Affinage

CDC37

Hsp90 co-chaperone Cdc37 · UniProt Q16543

Length
378 aa
Mass
44.5 kDa
Annotated
2026-06-09
100 papers in source corpus 63 papers cited in narrative 62 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDC37 (p50Cdc37) is a kinase-specific cochaperone of HSP90 that selectively recruits, folds, and stabilizes a large fraction of the cellular protein kinome, originally defined as an essential cell-cycle gene acting at Start in yeast and as a regulator of receptor-tyrosine-kinase signaling and cell-cycle kinases in metazoa (PMID:6346060, PMID:8020093, PMID:7753858). It functions as a two-component scaffold: an N-terminal domain (residues 1–126) recognizes client kinases by engaging the αC-helix/β4-β5 strands and the glycine-rich GXFG loop of the kinase N-lobe, while a middle domain (128–282) docks onto the HSP90 N-terminal domain (PMID:14580204, PMID:15258137, PMID:16611982). Mechanistically, CDC37 binds the HSP90 N-domain surface required for ATP-dependent dimerization and inserts an arginine into the ATP pocket to arrest the HSP90 ATPase cycle during client loading (PMID:14718169). Cryo-EM of the HSP90–CDC37–CDK4 and full-length HSP90–CDC37–RAF1 complexes shows the client kinase N-lobe completely unfolded and trapped within the HSP90 dimer, with CDC37 mimicking part of the N-lobe and wedging between the kinase lobes to stabilize this open state (PMID:27339980, PMID:36055235); CDC37 acts as a general kinase "scanning factor" that discriminates clients from non-clients by challenging their conformational stability through local unfolding (PMID:27105117). The cycle is regulated by phosphorylation: CK2 phosphorylation of CDC37 at Ser13 is required for efficient kinase-client binding and HSP90 recruitment (PMID:15082798), complex-specific dephosphorylation of pSer13 by PP5/Ppt1 triggers client activation and release in a "factory reset" mechanism (PMID:18922470, PMID:36446791), and tyrosine phosphorylation of CDC37 (Y4/Y298) and HSP90 (Y197) provides directionality by dissociating client and CDC37 from the chaperone machine (PMID:22727666). Through this activity CDC37 stabilizes a broad client set spanning CDK4/CDK6, Raf-1/B-Raf, v-Src, Akt, IKK, JAK1, Aurora B, ULK1, RIP3 and many others, governing cell-cycle progression, MAPK and NF-κB signaling, mitophagy and necroptosis (PMID:8666233, PMID:10022854, PMID:12176997, PMID:11864612, PMID:12374737, PMID:21855797, PMID:25852146). CDC37 also retains HSP90-independent chaperone activity, directly binding and maturing certain kinases and non-kinase clients such as the hepadnavirus reverse transcriptase and tau (PMID:9242486, PMID:11986322, PMID:12499358, PMID:21367866). Loss of CDC37 function leads to cotranslational proteasomal or autophagic degradation of nascent client kinases (PMID:17242065, PMID:10629030). Because ATP-competitive kinase inhibitors directly compete with CDC37 for the kinase N-lobe, they deprive oncogenic kinases of chaperone support and promote their degradation (PMID:23502424).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1983 Medium

    Established CDC37 as an essential gene controlling a discrete cell-cycle decision point, framing the question of which molecular activity underlies this requirement.

    Evidence Genetic complementation and transcriptional mapping in S. cerevisiae

    PMID:6346060

    Open questions at the time
    • No molecular function assigned
    • No protein partners identified
    • Connection to kinases not yet made
  2. 1994 High

    Linked Cdc37 to both receptor-tyrosine-kinase signaling and cell-cycle kinase regulation, hinting that kinases are the common denominator of its function.

    Evidence Genetic screen and dominant enhancement of Dmcdc2 mutations in Drosophila

    PMID:8020093

    Open questions at the time
    • Mechanism of kinase regulation unknown
    • Direct binding not demonstrated
    • HSP90 link not yet established
  3. 1996 High

    Identified CDC37 as a kinase-targeting subunit of HSP90 and defined CDK4 and v-Src as clients, recasting the gene as a kinase-specific HSP90 cochaperone.

    Evidence Co-IP, insect-cell coexpression, geldanamycin inhibition, half-life and fractionation assays (yeast and mammalian)

    PMID:8666233 PMID:8885235 PMID:9150368

    Open questions at the time
    • Domain architecture undefined
    • Structural basis of HSP90 binding unknown
    • Whether activity is HSP90-dependent or autonomous unresolved
  4. 1997 High

    Demonstrated that CDC37 has autonomous chaperone activity and client specificity distinct from HSP90, and extended its role to spindle pole body duplication via Mps1.

    Evidence In vitro refolding assays, genetic complementation, multicopy suppressor screen and kinase activity assays

    PMID:9060463 PMID:9132011 PMID:9242486

    Open questions at the time
    • Structural basis of autonomous chaperone activity unknown
    • How client specificity is encoded unresolved
  5. 1999 High

    Showed CDC37 is the primary determinant of HSP90 recruitment to clients (Raf-1, Ste11, ZAP70), establishing a defined ternary-complex requirement for kinase activity.

    Evidence Baculovirus coexpression, dominant-negative mutants, geldanamycin, co-IP and signaling assays

    PMID:10022854 PMID:10574909 PMID:10664467

    Open questions at the time
    • Order of complex assembly unclear
    • Structural geometry of ternary complex unknown
  6. 2001 High

    Defined a two-domain architecture in which the CDC37 N-terminus binds nascent kinases cotranslationally while the C-terminal region binds HSP90, and showed HSP90 nucleotide state gates CDC37's kinase-binding activity.

    Evidence Reticulocyte-lysate translation, truncation domain mapping, geldanamycin, kinase activity assay (HRI)

    PMID:11036079

    Open questions at the time
    • Precise domain boundaries not yet mapped
    • Atomic structure of either interface absent
  7. 2002 High

    Established the biochemical mechanism of HSP90 regulation (ATPase suppression, dimeric binding) and broadened the client repertoire to Akt, IKK, LKB1, Aurora B and a Hsp90-independent viral RT, plus a CK2-Cdc37 feedback loop.

    Evidence ATPase assays, analytical ultracentrifugation, co-IP, gel filtration, purified-protein binding, site-directed phosphomutants

    PMID:11864612 PMID:11916974 PMID:11986322 PMID:12176997 PMID:12374737 PMID:12435747 PMID:12489981

    Open questions at the time
    • Structural basis of ATPase suppression not yet visualized
    • How phosphorylation controls binding mechanistically unknown
  8. 2003 High

    Revealed Hsp90-independent client maturation (Spc1) and mapped client-determining motifs, refining how CDC37 selectively engages kinases.

