Affinage

AHSA1

Activator of 90 kDa heat shock protein ATPase homolog 1 · UniProt O95433

Round 2 corrected
Length
338 aa
Mass
38.3 kDa
Annotated
2026-04-28
130 papers in source corpus 23 papers cited in narrative 23 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AHSA1 (Aha1) is a conserved Hsp90 cochaperone that stimulates the intrinsic ATPase activity of Hsp90 up to ~5-fold by binding cooperatively across the middle and N-terminal domains of the Hsp90 dimer, thereby accelerating the conformational transitions required for client protein folding and activation (PMID:12504007, PMID:12604615, PMID:20089831, PMID:29045865). Its cochaperone activity is regulated by post-translational modifications on both Aha1 (c-Abl phosphorylation at Y223) and Hsp90 (SUMOylation at K191, S-nitrosylation at Cys521, CK2 phosphorylation at T22), and by competitive cochaperone interactions in which Cpr6 enhances and p23 terminates Aha1 engagement with Hsp90 (PMID:26235616, PMID:24462205, PMID:35334246, PMID:23396352). Partial silencing of AHSA1 rescues cell-surface trafficking of ΔF508-CFTR, while excess Aha1 drives tau phosphorylation and aggregation in Alzheimer's disease models and promotes proteasome-inhibitor resistance in multiple myeloma through chaperoning of CDK6 and PSMD2, establishing AHSA1 as a tunable node whose activity level determines client fate (PMID:17110338, PMID:28827321, PMID:33832539, PMID:34991674). Small molecules targeting either the Aha1 C-terminal domain or the Aha1-interaction site on Hsp90's N-terminal domain selectively block Aha1-stimulated ATPase activity without affecting basal Hsp90 function, validating AHSA1 as a pharmacological target (PMID:28851842, PMID:32017918).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2002 High

    The fundamental question of whether Hsp90 ATPase activity is accelerated by a dedicated cochaperone was answered by the identification of Aha1 as a ubiquitous, stress-regulated activator that directly binds Hsp90 and stimulates ATP hydrolysis, linking ATPase stimulation to in vivo client activation.

    Evidence In vitro ATPase assay with purified proteins, co-immunoprecipitation, and yeast v-Src client activation assay

    PMID:12504007

    Open questions at the time
    • Binding site on Hsp90 not mapped
    • Mechanism of ATPase stimulation unknown
    • Client repertoire beyond v-Src undefined
  2. 2003 High

    The binding site was localized to the Hsp90 middle domain (residues 272–617), and the magnitude of ATPase stimulation was quantified at ~5-fold, establishing the architecture of the Aha1–Hsp90 interface.

    Evidence Purified protein binding assays with Hsp90 domain constructs and in vitro ATPase measurements in S. cerevisiae

    PMID:12604615

    Open questions at the time
    • N-terminal domain contacts not yet identified
    • Conformational mechanism of stimulation unresolved
    • Role of Aha1 C-terminal domain unknown
  3. 2006 High

    The physiological relevance of Aha1 dosage was demonstrated when partial AHSA1 silencing rescued ΔF508-CFTR surface trafficking, showing that Aha1-driven Hsp90 ATPase activity gates client triage decisions at the ER.

    Evidence Proteomics-guided identification of CFTR chaperome, siRNA knockdown of AHSA1, cell-surface CFTR rescue assay

    PMID:17110338

    Open questions at the time
    • Mechanism linking ATPase rate to CFTR retention vs. export unclear
    • Whether other cochaperones compensate upon Aha1 reduction untested
  4. 2010 High

    A cooperative two-domain binding model was established in which the Aha1 N- and C-terminal domains bridge the Hsp90 dimer interface, and Hsp90 N-domain phosphorylation by Swe1/WEE1 was shown to modulate Aha1 association, revealing that post-translational modifications tune the cochaperone interaction.

    Evidence Mass spectrometry-based domain mapping, mutagenesis, in vivo CFTR folding assay; in vitro kinase assay with phosphomimetic Hsp90 Y24 mutants and co-IP

    PMID:20089831 PMID:20159553

    Open questions at the time
    • Atomic-resolution structure of full-length Aha1–Hsp90 complex unavailable
    • How Y24 phosphorylation changes Aha1 affinity quantitatively unresolved
  5. 2011 High

    CK2-mediated phosphorylation of Hsp90 at T22 was found to impair cochaperone interactions, and Aha1 overexpression rescued this defect, demonstrating that Aha1 can functionally override inhibitory Hsp90 N-domain phosphorylation.

