyp1b1 and Ahrr require AIP for normal dioxin induction, while Cyp1a1 and Cyp1a2 do not. Conditional hepatocyte-specific Aip knockout mouse model, gene expression analysis, toxicity studies The Journal of biological chemistry High 20829355
2010 Mice heterozygous for Aip develop pituitary adenomas (predominantly GH-secreting) with complete penetrance by 15 months, showing loss of AIP in tumors. AIP-deficient tumors have higher Ki-67 proliferation rates and show loss of ARNT (AhR nuclear translocator) protein expression, implicating aberrant ARNT function in AIP-related tumorigenesis. Aip heterozygous knockout mouse model, immunohistochemistry, Ki-67 proliferation analysis The American journal of pathology High 20709796
2011 AIP directly mediates import of survivin to mitochondria via Tom20, enabling survivin's anti-apoptotic function. Homozygous Aip deletion in mice causes embryonic lethality (by E13.5-14), increased apoptosis of erythropoietic progenitors, and loss of survivin in cytosolic and mitochondrial compartments. A survivin mutant that does not bind AIP cannot be imported to mitochondria and fails to inhibit apoptosis. Aip homozygous 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 alpha (ERα) but not ERβ in an isoform-specific manner and negatively regulates ERα-mediated transcription. XAP2 is recruited to ERα-regulated gene promoters. XAP2 mutations abolishing ERα interaction eliminate this regulatory effect. Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, transcriptional reporter assay, mutagenesis PloS one Medium 21984905
2012 The crystal structure of the AIP TPR domain was determined at high resolution, revealing that disease-associated C-terminal alpha-7 helix (Cα-7h) mutations (R304*, R304Q, Q307*, R325Q) disrupt client protein (AhR, PDE4A5) binding to Cα-7h without affecting chaperone (Hsp90, TOMM20) binding. A molecular switch in the AIP TPR domain allows recognition of both Hsp90 MEEVD and TOMM20 EDDVE motifs. X-ray crystallography, mutagenesis, structural analysis PloS one High 23300914
2012 Missense variants in AIP disrupt AIP-PDE4A5 interaction (assessed by yeast two-hybrid) in a variable manner. A promoter mutation reduces in vitro AIP transcription. Stimulation of the PKA pathway positively regulates the AIP promoter. Silent mutations in AIP can cause abnormal splicing leading to truncated protein or reduced AIP expression. Yeast two-hybrid, luciferase/beta-galactosidase reporter assay, minigene splicing assay, promoter activity assay Human mutation Medium 20506337
2012 Somatostatin analog (octreotide/lanreotide) treatment increases AIP mRNA and protein expression in GH3 cells, as well as ZAC1 mRNA. Overexpression of wild-type (but not mutant) AIP increases ZAC1 mRNA expression, while AIP siRNA knockdown reduces ZAC1 mRNA. AIP siRNA knockdown increases GH3 cell metabolic activity and clonogenic ability. siRNA, plasmid transfection, qPCR, immunostaining, luciferase reporter, metabolic assay, colony formation assay The Journal of clinical endocrinology and metabolism Medium 22659247
2013 AIP overexpression in GH3 cells reduces forskolin-induced cAMP signaling (total cAMP, CRE-luciferase, target gene expression) and GH secretion. AIP knockdown increases cAMP signaling. The R304X mutant AIP lacks this activity. The effect is not fully explained by the AIP-PDE interaction, suggesting other interacting partners mediate this cAMP-suppressive function. Overexpression and knockdown (siRNA) in GH3 cells, cAMP assay, luciferase reporter, qPCR, GH secretion assay, PDE inhibitor treatment Endocrine-related cancer Medium 23702468
2014 AIP deficiency leads to elevated intracellular cAMP concentrations through defective Gαi-2 and Gαi-3 proteins that normally inhibit cAMP synthesis. In AIP-deficient somatotropinomas, Gαi-2 protein expression is reduced. AIP deficiency also reduces phosphorylated ERK1/2 and CREB levels in mouse and human somatotropinomas. Gene expression microarray, cAMP measurement, G protein alpha subunit knockdown, immunostaining of human and mouse tumors Oncogene Medium 24662816
2014 AIP (XAP2) physically interacts with CARMA1 in T cells, augmenting CARMA1-BCL10-MALT1 (CBM) complex formation, thereby promoting optimal IKK/NF-κB signaling and IL-2 production in response to TCR/CD28 co-stimulation. Co-immunoprecipitation, knockdown, T cell stimulation assay, NF-κB reporter, IL-2 measurement Cell communication and signaling Medium 25245034