    Evidence Genetic screens, co-IP, kinase and stress-signaling assays (fission yeast)

    PMID:12861001

    Open questions at the time
    • Generality of HSP90-independent function unclear
    • Structural determinant of client selectivity not defined
  9. 2004 High

    Solved the crystal structure of the HSP90 N-domain/CDC37 core complex, defining at atomic resolution how CDC37 inserts an arginine into the ATP pocket and fixes the lid open to arrest the ATPase cycle, and delineated CDC37's three-domain organization and kinase N-lobe recognition.

    Evidence X-ray crystallography, SAXS, limited proteolysis/MS domain mapping, scanning mutagenesis, ATPase and binding assays, CK2 Ser13 phosphorylation mapping

    PMID:12437126 PMID:14580204 PMID:14718169 PMID:14742721 PMID:15082798 PMID:15223329 PMID:15258137

    Open questions at the time
    • Structure of full kinase-bound ternary complex still absent
    • Conformational state of trapped client not visualized
  10. 2006 High

    Provided the first 3D view of the full HSP90-CDC37-CDK4 ternary complex and identified the kinase glycine-rich loop as a CDC37 recognition element, connecting client engagement to the ATPase cycle.

    Evidence Single-particle electron microscopy, phage display, LC-MS/MS, chimeric-kinase mutagenesis and co-IP

    PMID:16611982 PMID:16949366

    Open questions at the time
    • Resolution insufficient to resolve client unfolding
    • Atomic contacts within the complex unresolved
  11. 2008 High

    Defined the regulatory phosphatase arm of the cycle, showing PP5/Ppt1 dephosphorylates pSer13-CDC37 specifically within the ternary HSP90 complex to control client activation and release, and crystallized the CDC37 middle domain identifying Leu-205 for HSP90 binding.

    Evidence Phosphospecific antibodies, in vitro phosphatase assays, genetic knockdown, crystallography, NMR, peptide-array and mutagenesis (multiple clients including PKC)

    PMID:18922470 PMID:19073599 PMID:19091746 PMID:19858214

    Open questions at the time
    • Coupling between dephosphorylation and physical release not structurally resolved
    • Nucleotide-state preference and inhibitor mechanism only biochemically defined
  12. 2012 High

    Mapped tyrosine-phosphorylation events on CDC37 and HSP90 that impose directionality on the chaperone cycle, and documented a kinase-independent function in which CDC37 alone can drive HSP90 dissociation and client nuclear translocation.

    Evidence Site-directed phosphotyrosine mutagenesis, co-IP, ATPase assays, TAP, nuclear translocation and reporter assays (ERK5)

    PMID:22727666 PMID:23428871

    Open questions at the time
    • Kinases responsible for tyrosine phosphorylation in vivo not fully defined
    • Generality of kinase-independent translocation role unclear
  13. 2013 High

    Established that CDC37 directly antagonizes client ATP binding and that ATP-competitive kinase inhibitors compete with CDC37 for the kinase N-lobe, providing a mechanistic rationale for inhibitor-induced client degradation in cancer; also showed CDC37 can stabilize clients with greatly reduced direct HSP90 binding.

    Evidence In vitro ATP-binding/competition assays, co-IP, inhibitor treatment, client degradation assays, HSP90-binding-deficient CDC37 mutants

    PMID:23502424 PMID:24292678

    Open questions at the time
    • How CDC37 stabilizes clients without direct HSP90 binding mechanistically unresolved
  14. 2016 High

    Cryo-EM of the HSP90-CDC37-CDK4 complex revealed the client kinase N-lobe fully unfolded and trapped, with CDC37 mimicking the N-lobe and wedging between lobes, and defined CDC37 as a scanning factor that sorts clients by challenging their conformational stability.

    Evidence Cryo-EM (3.9 Å), NMR, hydrogen-deuterium exchange, client vs non-client binding assays

    PMID:27105117 PMID:27339980

    Open questions at the time
    • Snapshot of a single state; dynamics of loading and release not captured
    • Generality across diverse kinase folds not fully established
  15. 2022 High

    Full-length cryo-EM structures of RAF1- and BRAFV600E-containing HSP90-CDC37 complexes (the latter with PP5) defined the structural basis of RAF-family discrimination and revealed PP5 activation on the complex performing a comprehensive 'factory reset' dephosphorylation prior to client release.

    Evidence Cryo-EM of full-length complexes, proteomic phosphatase-activity analysis, co-IP

    PMID:36055235 PMID:36446791

    Open questions at the time
    • Kinetics of the full load-release cycle not resolved
    • How diverse non-RAF clients are accommodated structurally unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CDC37's HSP90-independent chaperone activity operates mechanistically, and how a single cochaperone is tuned to handle the full diversity of its kinase and non-kinase clients, remains unresolved.
  • Structural basis of autonomous (HSP90-free) chaperone function undefined
  • Determinants distinguishing client from non-client across the kinome not exhaustively mapped
  • In vivo regulation of phospho-switches by upstream kinases incompletely characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 5 GO:0098772 molecular function regulator activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0060090 molecular adaptor activity 3
Localization
GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1640170 Cell Cycle 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-168256 Immune System 3 R-HSA-9612973 Autophagy 2 R-HSA-5357801 Programmed Cell Death 1
Partners
AKTCDK4CDK6CSNK2 (CK2)HSP90PP5RAF1STI1
Complex memberships
HSP90-CDC37 cochaperone complexIKK complex