    Evidence In vitro CK2 kinase assay, phosphomimetic mutagenesis, ATPase assay, yeast genetic rescue

    PMID:21419342

    Open questions at the time
    • Whether T22 and Y24 modifications cooperate or compete in regulating Aha1 binding unknown
    • Relevance to mammalian Hsp90 regulation not directly tested
  6. 2013 High

    The ordered cochaperone cycle was reconstituted: Aha1 accelerates Hsp90 conformational closure, Cpr6 enhances Aha1 affinity and synergistically displaces the inhibitory Sti1/Hop, and p23 releases Aha1 to complete the cycle, establishing the kinetic framework for cochaperone succession.

    Evidence FRET-based conformational assays, in vitro ATPase stimulation, and cochaperone competition experiments with purified components

    PMID:23396352

    Open questions at the time
    • Client protein influence on cochaperone succession not tested
    • Stoichiometry of ternary complexes in vivo unknown
  7. 2014 High

    SUMOylation of a conserved Hsp90 N-domain lysine (K191 human/K178 yeast) was identified as a recruitment signal for Aha1, elevated in transformed cells and sensitizing them to Hsp90 inhibitors, linking Aha1 engagement to oncogenic signaling.

    Evidence Co-immunoprecipitation, site-directed mutagenesis, cell-based SUMOylation assays across yeast and mammalian systems

    PMID:24462205

    Open questions at the time
    • SUMO E3 ligase responsible not identified
    • Whether SUMOylation is regulated by the chaperone cycle itself unknown
  8. 2015 High

    c-Abl-mediated phosphorylation of Aha1 at Y223 was shown to enhance Hsp90 binding and ATPase stimulation while biasing client selectivity toward kinases and away from non-kinase clients (CFTR, GR), and also triggering Aha1 ubiquitination and degradation, establishing the first direct PTM on Aha1 that regulates its function.

    Evidence In vitro kinase assay, co-IP, Y223 mutagenesis, ATPase assay, client chaperoning readouts, pharmacologic c-Abl inhibition

    PMID:26235616

    Open questions at the time
    • E3 ubiquitin ligase mediating Aha1 degradation unidentified
    • How Y223 phosphorylation biases client specificity structurally unresolved
  9. 2017 High

    Aha1 was linked to tauopathy pathogenesis: Aha1 co-localizes with tau pathology in human AD brain, and overexpression in tau transgenic mice promotes insoluble/oligomeric tau accumulation and cognitive deficits, while pharmacologic inhibition (KU-177) reduces tau aggregation.

    Evidence In vitro tau aggregation, immunohistochemistry of human AD brain, AAV-based overexpression in tau transgenic mice with behavioral testing

    PMID:28827321

    Open questions at the time
    • Whether Aha1 directly chaperones tau or acts indirectly through Hsp90 client network unclear
    • Therapeutic window for Aha1 inhibition in neurodegeneration undefined
  10. 2017 High

    Small-molecule targeting of the Aha1–Hsp90 interface was achieved: an inhibitor binding the Hsp90 N-terminal domain near the ATP site blocks Aha1-stimulated but not basal ATPase, and single-molecule FRET resolved the kinetic basis of Aha1 action on both open and closed Hsp90 conformational transitions.

    Evidence FRET-based ATPase screen, NMR of inhibitor–Hsp90 complex, three-color single-molecule FRET kinetic analysis

    PMID:28851842 PMID:29045865

    Open questions at the time
    • In vivo efficacy and selectivity of N-domain-targeting inhibitor not assessed
    • Full structural model of inhibitor-bound ternary complex lacking
  11. 2019 High

    An extracellular role for Aha1 was established: secreted Aha1 displaces TIMP2 from extracellular Hsp90 to reactivate MMP2, functioning as a molecular switch controlling matrix proteolysis and tumor invasion.

    Evidence Co-immunoprecipitation, ATPase assay, gene knockout, blocking antibodies, gelatinolytic activity assay in HT1080 cells

    PMID:31412254

    Open questions at the time
    • Mechanism of Aha1 secretion unknown
    • Whether extracellular Aha1 function is relevant beyond cancer invasion untested
  12. 2020 High

    A first-in-class inhibitor (SEW04784) binding the Aha1 C-terminal domain was characterized, weakening asymmetric Aha1–Hsp90 binding and selectively blocking Aha1-dependent functions including client refolding, androgen receptor signaling, and phospho-tau accumulation.

    Evidence NMR of SEW84–Aha1 C-domain, in vitro/in vivo luciferase refolding, AR reporter, tau clearance assays

    PMID:32017918

    Open questions at the time
    • Pharmacokinetics and in vivo drug-like properties not reported
    • Selectivity against other Hsp90 cochaperones not assessed
  13. 2022 High

    Two additional regulatory inputs were defined: S-nitrosylation of Hsp90 Cys521 disrupts the Hsp90–Aha1 interaction while favoring CDC37 binding, acting as a redox-sensitive switch; and AHSA1 was shown to chaperone CDK6 and PSMD2 in multiple myeloma, with elevated AHSA1 driving proteasome inhibitor resistance that is reversed by KU-177 or Bufalin binding at Aha1-K137.