2016 AIP is a stable protein (half-life ~43.5 h in HEK293) with turnover driven by ubiquitination via the FBXO3-containing SKP1-CUL1-F-box protein (SCF) E3 ubiquitin ligase complex. Missense AIP mutations lead to rapid proteasomal degradation (classified as short or very short half-life); proteasome inhibition rescues mutant protein levels. Protein half-life correlates with age at diagnosis in acromegaly/gigantism patients. Cycloheximide chase, proteasome inhibition, GST pull-down with quantitative mass spectrometry, co-immunoprecipitation, gene knockdown, clinical correlation The Journal of clinical endocrinology and metabolism High 27253664
2016 AIP mutations impair AhR signaling: AIP-mutated patient fibroblasts have approximately half the AIP protein of wild-type cells; expression of AhR target genes CYP1B1 and AHRR is significantly altered. Knockdown of endogenous Aip in GH3 cells attenuates Cyp1b1 induction by the AhR ligand kynurenine. Both mutant AIP expression and Aip knockdown affect kynurenine-dependent GH secretion from GH3 cells. Patient fibroblasts, siRNA knockdown, GH3 cell transfection, gene expression analysis, 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. The interaction is enhanced when all three are present and maintained during Cα-R1α dissociation by PKA activation. The pathogenic AIP p.R304* mutation reduces interaction with R1α/Cα. Cα stabilizes AIP protein levels. AIP reduction by siRNA increases PKA activity, which is disproportionately enhanced during PDE4 inhibition. Co-immunoprecipitation, siRNA knockdown, PKA activity assay, protein stability assay Human molecular genetics Medium 29726992
2018 In pull-down/quantitative mass spectrometry experiments against rat somatotropinoma cell lysates, AIP directly interacts with HSP90AA1, HSP90AB1, HSPA8, and novel partners HSPA5, HSPA9 (chaperones), TUBB, TUBB2A, NME1, and SOD1. Disease-associated variants p.R304* and p.R304Q show impaired interactions with HSPA8, HSP90AB1, NME1, and SOD1; p.R304* also shows reduced binding to TUBB and TUBB2A. Pull-down with quantitative mass spectrometry, co-immunoprecipitation, co-localization, RNA microarray Oncotarget Medium 29507682
2019 AIP-mutation-positive pituitary tumors are infiltrated by large numbers of macrophages compared to sporadic tumors; pituitary-specific Aip-knockout mouse tissue recapitulates this phenotype. AIP knockdown in GH3/somatomammotroph cells enhances EMT-like phenotype and invasion in response to macrophage-conditioned media. Tumor-derived CCL5 is upregulated in AIP-mutation-positive adenomas, and Aip-knockdown cell-conditioned media increases macrophage migration via a CCL5/CCR5 pathway. Macrophage infiltration analysis, Aip-knockout mouse tissue, in vitro migration/invasion assays, conditioned media experiments, CCL5/CCR5 pathway inhibition with maraviroc Oncogene Medium 30867568
2020 AIP-mutated somatotropinomas overexpress miR-34a; ectopic expression of AIPmut (p.R271W) in Aip-/- MEFs upregulates miR-34a. miR-34a directly targets Gnai2 (encoding Gαi2), reducing Gαi2 levels and increasing intracellular cAMP in GH3 cells. High miR-34a expression blunts octreotide-mediated GH inhibition and anti-proliferative effects. This defines a mutant AIP → miR-34a → Gαi2 ↓ → cAMP ↑ → somatotroph proliferation/octreotide resistance pathway. miRNA array, ectopic mutant AIP expression in Aip-/- MEFs, miR-34a overexpression in GH3, luciferase reporter for direct Gnai2 targeting, GH inhibition assay, proliferation/apoptosis assays, human/mouse tumor immunostaining International journal of cancer High 32856736
2021 AIP is required at the plasma membrane to form a complex with monomeric intracellular RET receptor, caspase-3, and PKCδ, activating a PIT1/CDKN2A-ARF/p53 apoptosis pathway specifically in somatotrophs. AIP deficiency blocks RET/caspase-3/PKCδ activation, preventing apoptosis. Pathogenic AIP variants failed to inhibit RET-induced apoptosis while non-pathogenic variants did not. In adult male rats, altered AIP induces gigantism and pituitary hyperplasia by blocking the RET apoptotic pathway. AIP-mutated tumors have less CDKN2A-ARF expression and somatotroph adenomas overexpress the RET-ligand GDNF. Co-immunoprecipitation, in vitro apoptosis assay with mutant panel, virogenomics in neonatal rats, Aip-knockout mouse tumor analysis, patient tumor immunostaining Oncogene High 34588620