Evidence

Reading pass · 62 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1983 CDC37 is an essential gene in Saccharomyces cerevisiae required for function at Start, the controlling event of the cell division cycle; the CDC37 locus was isolated, transcriptionally characterized, and mapped. Genetic complementation, plasmid library screening, R-loop analysis, Northern blotting Molecular and cellular biology Medium 6346060
1994 Drosophila Cdc37 (E(sev)3B) is required for signaling by the Sevenless receptor tyrosine kinase; mutations in cdc37 dominantly enhance mutations in Dmcdc2, linking Cdc37 to both RTK signaling and cell cycle kinase regulation. Genetic screen, epistasis analysis, dominant enhancement of Dmcdc2 mutations Cell High 8020093
1995 Yeast Cdc37 is required for association of the protein kinase Cdc28 with both G1 cyclins (Cln2) and mitotic cyclins (Clb2); loss of Cdc37 function causes decreased Cdc28 activity and reduced cyclin binding. Temperature-sensitive mutant analysis, co-immunoprecipitation, kinase activity assays Proceedings of the National Academy of Sciences of the United States of America High 7753858
1995 Vertebrate Cdc37 (first cloned) binds hyaluronan, chondroitin sulfate, and heparin in vitro via glycosaminoglycan-binding motifs, suggesting a role for glycosaminoglycans in cell division control. cDNA cloning, in vitro glycosaminoglycan binding assay, immunoscreening The Journal of biological chemistry Low 7608185
1996 Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4; Cdc37 is sufficient to target Hsp90 to Cdk4; the Cdc37/Hsp90 complex associates preferentially with Cdk4 not bound to D-type cyclins and promotes Cdk4 stability. Co-immunoprecipitation, insect cell coexpression, pharmacological Hsp90 inhibition (geldanamycin), half-life measurement Genes & development High 8666233
1996 Mammalian CDC37 physically interacts with CDK4 and CDK6 but not with Cdc2, Cdk2, Cdk3, Cdk5, or cyclins; Cdc37 does not directly activate or inhibit Cdk4/cyclin D1 kinase but facilitates complex assembly between Cdk4 and cyclin D1 in vitro; Cdc37 competes with p16 for binding to Cdk4. Yeast two-hybrid, co-immunoprecipitation, in vitro binding and kinase assays, competition assay Oncogene High 9150368
1996 CDC37 is required for p60v-src activity and its maintenance in a soluble, biologically active form in yeast; loss of Cdc37 function reduces v-Src-dependent tyrosine phosphorylation and shifts v-Src to urea-solubilized (insoluble) fractions. Temperature-sensitive cdc37 mutant analysis, Western blotting, fractionation, tyrosine phosphorylation assay Molecular biology of the cell High 8885235
1997 Cdc37 functions as an autonomous molecular chaperone: in vitro it maintains denatured beta-galactosidase in an activation-competent state and stabilizes mature but unstable casein kinase II; in vivo, Cdc37 overexpression compensates for decreased Hsp90 function specifically for v-Src kinase but not for the glucocorticoid receptor, demonstrating chaperone specificity. In vitro refolding assay, in vivo genetic complementation, kinase stability assays Genes & development High 9242486
1997 CDC37 is required for proper spindle pole body (SPB) duplication in yeast; CDC37 was identified as a multicopy suppressor of mps1-1; in cdc37-1 mutants, Mps1 kinase activity is markedly reduced despite normal Mps1 protein levels, indicating CDC37 is required for Mps1 kinase activity. Multicopy suppressor screen, genetic epistasis, kinase activity assay, electron microscopy The Journal of cell biology High 9060463
1997 p50 (mammalian Cdc37) is the 50-kDa protein in Raf-1 and pp60(v-src) complexes; immunocytochemistry shows primarily cytoplasmic localization around the nuclear membrane. Protein purification, peptide sequencing, cDNA cloning, co-immunoprecipitation, immunocytochemistry Biochemistry Medium 9132011
1998 p50(cdc37) binds directly to the catalytic domain of Raf (sufficient for interaction); p50(cdc37) binds to a site on Hsp90 topologically adjacent to but distinct from the TPR acceptor site; p50(cdc37) and TPR domain proteins form mutually exclusive complexes with Hsp90. Co-immunoprecipitation, direct binding assays, competition assays with TPR domain proteins The Journal of biological chemistry High 9685350
1999 p50(cdc37) is the primary determinant of Hsp90 recruitment to Raf-1; coexpression of p50(cdc37) with Raf-1 activates Raf-1 in Sf9 cells; a p50(cdc37) mutant unable to recruit Hsp90 inhibits Raf-1 and MAPK activation; formation of a ternary Raf-1–p50(cdc37)–Hsp90 complex is required for Raf-1 kinase activity. Baculovirus coexpression, dominant-negative mutant, geldanamycin treatment, kinase activity assay Molecular and cellular biology High 10022854
1999 Cdc37 is required for activity of the yeast kinase Ste11; Cdc37, Ste11, and Hsp90 co-precipitate pairwise; loss of Cdc37 impairs pheromone signaling and Ste11 accumulation/functional maturation, establishing Ste11 as the first endogenous Cdc37 client in yeast. Genetic cdc37 mutant analysis, co-immunoprecipitation, pheromone signaling assays FEBS letters Medium 10664467
1999 ZAP70 kinase domain mutant (M572L) is bound and restored by Cdc37 overexpression; this restoration requires functional HSP90; Cdc37 acts as a molecular chaperone for a temperature-sensitive kinase domain mutant of ZAP70. Mutant ZAP70 expression, Cdc37 overexpression rescue, co-immunoprecipitation, kinase activity assay The Journal of biological chemistry Medium 10574909
2000 Cdc37 promotes stability of both Cdc28 and Cak1 kinases in yeast; pulse-chase analysis shows Cdc28 and Cak1 are destabilized when Cdc37 function is absent during (but not after) translation, indicating a cotranslational role in kinase folding. Temperature-sensitive mutant, pulse-chase analysis, co-expression in insect cells, kinase activity assay Molecular and cellular biology High 10629030
2000 p50(cdc37) is a nonexclusive Hsp90 cochaperone found in immunoadsorptions with multiple cochaperones (FKBP52, cyp40, p60HOP, Hsp70, p23); it participates in Hsp90-mediated folding of immature kinase molecules and responds to Hsp90's nucleotide-regulated conformational switching. Co-immunoprecipitation with multiple antibodies, salt-stability assay, geldanamycin treatment Biochemistry Medium 10858314
2000 Cdc37 functionally interacts with human androgen receptor (AR) via its ligand-binding domain but not with glucocorticoid receptor; dominant-negative Cdc37 downregulates full-length AR; Cdc37 has broader polypeptide client specificity than kinases alone. Reticulocyte lysate binding assay, yeast model, dominant-negative overexpression, immunoprecipitation The Journal of biological chemistry Medium 11085988