    Evidence Biotin switch/LC-MS/MS for SNO, co-IP and PLA, Hsp90 C521 mutagenesis in endothelial cells and ApoE−/− mice; proteome microarray target ID, MST binding, K137 mutagenesis, xenograft model

    PMID:34991674 PMID:35334246

    Open questions at the time
    • Whether Cys521 SNO and K191 SUMOylation are coordinated unknown
    • Full client repertoire in myeloma not defined
    • Structural basis of Bufalin–Aha1-K137 interaction at atomic resolution lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: (1) the high-resolution structure of a full-length Aha1–Hsp90–client ternary complex, (2) the mechanism by which Aha1 dosage selectively biases client triage toward degradation vs. folding, and (3) whether extracellular Aha1 functions are physiologically relevant beyond tumor settings.
  • No full-length ternary complex structure
  • Client triage decision mechanism unknown
  • Physiological role of extracellular Aha1 in non-cancer contexts untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 6 GO:0098772 molecular function regulator activity 5
Localization
GO:0005829 cytosol 3 GO:0005576 extracellular region 1
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-1643685 Disease 3 R-HSA-8953897 Cellular responses to stimuli 3
Partners
ABL1CDC37CPR6HSP90AA1HSP90AB1PTGES3TIMP2
Complex memberships
Hsp90 chaperone complexHsp90–Aha1–Cpr6 ternary complexeHsp90–Aha1 extracellular complex