2022 Cryo-EM structure of the human AhR-Hsp90-XAP2 complex at 2.85 Å resolution reveals a closed-conformation Hsp90 dimer with AhR threaded through its lumen and XAP2 acting as a structural brace. The structure reveals the AhR PAS-B domain organization including the ligand-binding pocket, explaining the structural determinants of ligand-binding specificity and promiscuity. Cryo-EM structural determination at 2.85 Å resolution 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 558 10805659
2006 Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science (New York, N.Y.) 413 16728643
2004 Paraptosis: mediation by MAP kinases and inhibition by AIP-1/Alix. Cell death and differentiation 314 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 232 23371967
1999 Characterization of the AhR-hsp90-XAP2 core complex and the role of the immunophilin-related protein XAP2 in AhR stabilization. Biochemistry 181 10413464
1998 Characterization of the Ah receptor-associated protein, ARA9. The Journal of biological chemistry 166 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 150 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 133 22319033
2003 Attenuation of the activity of the cAMP-specific phosphodiesterase PDE4A5 by interaction with the immunophilin XAP2. The Journal of biological chemistry 132 12810716
2010 Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families. Human mutation 131 20506337
2000 The immunophilin-like protein XAP2 regulates ubiquitination and subcellular localization of the dioxin receptor. The Journal of biological chemistry 130 11013261
2013 Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis. European journal of endocrinology 119 23321498
2011 High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas. European journal of endocrinology 119 21753072
2015 Landscape of Familial Isolated and Young-Onset Pituitary Adenomas: Prospective Diagnosis in AIP Mutation Carriers. The Journal of clinical endocrinology and metabolism 111 26186299
2012 Somatostatin analogs modulate AIP in somatotroph adenomas: the role of the ZAC1 pathway. The Journal of clinical endocrinology and metabolism 105 22659247
2011 AIP and its interacting partners. The Journal of endocrinology 103 21454441
2011 AIP mutation in pituitary adenomas in the 18th century and today. The New England journal of medicine 98 21208107
2022 Cryo-EM structure of the agonist-bound Hsp90-XAP2-AHR cytosolic complex. Nature communications 95 36385050
1996 XAP2, a novel hepatitis B virus X-associated protein that inhibits X transactivation. Nucleic acids research 91 8972861
2000 ARA9 modifies agonist signaling through an increase in cytosolic aryl hydrocarbon receptor. The Journal of biological chemistry 88 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 81 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
2000 Aryl hydrocarbon (Ah) receptor levels are selectively modulated by hsp90-associated immunophilin homolog XAP2. Cell stress & chaperones 77 11005382
2014 AIP inactivation leads to pituitary tumorigenesis through defective Gαi-cAMP signaling. Oncogene 74 24662816
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 67 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 63 23300914
2018 Reprogramming Probiotic Lactobacillus reuteri as a Biosensor for Staphylococcus aureus Derived AIP-I Detection. ACS synthetic biology 62 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
2012 Germline mutations of AIP gene in somatotropinomas resistant to somatostatin analogues. European journal of endocrinology 54 23038625
2020 Significant Benefits of AIP Testing and Clinical Screening in Familial Isolated and Young-onset Pituitary Tumors. The Journal of clinical endocrinology and metabolism 49 31996917
2009 AIP-1 ameliorates beta-amyloid peptide toxicity in a Caenorhabditis elegans Alzheimer's disease model. Human molecular genetics 49 19414486
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
2001 Apoptosis-inducing protein, AIP, from parasite-infected fish induces apoptosis in mammalian cells by two different molecular mechanisms. Cell death and differentiation 49 11319613
2013 Somatostatin analogues increase AIP expression in somatotropinomas, irrespective of Gsp mutations. Endocrine-related cancer 48 23940012
2009 The expression of AIP-related molecules in elucidation of cellular pathways in pituitary adenomas. The American journal of pathology 48 19850893