2001 p50(cdc37) interacts co-translationally with nascent HRI kinase chains; the N-terminal domain of p50(cdc37) binds immature HRI while the C-terminal region binds Hsp90; p50(cdc37) stimulates HRI activation in response to heme deficiency; geldanamycin disrupts both Hsp90 and p50(cdc37) binding to HRI, indicating that Hsp90's nucleotide conformation regulates p50(cdc37)'s kinase-binding activity. Reticulocyte lysate translation, co-immunoprecipitation, domain mapping with truncation mutants, geldanamycin treatment, kinase activity assay The Journal of biological chemistry High 11036079
2001 Cdc37 co-immunoprecipitates with MOK kinase along with Hsp90, Hsc70, Hsp70, and Hsp60 but not GRP94, FKBP52, or Hop; kinase catalytic subdomains I-IV are required for Hsp90 binding. Co-immunoprecipitation, deletion mutant mapping, geldanamycin-induced degradation assay The Journal of biological chemistry Medium 11278794
2002 Cdc37 (p50/CDC37) is a novel interaction partner of the duck hepatitis B virus reverse transcriptase (RT); p50 binds the RT independently of Hsp90 (demonstrated with p50deltaC mutant); this interaction is required for reverse transcription initiation in vitro and for viral DNA replication and RNA packaging in transfected cells. Co-immunoprecipitation, pull-down assay (in vitro and in vivo), purified protein direct interaction, functional reverse transcription assay, viral replication assay The Journal of biological chemistry High 11986322
2002 Intracellular Akt forms a complex with Hsp90 and Cdc37; Hsp90 inhibition causes ubiquitination and proteasomal degradation of Akt, shortening its half-life from 36 to 12 h; Akt and PDK1 are the only PKA/PKB/PKC-family members affected by Hsp90 inhibitors. Co-immunoprecipitation, Hsp90 inhibitor (geldanamycin) treatment, pulse-chase half-life measurement, ubiquitination assay, proteasome inhibitor The Journal of biological chemistry High 12176997
2002 Cdc37 and Hsp90 are components of the ~900 kDa IKK complex; Cdc37 directly binds Hsp90 and directly binds the kinase domain of IKKα/IKKβ; geldanamycin disrupts this heterocomplex, preventing TNF-induced IKK activation, NF-κB activation, and IKK recruitment to TNF-R1. Co-immunoprecipitation, direct binding assay, gel filtration, geldanamycin treatment, NF-κB reporter assay, membrane recruitment assay Molecular cell High 11864612
2002 Cdc37p/p50(cdc37) suppresses Hsp90 ATPase activity (like Sti1/Hop/p60); Cdc37p binds Hsp90 as a dimer; suppressed ATPase is restored by immunophilin cochaperone Cpr6/Cyp40; unlike Sti1, Cdc37p forms a stable complex with geldanamycin-bound Hsp90. ATPase activity assay, analytical ultracentrifugation, geldanamycin displacement assay The Journal of biological chemistry High 11916974
2002 In yeast, CDC37 is a multicopy suppressor of CKII (cka2-13ts); Cdc37 is a physiological substrate of CKII, phosphorylated at Ser-14 and/or Ser-17; cdc37-S14,17A strains show severe growth defects and reduced CKII activity, and CKII activity is elevated at cell cycle phases requiring Cdc37; this defines a positive feedback loop between CKII and Cdc37. Multicopy suppressor screen, metabolic labeling + immunoprecipitation, site-directed mutagenesis (S14A, S17A, S14,17E), CKII kinase activity assay The Journal of biological chemistry High 12435747
2002 Cdc37 is essential for chromosome segregation and cytokinesis in Drosophila; Cdc37 loss-of-function phenotypes closely resemble Aurora B inactivation; Aurora B interacts with and requires the Cdc37/Hsp90 complex for stability. Drosophila genetics (loss-of-function), epistasis, co-immunoprecipitation, mitosis/meiosis phenotype analysis The EMBO journal High 12374737
2002 The protein kinase-binding domain of Cdc37 alone is sufficient for yeast cell viability, for efficient MAP kinase pathway signaling, and for partial v-Src folding independent of Hsp90; CDC37 overexpression suppresses Sti1 deletion defects in v-Src folding. CDC37 truncation mutants, yeast viability assay, MAP kinase signaling reporter, v-Src folding assay The Journal of cell biology High 12499358
2003 Hsp90 and Cdc37 interact with the kinase domain of LKB1 and regulate LKB1 stability; Hsp90 inhibitors (geldanamycin, novobiocin) cause proteasomal ubiquitination and degradation of LKB1; a sporadic testicular cancer point mutation in LKB1 weakens interaction with both Hsp90 and Cdc37. LKB1 purification, co-immunoprecipitation, Hsp90 inhibitor treatment, ubiquitination assay, cancer mutation analysis The Biochemical journal High 12489981
2003 Cdc37 is a positive regulator of Spc1 SAPK in fission yeast; Cdc37 physically interacts with Spc1; cdc37 mutation reduces Spc1 protein levels and stress-induced Spc1 phosphorylation by Wis1 MAPKK; Hsp90 mutation does not affect Spc1, indicating a Hsp90-independent function of Cdc37 for this client. Genetic screen, co-immunoprecipitation, kinase assay, stress signaling reporter assay Molecular and cellular biology High 12861001
2004 Crystal structure of the Hsp90 N-domain/Cdc37 core complex reveals that dimeric p50(cdc37) binds surfaces of the Hsp90 N-domain implicated in ATP-dependent N-terminal dimerization; Cdc37 inserts an arginine side chain into the ATP binding pocket to disable catalysis and fixes the lid in an open conformation, arresting the Hsp90 ATPase cycle during client-protein loading. X-ray crystallography, ATPase activity assay, mutagenesis Cell High 14718169
2004 Mammalian CK2 phosphorylates Cdc37 at Ser13 in vitro and in vivo; Ser13 is the unique in vivo phosphorylation site; CK2 phosphorylation of Ser13 is essential for Cdc37's optimal binding to multiple kinase clients (Raf1, Akt, Aurora-B, Cdk4, Src, MOK, MAK, MRK) and for recruitment of Hsp90 to kinase-Cdc37 complexes. In vitro kinase assay with purified CK2, site-directed mutagenesis, in vivo phosphorylation (metabolic labeling), co-immunoprecipitation, CK2 inhibitor treatment Molecular and cellular biology High 15082798
2004 Cdc37 comprises three discrete structural domains by limited proteolysis: N-terminal domain (residues 1-126) binds client kinases; middle domain (residues 128-282) binds Hsp90; C-terminal domain (283-378) has no ascribed function; residues S127-G163 serve as an interdomain switch; W7A and scanning alanine mutagenesis identified N-terminal residues critical for high-affinity kinase binding. Limited proteolysis, MALDI-TOF MS, peptide microsequencing, domain truncation, scanning alanine mutagenesis, functional binding assay Biochemistry High 14580204
2004 Cdc37 recognizes alpha-C-helix and beta4-beta5 strands of the kinase N-lobe as primary binding determinants; Hsp90 requires interaction with adjacent subdomain structures spanning both N- and C-lobes to form high-affinity complexes; Cdc37 interacts only with the N-lobe of kinase catalytic domains. Crystal structure-guided kinase construct design, pull-down assay, salt-stability binding assay, molybdate-independent binding assay The Journal of biological chemistry High 15258137