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Aha1 (activator of Hsp90 ATPase) was identified as a ubiquitous, stress-regulated cochaperone that directly binds Hsp90 and stimulates its intrinsic ATPase activity in vitro, and is required in vivo for Hsp90-dependent activation of client proteins such as v-Src. In vitro ATPase assay with purified proteins, co-immunoprecipitation, yeast genetic studies (v-Src client activation assay) Molecular cell High 12504007
2003 Aha1 (and its relative Hch1) binds to the middle domain of Hsp90 (amino acids 272–617) in Saccharomyces cerevisiae, stimulates Hsp90 ATPase activity ~5-fold, and contributes to efficient activation of the heterologous client v-Src; Aha1/Hch1 become essential for cell viability when Hsp90 levels are limiting. Purified protein binding assays, in vitro ATPase stimulation, yeast gene deletion, v-Src client activation assay The Journal of biological chemistry High 12604615
2006 Partial siRNA silencing of the Hsp90 cochaperone Aha1 rescues cell-surface trafficking of the misfolded ΔF508 CFTR variant in cystic fibrosis cells, demonstrating that Aha1-driven Hsp90 ATPase activity in the ER chaperome determines whether ΔF508 CFTR is retained or exported. Proteomics (CFTR interactome), siRNA knockdown, cell-surface rescue assay of ΔF508 CFTR Cell High 17110338
2010 The N- and C-terminal domains of human Aha1 cooperatively bind across the dimer interface of Hsp90 to stimulate ATP hydrolysis; mutations in either domain impair Hsp90 ATPase stimulation in vitro and impair chaperoning of wild-type and ΔF508 CFTR in vivo, establishing a model in which Aha1 modulates the dwell time of Hsp90 with client by regulating N-terminal dimer structural transitions. Mass spectrometry-based domain interaction mapping, in vitro ATPase assay with domain mutants, in vivo CFTR folding/trafficking assay Molecular biology of the cell High 20089831
2013 Aha1 accelerates the intrinsically slow conformational transitions of yeast Hsp90 toward an N-terminally associated state but does not fully close the nucleotide-binding pocket; a ternary Hsp90–Aha1–Cpr6 complex was identified in which Cpr6 increases Aha1 affinity for Hsp90 and further stimulates ATPase activity, while Aha1 and Cpr6 synergistically displace the inhibitory cochaperone Sti1, and Aha1 is ultimately released by p23 to complete the cycle. FRET-based conformational assays, in vitro ATPase assay, co-chaperone competition experiments, biochemical reconstitution Nature structural & molecular biology High 23396352
2013 Computational modeling revealed that Aha1 modulates Hsp90 allosteric interactions by targeting regulatory hinge regions, restricting collective motions and stabilizing the closed, dimerized (ATPase-competent) conformation of Hsp90, in contrast to p23 which acts as a 'molecular brake' slowing inter-domain allosteric signals. Protein docking, molecular dynamics simulation, protein structure network analysis, energy landscape modeling PloS one Low 23977182
2014 Asymmetric SUMOylation of a conserved lysine in the N domain of Hsp90 (K178 in yeast, K191 in human) facilitates recruitment of the cochaperone Aha1, and this SUMOylation is elevated in transformed cells, sensitizing them to Hsp90 inhibitors. Co-immunoprecipitation, site-directed mutagenesis, cell-based SUMOylation assays, yeast genetic studies Molecular cell High 24462205
2015 c-Abl kinase phosphorylates human Aha1 at Y223, promoting its interaction with Hsp90 and consequently increasing Hsp90 ATPase activity, enhancing Hsp90 interaction with kinase clients, and compromising chaperoning of non-kinase clients (glucocorticoid receptor, CFTR); Y223 phosphorylation also leads to ubiquitination and proteasomal degradation of Aha1. In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis (Y223), ATPase assay, pharmacologic c-Abl inhibition, ex vivo cancer cell treatment Cell reports High 26235616
2015 Aha1 is the strongest known activator of Hsp90 ATPase activity and participates in the chaperone cycle with opposing effects to p23 (which inhibits ATPase); both cochaperones are conserved from yeast to humans and have been integrated into a model of the Hsp90 cycle. Review synthesizing biochemical and genetic evidence from prior studies Sub-cellular biochemistry Medium 25487019
2015 Silencing AHSA1 in human osteosarcoma cells (MG-63 and Saos2) inhibited cell growth, migration, and invasion, and increased apoptosis; it also decreased Hsp90 ATPase activity and increased levels of Wnt/β-catenin pathway negative regulators (Axin-2, GSK3β) while decreasing Wnt-5a and β-catenin, placing AHSA1 upstream of the Wnt/β-catenin pathway in osteosarcoma. siRNA knockdown, cell proliferation/migration/invasion assays, ATPase activity assay, western blot for pathway components Biomedicine & pharmacotherapy Medium 26796264
2017 Aha1 co-chaperone dramatically increases production of aggregated tau in an Hsp90-dependent manner; an Aha1 inhibitor (KU-177) reduces insoluble tau accumulation; Aha1 co-localizes with tau pathology in human AD brain tissue correlating with disease progression; Aha1 overexpression in a tau transgenic mouse model promoted insoluble and oligomeric tau accumulation and cognitive deficits. In vitro tau aggregation assay, pharmacologic inhibition (KU-177), immunohistochemistry of human brain, tau transgenic mouse model with cognitive testing, western blot for tau species Proceedings of the National Academy of Sciences of the United States of America High 28827321
2017 A FRET-based screen identified a small-molecule inhibitor that abrogates Aha1-induced ATPase stimulation of Hsp90 without significantly affecting basal Hsp90 ATPase; NMR spectroscopy showed the inhibitor binds the N-terminal domain of Hsp90 near the ATP-binding site, overlapping a transient Aha1-interaction site, and does not dissociate the Aha1–Hsp90 complex but prevents the catalytically required N-terminal domain interaction. FRET-based ATPase assay, NMR spectroscopy, in vivo client protein activation assay The Journal of biological chemistry High 28851842