2012 Familial pituitary adenomas - who should be tested for AIP mutations? Clinical endocrinology 47 22612670
2002 Two distinct regions of the immunophilin-like protein XAP2 regulate dioxin receptor function and interaction with hsp90. The Journal of biological chemistry 47 11805120
2019 Surgery, Octreotide, Temozolomide, Bevacizumab, Radiotherapy, and Pegvisomant Treatment of an AIP Mutation‒Positive Child. The Journal of clinical endocrinology and metabolism 46 31125088
2019 AIP-mutated acromegaly resistant to first-generation somatostatin analogs: long-term control with pasireotide LAR in two patients. Endocrine connections 45 30851160
2007 Mutation analysis of aryl hydrocarbon receptor interacting protein (AIP) gene in colorectal, breast, and prostate cancers. British journal of cancer 45 17242703
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 44 27253664
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
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 44 20829355
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 40 14730974
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
2017 Simplified AIP-II Peptidomimetics Are Potent Inhibitors of Staphylococcus aureus AgrC Quorum Sensing Receptors. Chembiochem : a European journal of chemical biology 37 28006082
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 34 32856736
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
2014 Familial isolated pituitary adenomas (FIPA) and mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocrinology and metabolism clinics of North America 33 25732638
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
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 33 16085934
2010 AIP gene and familial isolated pituitary adenomas. Molecular and cellular endocrinology 32 20457215
2000 Epstein-Barr virus encoded nuclear protein EBNA-3 binds XAP-2, a protein associated with Hepatitis B virus X antigen. Oncogene 32 10777214
2018 Multi-chaperone function modulation and association with cytoskeletal proteins are key features of the function of AIP in the pituitary gland. Oncotarget 31 29507682
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
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 Acromegaly Is More Severe in Patients With AHR or AIP Gene Variants Living in Highly Polluted Areas. The Journal of clinical endocrinology and metabolism 28 26963951
2016 cAMP-specific PDE4 phosphodiesterases and AIP in the pathogenesis of pituitary tumors. Endocrine-related cancer 28 27267386
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
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 27 21546764
2015 Increasing AIP Macrocycle Size Reveals Key Features of agr Activation in Staphylococcus aureus. Chembiochem : a European journal of chemical biology 26 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
2014 Frequency of AIP gene mutations in young patients with acromegaly: a registry-based study. The Journal of clinical endocrinology and metabolism 24 25093619
2021 RET signalling provides tumorigenic mechanism and tissue specificity for AIP-related somatotrophinomas. Oncogene 23 34588620
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
2017 Impact of AIP and inhibitory G protein alpha 2 proteins on clinical features of sporadic GH-secreting pituitary adenomas. European journal of endocrinology 22 27998919
2013 Aryl hydrocarbon receptor interacting protein (AIP) mutations occur rarely in sporadic parathyroid adenomas. The Journal of clinical endocrinology and metabolism 22 23633209
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
2018 Interaction of AIP with protein kinase A (cAMP-dependent protein kinase). Human molecular genetics 20 29726992
2016 Analysis of GPR101 and AIP genes mutations in acromegaly: a multicentric study. Endocrine 20 26815903
2016 AIP mutations impair AhR signaling in pituitary adenoma patients fibroblasts and in GH3 cells. Endocrine-related cancer 20 27080473
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
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
2020 Updates on the diagnosis and management of the most common hereditary porphyrias: AIP and EPP. Hematology. American Society of Hematology. Education Program 18 33275677
2007 AIP Mutations are not identified in patients with sporadic pituitary adenomas. Endocrine pathology 18 17916996