2004 Cdc37 and Sti1 physically interact directly (without Hsp90); the combination of cdc37 and sti1 mutations is synthetically lethal in yeast; Cdc37 overexpression suppresses sti1 deletion and restores stable Hsp90 binding to Ste11. GST pull-down with purified proteins, co-immunoprecipitation, synthetic lethality screen, genetic suppression Molecular biology of the cell / Biological chemistry Medium 12437126 14742721
2004 SAXS solution structure of human Hsp90β-Cdc37 complex shows that a Cdc37 dimer binds the two N-terminal domain/linker regions of the Hsp90 dimer, fixing them in a single conformation suitable for client protein recognition. Small angle X-ray scattering (SAXS), biochemical characterization Journal of molecular biology Medium 15223329
2005 JAK1 (but not JAK2) interacts with Hsp90 and CDC37; both interactions are destabilized by Hsp90 inhibitors; CDC37 and Hsp90 are required for interferon type I and II signaling through stabilization of JAK1. Co-immunoprecipitation, siRNA knockdown, Hsp90 inhibitor treatment, interferon signaling assay (STAT1 phosphorylation, antiviral response) The Journal of biological chemistry Medium 16280321
2006 Single-particle electron microscopy of the Hsp90-Cdc37-Cdk4 ternary complex defines its 3D structure and stoichiometry; comparison with Hsp90 crystal structure localizes Cdc37 and Cdk4 positions and suggests conformational changes in kinase coupled to Hsp90 ATPase cycle. Complex purification, stoichiometry determination, single-particle electron microscopy, crystal structure comparison Molecular cell High 16949366
2006 Cdc37 interacts with the glycine-rich loop (GXFG motif in canonical GXGXXG) of protein kinase N-lobes; the GSGSFG motif of Raf-1 is necessary for Cdc37 association; the C-terminal portions of kinases determine differential affinity for Cdc37; an unphosphorylated activation segment threonine in non-client kinases permits transient Cdc37 interaction. Phage display, LC-MS/MS, deletion and chimeric kinase mutants, co-immunoprecipitation Molecular and cellular biology High 16611982
2006 In C. elegans embryos, CDC-37 (Cdc37 homolog) is required for establishment phase of embryonic polarity; CDC-37 reduction allows PAR-3-independent cortical accumulation of PAR-6 and PKC-3; CDC-37 acts by maintaining PKC-3 levels and influencing other client proteins; two sites for PAR-6 cortical association are revealed. RNAi knockdown (cdc-37), live imaging, immunofluorescence, epistasis with par mutants Development (Cambridge, England) Medium 16943281
2007 Cdc37 is required for Ste11-mediated pheromone signaling in yeast; Cdc37 matures de novo synthesized IKKs into enzymatically competent kinases; Cdc37 recruits Hsp90 to the IKK complex transiently and preferentially via IKKα; Cdc37 binding is conferred by both N-terminal and C-terminal residues. RNAi knockdown, IKK kinase maturation assay, co-immunoprecipitation, domain mapping The Journal of biological chemistry Medium 17728246
2007 Cdc37 is required for stability of ~50% of the yeast kinome (51/65 kinases tested); pulse-labeling shows Cdc37 protects nascent kinase chains from rapid cotranslational degradation; kinase abundance can be restored at reduced temperature without fully restoring activity. Large-scale kinase abundance measurement in cdc37 mutant yeast, pulse-chase labeling, temperature-shift experiments The Journal of cell biology High 17242065
2007 Pink1 kinase is a novel Cdc37/Hsp90 client kinase; the Cdc37/Hsp90 chaperone system influences both the subcellular distribution and the 66/55 kDa protein ratio of Pink1; PD-causing Pink1 mutations decrease while Parkin expression increases the Pink1 66/55 kDa ratio. Mass spectrometry of immunoisolated Pink1 complexes, co-immunoprecipitation, Hsp90 inhibitor treatment, subcellular fractionation Human molecular genetics High 18003639
2007 Aurora B kinase requires Cdc37/Hsp90 complex for stability (confirmed in Drosophila); MLK3 associates with Hsp90 and p50(cdc37) through its catalytic domain; geldanamycin reduces MLK3 levels and blocks TNF-α-induced MLK3 and JNK activation. Co-immunoprecipitation, affinity purification with LC-MS/MS identification, geldanamycin treatment, kinase activity assay The Journal of biological chemistry Medium 15001580
2008 Cdc37 Ser13 phosphorylation is constitutive in uncomplexed Cdc37, in binary kinase-Cdc37 complex, and in ternary Hsp90-Cdc37-kinase complex; PP5/Ppt1 phosphatase specifically dephosphorylates pSer13-Cdc37 when in the ternary Hsp90 complex but not isolated Cdc37; this targeted dephosphorylation directly regulates activation of kinase clients by Hsp90-Cdc37. Phosphospecific antibodies, in vitro phosphatase assay, yeast and human tumor cell co-immunoprecipitation, PP5/Ppt1 genetic knockdown, kinase client activation assay Molecular cell High 18922470
2008 Conventional and novel (but not atypical) PKC isozymes bind Cdc37 and Hsp90 through a conserved PXXP motif in the C-terminal tail; mutation of both Pro-616 and Pro-619 abolishes PKC phosphorylation and activity; Hsp90 and Cdc37 inhibitors reduce the rate of PKC processing phosphorylation; Hsp90 binding regions on PKC are identified around the PXXP segment via peptide array overlay. Co-immunoprecipitation, site-directed mutagenesis (PXXP and Tyr-446 to Ala), Hsp90/Cdc37 inhibitor treatment, peptide array overlay, processing phosphorylation assay The Journal of biological chemistry High 19091746
2008 Celastrol disrupts Hsp90-Cdc37 interaction by binding to the Hsp90 C-terminal domain (not the ATP pocket), protecting it from trypsin digestion; Cdc37 binds ADP-bound/nucleotide-free Hsp90 but not ATP-bound Hsp90; classical Hsp90 inhibitors (geldanamycin) do not disrupt Hsp90-Cdc37 interaction. GST pull-down, ELISA, proteolytic fingerprinting, celastrol binding assay, ATPase assay The Journal of biological chemistry High 19858214
2010 Hsp90-Cdc37 complex is part of the p38α signaling complex; Cdc37 directly binds p38α; Cdc37 expression is sufficient and necessary to suppress noncanonical p38α autophosphorylation but has no impact on canonical MKK3-mediated p38 activation. Proteomics + biochemical co-immunoprecipitation, Cdc37 knockdown/overexpression, p38 activation assay (autophosphorylation vs canonical), cardiomyocyte system Circulation research High 20299663
2011 Hsp90-Cdc37 complex stabilizes and activates Ulk1 kinase; Ulk1-Hsp90-Cdc37 interaction is required for phosphorylation and release of Atg13 from Ulk1 and for Atg13 recruitment to damaged mitochondria; Hsp90-Cdc37, Ulk1, and Atg13 phosphorylation are all required for efficient mitophagy. Co-immunoprecipitation, Hsp90 inhibitor treatment, Cdc37 knockdown, mitophagy assay, phosphorylation analysis Molecular cell High 21855797