2017 Single-molecule FRET analysis revealed that Aha1 accelerates Hsp90 ATPase activity by affecting kinetic transitions in both the open and closed conformations of Hsp90 in a nucleotide-dependent and independent manner, and that the presence of the first nucleotide prolongs binding of the second nucleotide, demonstrating cooperative nucleotide binding regulated by Aha1. Three-color single-molecule FRET with fluorescently labeled nucleotide reporter, kinetic analysis of state transitions Biophysical journal High 29045865
2019 Extracellular AHA1 (eHSP90 co-chaperone) competes with TIMP2 for binding to extracellular Hsp90 (eHSP90): TIMP2 inhibits eHSP90 ATPase activity and keeps client MMP2 in an inhibitory state, while secreted AHA1 displaces TIMP2 from the eHSP90 complex to reactivate MMP2, functioning as a molecular switch regulating matrix proteolysis and tumor cell invasion. Co-immunoprecipitation, ATPase activity assay, gene knockout, blocking antibodies, gelatinolytic activity assay in HT1080 cancer cells Cell reports High 31412254
2020 SEW04784 (SEW84) was identified as a first-in-class inhibitor of Aha1-stimulated Hsp90 ATPase activity that does not inhibit basal Hsp90 ATPase; NMR analysis showed SEW84 binds the C-terminal domain of Aha1, weakening its asymmetric binding to Hsp90; SEW84 blocks Aha1-dependent refolding of firefly luciferase in vitro and in vivo, inhibits androgen receptor transcriptional activity, and promotes clearance of phosphorylated tau. NMR spectroscopy, in vitro and in vivo luciferase refolding assay, ATPase assay, androgen receptor reporter assay, tau clearance in cellular and tissue models Cell chemical biology High 32017918
2021 Aha1 overexpression in hippocampi of aged wild-type mice promoted phosphorylation of AD-relevant tau species and impaired associative learning, demonstrating that chaperone imbalance favoring Aha1 is sufficient to initiate tau accumulation and cognitive dysfunction in the absence of tau transgenes. AAV-mediated Aha1 overexpression in vivo, behavioral testing (associative learning), immunohistochemistry for phospho-tau species, assessment of gliosis Acta neuropathologica communications Medium 33832539
2022 S-nitrosylation (SNO) of Hsp90 at Cys521 suppresses its interaction with AHA1 while promoting association with CDC37; Hsp90 Cys521 mutation increased eNOS activity and inhibited NF-κB signaling in endothelial cells and mitigated atherosclerosis in ApoE-/- mice, establishing Cys521 SNO as a conformational switch that modulates the Hsp90–AHA1 co-chaperone interaction. Biotin switch assay + LC-MS/MS, co-immunoprecipitation, proximity ligation assay, Hsp90 Cys521 mutant transfection, endothelial functional assays, AAV delivery in ApoE-/- mouse model Redox biology High 35334246
2022 AHSA1 acts as a co-chaperone of HSP90A to activate CDK6 and PSMD2 (key regulators of MM proliferation and proteasome inhibitor resistance, respectively); AHSA1-K137 was identified as the specific binding site for the inhibitor Bufalin on AHSA1, and mutation of K137 decreased AHSA1–HSP90A interaction and suppressed CDK6 and PSMD2 chaperoning; the AHSA1 selective inhibitor KU-177 abrogated proliferation and PI resistance induced by elevated AHSA1. Proteome microarray (target identification), co-immunoprecipitation, mass spectrometry, site-directed mutagenesis (K137), microscale thermophoresis, western blot, xenograft model, flow cytometry in MM patient samples Journal of experimental & clinical cancer research High 34991674
2013 In a zebrafish model of HDR syndrome (GATA3 mutation), Ahsa1 and Hsp90 activity unexpectedly promoted more severe craniofacial phenotypes, demonstrating that Ahsa1/Hsp90 chaperone function modulates phenotypic severity of a transcription factor (Gata3) mutation in vivo. Zebrafish forward genetic screen, genetic epistasis analysis (ahsa1 mutation/knockdown combined with gata3 mutant), live imaging Disease models & mechanisms Medium 23720234
2016 In Neurospora crassa, deletion of Aha1 results in hypersensitivity to antifungal azoles and heat stress; Aha1 positively regulates transcriptional responses to ketoconazole stress through ergosterol biosynthesis genes (erg11 and erg6), demonstrating a role for Aha1 in antifungal drug resistance mediated through Hsp90-dependent regulation of sterol biosynthesis. Susceptibility testing of deletion mutants, LC-MS sterol analysis, transcriptional analysis of ergosterol pathway genes Frontiers in microbiology Medium 27761133
2017 The flavonoid derivative TL-2-8 dose-dependently inhibited AHA1 expression and decreased Hsp90–AHA1 complex formation in breast cancer cells, leading to decreased Hsp90 chaperone function, reduced PLK1 signaling, and induction of immature mitophagy via LAMP2 downregulation. Western blot (AHA1 and Hsp90 client expression), co-immunoprecipitation (Hsp90–AHA1 complex), cell viability/death assays, xenograft model Acta pharmacologica Sinica Medium 28504248
2011 Casein kinase 2 phosphorylates Hsp90 at T22 in the N-domain α-helix, which impacts interaction with cochaperones including Aha1; overexpression of Aha1 compensates for T22 phosphomimetic Hsp90 mutant defects by stimulating ATPase activity and restoring cochaperone interactions, demonstrating that Aha1 can override Hsp90 N-domain phosphorylation-induced defects. In vitro kinase assay (CK2), phosphomimetic mutagenesis, ATPase assay, co-immunoprecipitation, yeast genetic rescue Molecular cell High 21419342
2010 Swe1 (yeast WEE1) phosphorylates Hsp90 at Y24 (yeast)/Y38 (human Hsp90α) in the N-domain; this phosphorylation is cell-cycle associated and modulates Hsp90 chaperoning of a selected clientele including v-Src; the modification also affects Hsp90 interaction with cochaperones including Aha1. In vitro kinase assay, phosphomimetic/non-phosphorylatable mutants, client activation assays, co-immunoprecipitation Molecular cell High 20159553

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2010 Mechanisms and functions of p38 MAPK signalling. The Biochemical journal 1342 20626350
2000 The p38 signal transduction pathway: activation and function. Cellular signalling 1339 10676842
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2006 Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 517 17110338
2002 Activation of the ATPase activity of hsp90 by the stress-regulated cochaperone aha1. Molecular cell 439 12504007
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2003 Mechanism of p38 MAP kinase activation in vivo. Genes & development 402 12893778
2000 Inhibition of p38 MAP kinase as a therapeutic strategy. Immunopharmacology 398 10878289
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2014 A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways. Cell 325 25036637
2020 The p38 Pathway: From Biology to Cancer Therapy. International journal of molecular sciences 320 32168915
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2000 MAP kinase pathways activated by stress: the p38 MAPK pathway. Critical care medicine 296 10807318
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
2011 A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. Nature 269 21654808
2016 p38 MAPK Signaling in Osteoblast Differentiation. Frontiers in cell and developmental biology 258 27200351
1999 Both Erk and p38 kinases are necessary for cytokine gene transcription. American journal of respiratory cell and molecular biology 249 10101008
2007 The pathways to tumor suppression via route p38. Trends in biochemical sciences 229 17624785
2015 ∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis. Nature 209 26618866
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2017 Energy stress-induced lncRNA FILNC1 represses c-Myc-mediated energy metabolism and inhibits renal tumor development. Nature communications 178 28978906
2003 Aha1 binds to the middle domain of Hsp90, contributes to client protein activation, and stimulates the ATPase activity of the molecular chaperone. The Journal of biological chemistry 177 12604615
2006 p38 MAPK in development and cancer. Cell cycle (Georgetown, Tex.) 174 16627995
2010 The Hsp90 cochaperone, FKBP51, increases Tau stability and polymerizes microtubules. The Journal of neuroscience : the official journal of the Society for Neuroscience 172 20071522
2020 UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature cell biology 168 32807901
2014 E-cadherin interactome complexity and robustness resolved by quantitative proteomics. Science signaling 162 25468996
2000 Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells. Genome research 161 11042152
2020 Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer. Molecular cell 159 32416067
2010 Swe1Wee1-dependent tyrosine phosphorylation of Hsp90 regulates distinct facets of chaperone function. Molecular cell 159 20159553
2009 Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6. Science signaling 159 20029029
2000 The p38 pathway provides negative feedback for Ras proliferative signaling. The Journal of biological chemistry 149 10978313
2017 Quantitative proteomics reveals that long non-coding RNA MALAT1 interacts with DBC1 to regulate p53 acetylation. Nucleic acids research 148 28973437
2020 Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly. Nature immunology 147 32251403
2010 Biological and structural basis for Aha1 regulation of Hsp90 ATPase activity in maintaining proteostasis in the human disease cystic fibrosis. Molecular biology of the cell 142 20089831
1997 Reactivating kinase/p38 phosphorylates tau protein in vitro. Journal of neurochemistry 136 9202310
2011 Threonine 22 phosphorylation attenuates Hsp90 interaction with cochaperones and affects its chaperone activity. Molecular cell 135 21419342
2011 Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein. The Journal of biological chemistry 131 21832049
2018 Role of p38 MAPK in Atherosclerosis and Aortic Valve Sclerosis. International journal of molecular sciences 130 30486366
2007 Novel strategies for inhibition of the p38 MAPK pathway. Trends in pharmacological sciences 127 17482683
2022 Serine metabolism orchestrates macrophage polarization by regulating the IGF1-p38 axis. Cellular & molecular immunology 123 36180780
2012 Roles of p38 MAPKs in invasion and metastasis. Biochemical Society transactions 122 22260669
2000 SPAK, a STE20/SPS1-related kinase that activates the p38 pathway. Oncogene 122 10980603
2014 Asymmetric Hsp90 N domain SUMOylation recruits Aha1 and ATP-competitive inhibitors. Molecular cell 109 24462205
2016 The Plasma Membrane H+-ATPase AHA1 Plays a Major Role in Stomatal Opening in Response to Blue Light. Plant physiology 106 27261063
2013 Integration of the accelerator Aha1 in the Hsp90 co-chaperone cycle. Nature structural & molecular biology 105 23396352