2011 Cdc37 co-localizes with tau in neuronal cells and physically interacts with tau from human brain; Cdc37 suppression destabilizes tau and alters its phosphorylation profile by reducing levels of specific tau kinases (Cdk5, Akt) without affecting others (GSK3β, Mark2); Cdc37 overexpression prevents tau clearance following Hsp90 inhibition. Co-immunoprecipitation from human brain, immunofluorescence colocalization, Cdc37 siRNA knockdown/overexpression, tau kinase level and phosphorylation analysis The Journal of biological chemistry Medium 21367866
2011 Cdc37 directly interacts with IRE1α through a conserved cytosolic motif; Cdc37 knockdown or disruption of Cdc37-IRE1α interaction increases basal IRE1α kinase activity; Cdc37-mediated Hsp90/Cdc37 interaction with IRE1α maintains basal IRE1α activity and contributes to normal insulin synthesis and secretion. Co-immunoprecipitation, Cdc37 siRNA knockdown, IRE1α activity assay, insulin synthesis/secretion measurement The Journal of biological chemistry Medium 22199355
2012 Cdc37 disruption triggers autophagic clearance of TDP-43; Cdc37 depletion causes proteolytic cleavage and nuclear retrotranslocation of TDP-43 followed by autophagic uptake; tau accumulation prevents clearance of cleaved TDP-43. Cdc37 siRNA knockdown, Hsp90 inhibitor treatment, TDP-43 localization assay, autophagy pathway analysis (beclin1 knockdown) The Journal of biological chemistry Medium 22674575
2012 Tyrosine phosphorylation of p50(Cdc37) at Y4 and Y298 disrupts client-p50(Cdc37) association; Hsp90 phosphorylation at Y197 dissociates p50(Cdc37) from Hsp90; these phosphorylation events provide directionality to the chaperone cycle; subsequent Hsp90 Y313 phosphorylation promotes AHA1 recruitment. Site-directed mutagenesis of phosphotyrosine sites, co-immunoprecipitation, in vitro phosphorylation, ATPase assay Molecular cell High 22727666
2013 Cdc37 directly antagonizes ATP binding to client kinases; ATP-competitive kinase inhibitors (vemurafenib, lapatinib) block Cdc37 binding to client kinases such as B-Raf and ErbB2, depriving them of access to the Hsp90-Cdc37 complex and causing their degradation in cancer cells. In vitro ATP binding assay, co-immunoprecipitation, kinase inhibitor treatment, client kinase degradation assay Nature chemical biology High 23502424
2013 ERK5 interacts with Hsp90-Cdc37 in resting cells; activation of ERK5 induces Hsp90 dissociation from the ERK5-Cdc37 complex via ERK5 C-tail autophosphorylation, leading to nuclear translocation; Cdc37 overexpression alone induces Hsp90 dissociation and nuclear translocation of kinase-inactive ERK5, demonstrating Cdc37-driven kinase-independent transcriptional activity. Tandem affinity purification, co-immunoprecipitation, Hsp90/Cdc37 inhibition, nuclear translocation assay, transcriptional reporter Molecular and cellular biology High 23428871
2015 RIP3 kinase activation during necroptosis requires a physical association with the HSP90-CDC37 cochaperone complex; CDC37 knockdown prevents cells from responding to necroptosis stimuli; HSP90 inhibitors block RIP3 activation and prevent systemic inflammatory response syndrome in TNF-α-treated rats. Co-immunoprecipitation, CDC37 siRNA knockdown, HSP90 inhibitor treatment, necroptosis assay, in vivo rat SIRS model Proceedings of the National Academy of Sciences of the United States of America High 25852146
2016 Cryo-EM structure of the Hsp90-Cdc37-Cdk4 complex at 3.9 Å reveals that the two lobes of Cdk4 are completely separated with the β4-β5 sheet unfolded; Cdc37 mimics part of the kinase N-lobe, stabilizing an open kinase conformation by wedging between the two lobes; Hsp90 clamps around the unfolded kinase β5 strand, protecting it in a trapped unfolded state. Cryo-electron microscopy (3.9 Å), complex reconstitution Science (New York, N.Y.) High 27339980
2016 Cdc37 acts as a general kinase scanning factor that participates in selective client recruitment by challenging the conformational stability of client kinases through local unfolding; stable complex formation requires multidomain cochaperone interface and is accompanied by conformational changes in clients but not nonclients; this metastable conformational state is the basis for Hsp90-dependence. NMR, hydrogen-deuterium exchange, in vitro binding and stability assays, client vs nonclient kinase discrimination assay Molecular cell High 27105117
2017 Assembly of CDK4 and CDK6 into protein complexes is differentially regulated by Cdc37-Hsp90; Cdc37-Hsp90 relinquishes CDK6 to D3- and virus-type cyclins and INK inhibitors, whereas CDK4 is less readily relinquished to cyclins; CIP/KIP CDK inhibitors cooperate with D-type cyclins to form Cdc37-resistant ternary CDK4/6-cyclin complexes. Co-immunoprecipitation, competition binding assay, differential release assay for CDK4 vs CDK6 Cell reports High 29091774
2008 Crystal structure of the 16-kDa middle domain of human Cdc37 at 1.88 Å shows it exists as a monomer; NMR and mutagenesis identify Leu-205 as a key residue for Cdc37-Hsp90 N-domain complex formation. X-ray crystallography (1.88 Å), NMR spectroscopy, site-directed mutagenesis (L205) The Journal of biological chemistry High 19073599
2022 CryoEM structure of the full-length RAF1-HSP90-CDC37 complex reveals that RAF1 kinase N-lobe is unfolded with its hydrophobic core trapped in the HSP90 dimer; CDC37 wraps around HSP90 and interacts with both N- and C-lobes of RAF1; the structure indicates how CDC37 discriminates between different RAF family members; disruption of CDC37-DFG segment interaction reveals pharmacological vulnerabilities for RAF1 degradation. Cryo-electron microscopy (full-length complex), structural analysis Molecular cell High 36055235
2022 CryoEM structures of the HSP90-CDC37-BRAFV600E-PP5 complex in autoinhibited and activated conformations reveal that PP5 is activated by recruitment to HSP90 complexes; the V600E mutation favors BRAF association with HSP90-CDC37; PP5 comprehensively dephosphorylates client proteins including BRAFV600E and CRAF, removing 14-3-3 interaction sites and performing a 'factory reset' prior to kinase release. CryoEM structure determination, proteomic phosphatase activity analysis, co-immunoprecipitation Nature communications High 36446791
2012 Cdc37 is present on the cell surface of breast cancer cells where it interacts with surface HSP90, HER2, and EGFR; functional inhibition of surface HSP90 disrupts the Cdc37/HSP90 and Cdc37/ErbB receptor complexes on the cell surface. Cell-impermeable anti-Cdc37 antibody, co-immunoprecipitation, cancer cell motility assay PloS one Medium 22912728
2013 CDC37 mutants with single/double point mutations at M164 and L205 (greatly reduced HSP90 binding) retain client kinase association and phenocopy wild-type CDC37 in increasing CDK4-HSP90 association and CDK4 levels; CDC37 can stabilize kinase clients through a mechanism not requiring its direct interaction with HSP90, but still requiring HSP90 activity. Site-directed mutagenesis (M164A, L205A, double mutant), co-immunoprecipitation, client kinase level and half-life measurement, siRNA rescue experiment Oncogene High 24292678

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. The Journal of biological chemistry 558 12176997
1996 Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. Genes & development 444 8666233
2002 TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90. Molecular cell 328 11864612
2016 Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase. Science (New York, N.Y.) 327 27339980
2008 A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells. Molecular cancer therapeutics 311 18202019
2004 The Mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50(cdc37). Cell 281 14718169
1994 Mutations in Hsp83 and cdc37 impair signaling by the sevenless receptor tyrosine kinase in Drosophila. Cell 254 8020093
2006 Structure of an Hsp90-Cdc37-Cdk4 complex. Molecular cell 248 16949366
1999 p50(cdc37) acting in concert with Hsp90 is required for Raf-1 function. Molecular and cellular biology 234 10022854
2002 Regulation of Hsp90 ATPase activity by the co-chaperone Cdc37p/p50cdc37. The Journal of biological chemistry 219 11916974
2005 Hsp90 and Cdc37 -- a chaperone cancer conspiracy. Current opinion in genetics & development 204 15661534
2011 Hsp90-Cdc37 chaperone complex regulates Ulk1- and Atg13-mediated mitophagy. Molecular cell 196 21855797
1997 Cdc37 is a molecular chaperone with specific functions in signal transduction. Genes & development 174 9242486
2008 Hsp90-dependent activation of protein kinases is regulated by chaperone-targeted dephosphorylation of Cdc37. Molecular cell 170 18922470
2009 Characterization of celastrol to inhibit hsp90 and cdc37 interaction. The Journal of biological chemistry 166 19858214
2015 A cytosolic heat shock protein 90 and cochaperone CDC37 complex is required for RIP3 activation during necroptosis. Proceedings of the National Academy of Sciences of the United States of America 142 25852146
1999 A model for the cytoplasmic trafficking of signalling proteins involving the hsp90-binding immunophilins and p50cdc37. Cellular signalling 137 10659992
2007 Pink1 Parkinson mutations, the Cdc37/Hsp90 chaperones and Parkin all influence the maturation or subcellular distribution of Pink1. Human molecular genetics 131 18003639
2004 CK2 controls multiple protein kinases by phosphorylating a kinase-targeting molecular chaperone, Cdc37. Molecular and cellular biology 128 15082798
1996 Physical interaction of mammalian CDC37 with CDK4. The Journal of biological chemistry 124 8703009
1995 Cdc37 is required for association of the protein kinase Cdc28 with G1 and mitotic cyclins. Proceedings of the National Academy of Sciences of the United States of America 124 7753858
2013 ATP-competitive inhibitors block protein kinase recruitment to the Hsp90-Cdc37 system. Nature chemical biology 120 23502424
2012 Dynamic tyrosine phosphorylation modulates cycling of the HSP90-P50(CDC37)-AHA1 chaperone machine. Molecular cell 111 22727666
2008 Targeting the oncogene and kinome chaperone CDC37. Nature reviews. Cancer 110 18511936
1998 p50(cdc37) binds directly to the catalytic domain of Raf as well as to a site on hsp90 that is topologically adjacent to the tetratricopeptide repeat binding site. The Journal of biological chemistry 106 9685350
2003 Cdc37 goes beyond Hsp90 and kinases. Cell stress & chaperones 100 14627196
1997 Cdc37: a protein kinase chaperone? Trends in cell biology 100 17708934
2008 Silencing the cochaperone CDC37 destabilizes kinase clients and sensitizes cancer cells to HSP90 inhibitors. Oncogene 98 18931700
2008 The chaperones Hsp90 and Cdc37 mediate the maturation and stabilization of protein kinase C through a conserved PXXP motif in the C-terminal tail. The Journal of biological chemistry 95 19091746
2002 A positive feedback loop between protein kinase CKII and Cdc37 promotes the activity of multiple protein kinases. The Journal of biological chemistry 90 12435747
2007 Cdc37 has distinct roles in protein kinase quality control that protect nascent chains from degradation and promote posttranslational maturation. The Journal of cell biology 88 17242065
2019 Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer. Science advances 87 31555737
2011 Apigenin inhibits proliferation and induces apoptosis in human multiple myeloma cells through targeting the trinity of CK2, Cdc37 and Hsp90. Molecular cancer 87 21871133
1995 A novel glycosaminoglycan-binding protein is the vertebrate homologue of the cell cycle control protein, Cdc37. The Journal of biological chemistry 87 7608185
2017 How Hsp90 and Cdc37 Lubricate Kinase Molecular Switches. Trends in biochemical sciences 84 28784328
2007 Targeting Cdc37 inhibits multiple signaling pathways and induces growth arrest in prostate cancer cells. Cancer research 84 18089825
1997 Interaction between Cdc37 and Cdk4 in human cells. Oncogene 84 9150368
2020 Triple knockdown of CDC37, HSP90-alpha and HSP90-beta diminishes extracellular vesicles-driven malignancy events and macrophage M2 polarization in oral cancer. Journal of extracellular vesicles 82 33144925
2001 Hsp90 regulates p50(cdc37) function during the biogenesis of the activeconformation of the heme-regulated eIF2 alpha kinase. The Journal of biological chemistry 81 11036079
2005 Role of HSP90, CDC37, and CRM1 as modulators of P16(INK4A) activity in rat liver carcinogenesis and human liver cancer. Hepatology (Baltimore, Md.) 80 16317707
2003 Heat-shock protein 90 and Cdc37 interact with LKB1 and regulate its stability. The Biochemical journal 78 12489981
2000 The oncoprotein kinase chaperone CDC37 functions as an oncogene in mice and collaborates with both c-myc and cyclin D1 in transformation of multiple tissues. Molecular and cellular biology 78 10825210
2000 p50(cdc37) is a nonexclusive Hsp90 cohort which participates intimately in Hsp90-mediated folding of immature kinase molecules. Biochemistry 78 10858314
2003 Functional dissection of cdc37: characterization of domain structure and amino acid residues critical for protein kinase binding. Biochemistry 75 14580204
2007 Signal responsiveness of IkappaB kinases is determined by Cdc37-assisted transient interaction with Hsp90. The Journal of biological chemistry 74 17728246
2016 Molecular Mechanism of Protein Kinase Recognition and Sorting by the Hsp90 Kinome-Specific Cochaperone Cdc37. Molecular cell 73 27105117
2000 Induction of human Cdc37 in prostate cancer correlates with the ability of targeted Cdc37 expression to promote prostatic hyperplasia. Oncogene 73 10822368
1996 CDC37 is required for p60v-src activity in yeast. Molecular biology of the cell 72 8885235
1997 A 50 kilodalton protein associated with raf and pp60(v-src) protein kinases is a mammalian homolog of the cell cycle control protein cdc37. Biochemistry 70 9132011
2004 Sti1 and Cdc37 can stabilize Hsp90 in chaperone complexes with a protein kinase. Molecular biology of the cell 67 14742721
2014 FW-04-806 inhibits proliferation and induces apoptosis in human breast cancer cells by binding to N-terminus of Hsp90 and disrupting Hsp90-Cdc37 complex formation. Molecular cancer 66 24927996
2002 The Cdc37 protein kinase-binding domain is sufficient for protein kinase activity and cell viability. The Journal of cell biology 65 12499358