2000 Regulation of MEF2 by p38 MAPK and its implication in cardiomyocyte biology. Trends in cardiovascular medicine 103 11150724
2014 Involvement of p38 MAPK in reactive astrogliosis induced by ischemic stroke. Brain research 100 24440774
2018 Maintaining bovine satellite cells stemness through p38 pathway. Scientific reports 98 30018348
2008 A p38 MAPK-MEF2C pathway regulates B-cell proliferation. Proceedings of the National Academy of Sciences of the United States of America 98 18955699
2017 Hsp90 activator Aha1 drives production of pathological tau aggregates. Proceedings of the National Academy of Sciences of the United States of America 97 28827321
2000 Hsp25 and the p38 MAPK pathway are involved in differentiation of cardiomyocytes. Developmental biology 96 10656759
1997 Kinetic mechanism for p38 MAP kinase. Biochemistry 93 9265622
2009 p38-{gamma}-dependent gene silencing restricts entry into the myogenic differentiation program. The Journal of cell biology 92 20026657
1998 Role of p38 MAP kinase in myocardial stress. Journal of molecular and cellular cardiology 91 9841266
2003 p38 Mitogen-activated protein kinases on the body surface--a function for p38 delta. The Journal of investigative dermatology 86 12713588
2017 JNK, p38, ERK, and SGK1 Inhibitors in Cancer. Cancers 83 29267206
2005 Activating p38 MAPK: new tricks for an old kinase. Cell cycle (Georgetown, Tex.) 82 16103752
2006 The p38 transduction pathway in prostatic neoplasia. The Journal of pathology 80 16369914
2019 Cardiac Fibroblast p38 MAPK: A Critical Regulator of Myocardial Remodeling. Journal of cardiovascular development and disease 79 31394846
2019 Arabidopsis H+-ATPase AHA1 controls slow wave potential duration and wound-response jasmonate pathway activation. Proceedings of the National Academy of Sciences of the United States of America 78 31527254
2010 APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway. American journal of physiology. Endocrinology and metabolism 71 20978232
2008 Targeting p38-MAPK in the ischaemic heart: kill or cure? Current opinion in pharmacology 69 18289939
2019 Co-chaperones TIMP2 and AHA1 Competitively Regulate Extracellular HSP90:Client MMP2 Activity and Matrix Proteolysis. Cell reports 65 31412254
2005 Structural comparison of p38 inhibitor-protein complexes: a review of recent p38 inhibitors having unique binding interactions. Current topics in medicinal chemistry 65 16178743
2018 Prions activate a p38 MAPK synaptotoxic signaling pathway. PLoS pathogens 60 30235355
2015 c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells. Cell reports 58 26235616
2022 Role of p38 MAPK Signalling in Testis Development and Male Fertility. Oxidative medicine and cellular longevity 50 36092154
2021 Atypical p38 Signaling, Activation, and Implications for Disease. International journal of molecular sciences 50 33920735
2017 The kinase TPL2 activates ERK and p38 signaling to promote neutrophilic inflammation. Science signaling 49 28420753
2016 Lactate induces FGF21 expression in adipocytes through a p38-MAPK pathway. The Biochemical journal 49 26769382
2014 LKB1 reduces ROS-mediated cell damage via activation of p38. Oncogene 49 25263448
2004 Catalysis and function of the p38 alpha.MK2a signaling complex. Biochemistry 48 15287722
2022 Crosstalk between p38 MAPK and GR Signaling. International journal of molecular sciences 47 35328742
2021 Hsp90 co-chaperones, FKBP52 and Aha1, promote tau pathogenesis in aged wild-type mice. Acta neuropathologica communications 46 33832539
2014 FKBP51 controls cellular adipogenesis through p38 kinase-mediated phosphorylation of GRα and PPARγ. Molecular endocrinology (Baltimore, Md.) 45 24933247
2012 p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice. The Journal of clinical investigation 45 22585574
2020 Co-regulation of the transcription controlling ATF2 phosphoswitch by JNK and p38. Nature communications 44 33188182
2014 FKBP51 reciprocally regulates GRα and PPARγ activation via the Akt-p38 pathway. Molecular endocrinology (Baltimore, Md.) 44 24933248
2018 LECT2 promotes inflammation and insulin resistance in adipocytes via P38 pathways. Journal of molecular endocrinology 43 29650721
2021 Impact of environmental toxicants on p38- and ERK-MAPK signaling pathways in the central nervous system. Neurotoxicology 42 34389354
2016 Activation of HuR downstream of p38 MAPK promotes cardiomyocyte hypertrophy. Cellular signalling 41 27521603
2017 A chemical compound inhibiting the Aha1-Hsp90 chaperone complex. The Journal of biological chemistry 39 28851842
2016 Regulation of Hippo signalling by p38 signalling. Journal of molecular cell biology 39 27402810
2006 CDC25B phosphorylation by p38 and MK-2. Cell cycle (Georgetown, Tex.) 39 16861915
2000 Immunolocalization of p38 MAP kinase in mouse brain. Brain research 39 11134625