2001 Specific association of a set of molecular chaperones including HSP90 and Cdc37 with MOK, a member of the mitogen-activated protein kinase superfamily. The Journal of biological chemistry 65 11278794
2004 Biochemical and structural studies of the interaction of Cdc37 with Hsp90. Journal of molecular biology 63 15223329
2004 Definition of protein kinase sequence motifs that trigger high affinity binding of Hsp90 and Cdc37. The Journal of biological chemistry 58 15258137
1997 The yeast CDC37 gene interacts with MPS1 and is required for proper execution of spindle pole body duplication. The Journal of cell biology 58 9060463
2011 The Hsp90 kinase co-chaperone Cdc37 regulates tau stability and phosphorylation dynamics. The Journal of biological chemistry 57 21367866
2008 The human Cdc37.Hsp90 complex studied by heteronuclear NMR spectroscopy. The Journal of biological chemistry 57 19073599
2021 Targeting the HSP90-CDC37-kinase chaperone cycle: A promising therapeutic strategy for cancer. Medicinal research reviews 56 33846988
2018 Targeting the Hsp90-Cdc37-client protein interaction to disrupt Hsp90 chaperone machinery. Journal of hematology & oncology 56 29699578
2012 Cdc37/Hsp90 protein complex disruption triggers an autophagic clearance cascade for TDP-43 protein. The Journal of biological chemistry 56 22674575
2009 Targeting CDC37: an alternative, kinase-directed strategy for disruption of oncogenic chaperoning. Cell cycle (Georgetown, Tex.) 53 19177013
2005 The heat shock protein 90-CDC37 chaperone complex is required for signaling by types I and II interferons. The Journal of biological chemistry 53 16280321
2002 Role of p50/CDC37 in hepadnavirus assembly and replication. The Journal of biological chemistry 53 11986322
2000 Cdc37 promotes the stability of protein kinases Cdc28 and Cak1. Molecular and cellular biology 53 10629030
2000 Functional interaction of human Cdc37 with the androgen receptor but not with the glucocorticoid receptor. The Journal of biological chemistry 53 11085988
2022 Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation. Molecular cell 52 36055235
2017 Differential Regulation of G1 CDK Complexes by the Hsp90-Cdc37 Chaperone System. Cell reports 52 29091774
1999 Temperature-sensitive ZAP70 mutants degrading through a proteasome-independent pathway. Restoration of a kinase domain mutant by Cdc37. The Journal of biological chemistry 51 10574909
2000 The molecular chaperone Cdc37 is required for Ste11 function and pheromone-induced cell cycle arrest. FEBS letters 50 10664467
2006 Depletion of the co-chaperone CDC-37 reveals two modes of PAR-6 cortical association in C. elegans embryos. Development (Cambridge, England) 49 16943281
2005 Cdk2: a genuine protein kinase client of Hsp90 and Cdc37. Biochemistry 49 16285732
2010 Specific regulation of noncanonical p38alpha activation by Hsp90-Cdc37 chaperone complex in cardiomyocyte. Circulation research 48 20299663
2004 Hsp90/p50cdc37 is required for mixed-lineage kinase (MLK) 3 signaling. The Journal of biological chemistry 48 15001580
2013 Canonical and kinase activity-independent mechanisms for extracellular signal-regulated kinase 5 (ERK5) nuclear translocation require dissociation of Hsp90 from the ERK5-Cdc37 complex. Molecular and cellular biology 47 23428871
2003 Stability of the Peutz-Jeghers syndrome kinase LKB1 requires its binding to the molecular chaperones Hsp90/Cdc37. Oncogene 47 14668798
2005 A central role for the Hsp90.Cdc37 molecular chaperone module in interleukin-1 receptor-associated-kinase-dependent signaling by toll-like receptors. The Journal of biological chemistry 46 15647277
2022 HSP90-CDC37-PP5 forms a structural platform for kinase dephosphorylation. Nature communications 45 36446791
2015 Cdc37 as a co-chaperone to Hsp90. Sub-cellular biochemistry 45 25487018
2002 Cdc37 is essential for chromosome segregation and cytokinesis in higher eukaryotes. The EMBO journal 45 12374737
2003 Identification of Cdc37 as a novel regulator of the stress-responsive mitogen-activated protein kinase. Molecular and cellular biology 43 12861001
2016 Optimization and biological evaluation of celastrol derivatives as Hsp90-Cdc37 interaction disruptors with improved druglike properties. Bioorganic & medicinal chemistry 42 27647369
2007 Cdc37 regulation of the kinome: when to hold 'em and when to fold 'em. Science's STKE : signal transduction knowledge environment 42 17488976
2007 Rapid activation of c-Src kinase by dioxin is mediated by the Cdc37-HSP90 complex as part of Ah receptor signaling in MCF10A cells. Biochemistry 41 17223712
2003 Cdc37 enhances proliferation and is necessary for normal human prostate epithelial cell survival. Cancer research 40 12907640
2022 Hsp90 S-nitrosylation at Cys521, as a conformational switch, modulates cycling of Hsp90-AHA1-CDC37 chaperone machine to aggravate atherosclerosis. Redox biology 39 35334246
2005 CK2 binds, phosphorylates, and regulates its pivotal substrate Cdc37, an Hsp90-cochaperone. Molecular and cellular biochemistry 39 16335536
2019 Discovery of Novel Celastrol Derivatives as Hsp90-Cdc37 Interaction Disruptors with Antitumor Activity. Journal of medicinal chemistry 38 31725288
2017 Novel Hsp90 inhibitor platycodin D disrupts Hsp90/Cdc37 complex and enhances the anticancer effect of mTOR inhibitor. Toxicology and applied pharmacology 37 28711525
2000 p50(Cdc37) can buffer the temperature-sensitive properties of a mutant of Hck. Molecular and cellular biology 37 10958693
2017 Structure-based virtual screening and optimization of modulators targeting Hsp90-Cdc37 interaction. European journal of medicinal chemistry 36 28482218
2013 Restricting direct interaction of CDC37 with HSP90 does not compromise chaperoning of client proteins. Oncogene 35 24292678
1983 Isolation and transcriptional characterization of three genes which function at start, the controlling event of the Saccharomyces cerevisiae cell division cycle: CDC36, CDC37, and CDC39. Molecular and cellular biology 35 6346060
2015 Hsp90·Cdc37 Complexes with Protein Kinases Form Cooperatively with Multiple Distinct Interaction Sites. The Journal of biological chemistry 34 26511315
2006 Cdc37 interacts with the glycine-rich loop of Hsp90 client kinases. Molecular and cellular biology 34 16611982
2012 Cell surface Cdc37 participates in extracellular HSP90 mediated cancer cell invasion. PloS one 33 22912728
2014 Correlation between PDZK1, Cdc37, Akt and breast cancer malignancy: the role of PDZK1 in cell growth through Akt stabilization by increasing and interacting with Cdc37. Molecular medicine (Cambridge, Mass.) 32 24869908
2011 Cdc37/Hsp90 protein-mediated regulation of IRE1α protein activity in endoplasmic reticulum stress response and insulin synthesis in INS-1 cells. The Journal of biological chemistry 32 22199355
2001 Identification and characterization of Harc, a novel Hsp90-associating relative of Cdc37. The Journal of biological chemistry 32 11413142
2002 The Hsp90 co-chaperones Cdc37 and Sti1 interact physically and genetically. Biological chemistry 31 12437126

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