2022 Hsp90 S-nitrosylation at Cys521, as a conformational switch, modulates cycling of Hsp90-AHA1-CDC37 chaperone machine to aggravate atherosclerosis. Redox biology 37 35334246
2023 Roles of p38 MAPK signalling in intervertebral disc degeneration. Cell proliferation 36 36872558
2019 Physalin A regulates the Nrf2 pathway through ERK and p38 for induction of detoxifying enzymes. BMC complementary and alternative medicine 36 31072358
2017 The flavonoid TL-2-8 induces cell death and immature mitophagy in breast cancer cells via abrogating the function of the AHA1/Hsp90 complex. Acta pharmacologica Sinica 33 28504248
2013 Differential modulation of functional dynamics and allosteric interactions in the Hsp90-cochaperone complexes with p23 and Aha1: a computational study. PloS one 33 23977182
2012 Stress-mediated p38 activation promotes somatic cell reprogramming. Cell research 33 23044805
2023 P38 kinase in gastrointestinal cancers. Cancer gene therapy 32 37248432
2021 BMI1 Drives Steroidogenesis Through Epigenetically Repressing the p38 MAPK Pathway. Frontiers in cell and developmental biology 31 33928089
2002 Pyridinylimidazole based p38 MAP kinase inhibitors. Current topics in medicinal chemistry 31 12171568
2001 Proteasome- and p38-dependent regulation of ERK3 expression. The Journal of biological chemistry 31 11148204
2019 Progesterone induces cell apoptosis via the CACNA2D3/Ca2+/p38 MAPK pathway in endometrial cancer. Oncology reports 30 31746409
2016 Oncogenic Mutation of AIMP2/p38 Inhibits Its Tumor-Suppressive Interaction with Smurf2. Cancer research 30 27197155
2015 AHSA1 regulates proliferation, apoptosis, migration, and invasion of osteosarcoma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 30 26796264
2023 Nr4a1 promotes renal interstitial fibrosis by regulating the p38 MAPK phosphorylation. Molecular medicine (Cambridge, Mass.) 29 37161357
2022 AHSA1 is a promising therapeutic target for cellular proliferation and proteasome inhibitor resistance in multiple myeloma. Journal of experimental & clinical cancer research : CR 29 34991674
2014 Sulforaphane-induced apoptosis involves p53 and p38 in melanoma cells. Apoptosis : an international journal on programmed cell death 29 24375172
2014 p38 MAPK regulates steroidogenesis through transcriptional repression of STAR gene. Journal of molecular endocrinology 29 24780837
2023 Impact of curcumin on p38 MAPK: therapeutic implications. Inflammopharmacology 28 37498375
2011 Activation of p38 MAP kinase and JNK pathways by UVA irradiation. Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology 27 21858326
2019 Sputum transcriptomics implicates increased p38 signalling activity in severe asthma. Respirology (Carlton, Vic.) 26 31808595
2021 p38 Signalling Pathway. International journal of molecular sciences 25 33498296
2020 Cannabidiol induces osteoblast differentiation via angiopoietin1 and p38 MAPK. Environmental toxicology 25 32656944
2020 Management of Hsp90-Dependent Protein Folding by Small Molecules Targeting the Aha1 Co-Chaperone. Cell chemical biology 24 32017918
2013 Ahsa1 and Hsp90 activity confers more severe craniofacial phenotypes in a zebrafish model of hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR). Disease models & mechanisms 24 23720234
2010 Somatostatin stimulates intestinal NHE8 expression via p38 MAPK pathway. American journal of physiology. Cell physiology 24 21106692
2016 Afzelin positively regulates melanogenesis through the p38 MAPK pathway. Chemico-biological interactions 23 27287415
2016 BMP7 retards peripheral myelination by activating p38 MAPK in Schwann cells. Scientific reports 23 27491681
2015 p23 and Aha1. Sub-cellular biochemistry 23 25487019
2023 SiNPs induce ferroptosis in HUVECs through p38 inhibiting NrF2 pathway. Frontiers in public health 22 36844840
2022 p38 activation and viral infection. Expert reviews in molecular medicine 22 35060846
2020 Activation of GPR40 induces hypothalamic neurogenesis through p38- and BDNF-dependent mechanisms. Scientific reports 22 32632088
2019 Liquiritin and Liquiritigenin Induce Melanogenesis via Enhancement of p38 and PKA Signaling Pathways. Medicines (Basel, Switzerland) 22 31234488
2008 Ouabain inhibits p38 activation in thymocytes. Cell biology international 22 18703152
2020 Bovine lactoferrin enhances osteogenesis through Smad2/3 and p38 MAPK activation. Journal of oral biosciences 21 32464258
2024 Stomatal opening under high temperatures is controlled by the OST1-regulated TOT3-AHA1 module. Nature plants 20 39613896
2017 Cooperative Nucleotide Binding in Hsp90 and Its Regulation by Aha1. Biophysical journal 20 29045865
2016 The Hsp90 Co-chaperones Sti1, Aha1, and P23 Regulate Adaptive Responses to Antifungal Azoles. Frontiers in microbiology 19 27761133
2006 Effects of leukotriene receptor antagonists on monocyte chemotaxis, p38 and cytoplasmic calcium. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology 19 16771778