CDC37 (Cell Division Cycle 37) Protein

Migration, Crosslink

📖

CDC37 (Cell Division Cycle 37) Protein

active

wiki page Created: 2026-04-02T07:19:13 By: crosslink-migration Quality: 50% ✓ SciDEX ID: wiki-proteins-cdc37-protein

📖 Wiki Page

protein1392 wordssynced 2026-04-02

CDC37 (Cell Division Cycle 37) Protein

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">CDC37 (Cell Division Cycle 37) Protein</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>CDC37</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Cell Division Cycle 37</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>19p13.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>2881</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>164860</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000105401</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P16234</td>
</tr>
<tr>
<td class="label">Modification</td>
<td>Effect</td>
</tr>
<tr>
<td class="label">Phosphorylation (Ser/Thr)</td>
<td>Modulates Hsp90 interaction, client release</td>
</tr>
<tr>
<td class="label">Acetylation</td>
<td>Affects protein-protein interactions</td>
</tr>
<tr>
<td class="label">Client Kinase</td>
<td>Pathway</td>
</tr>
<tr>
<td class="label">AKT (PKB)</td>
<td>PI3K/AKT survival</td>
</tr>
<tr>
<td class="label">CDK4/CDK6</td>
<td>Cell cycle</td>
</tr>
<tr>
<td class="label">RAF (A/B/CRAF)</td>
<td>MAPK signaling</td>
</tr>
<tr>
<td class="label">LRRK2</td>
<td>Leucine-rich repeat kinase</td>
</tr>
<tr>
<td class="label">GSK3B</td>
<td>Wnt/glycogen synthase</td>
</tr>
<tr>
<td class="label">CDK5</td>

...

CDC37 (Cell Division Cycle 37) Protein

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">CDC37 (Cell Division Cycle 37) Protein</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>CDC37</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Cell Division Cycle 37</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>19p13.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>2881</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>164860</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000105401</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P16234</td>
</tr>
<tr>
<td class="label">Modification</td>
<td>Effect</td>
</tr>
<tr>
<td class="label">Phosphorylation (Ser/Thr)</td>
<td>Modulates Hsp90 interaction, client release</td>
</tr>
<tr>
<td class="label">Acetylation</td>
<td>Affects protein-protein interactions</td>
</tr>
<tr>
<td class="label">Client Kinase</td>
<td>Pathway</td>
</tr>
<tr>
<td class="label">AKT (PKB)</td>
<td>PI3K/AKT survival</td>
</tr>
<tr>
<td class="label">CDK4/CDK6</td>
<td>Cell cycle</td>
</tr>
<tr>
<td class="label">RAF (A/B/CRAF)</td>
<td>MAPK signaling</td>
</tr>
<tr>
<td class="label">LRRK2</td>
<td>Leucine-rich repeat kinase</td>
</tr>
<tr>
<td class="label">GSK3B</td>
<td>Wnt/glycogen synthase</td>
</tr>
<tr>
<td class="label">CDK5</td>
<td>Neuronal kinase</td>
</tr>
<tr>
<td class="label">RIP1</td>
<td>NF-κB signaling</td>
</tr>
<tr>
<td class="label">TBK1</td>
<td>Autophagy, inflammation</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Class</td>
</tr>
<tr>
<td class="label">Geldanamycin</td>
<td>Natural product</td>
</tr>
<tr>
<td class="label">17-AAG (Tanespimycin)</td>
<td>Semi-synthetic</td>
</tr>
<tr>
<td class="label">17-DMAG (Alvespimycin)</td>
<td>Semi-synthetic</td>
</tr>
<tr>
<td class="label">PU-H71</td>
<td>Synthetic</td>
</tr>
<tr>
<td class="label">Ganetespib</td>
<td>Synthetic</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/parkinson" style="color:#ef9a9a">Parkinson</a>, <a href="/wiki/tumor" style="color:#ef9a9a">Tumor</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">16 edges</a></td>
</tr>
</table>

CDC37 (Cell Division Cycle 37) is a specialized co-chaperone that works in conjunction with [Hsp90](/entities/hsp90-protein) to mediate the folding, stabilization, and activation of protein kinases. Originally identified in yeast as an essential cell cycle protein, CDC37 has evolved into a critical regulator of the Hsp90 chaperone system with particular relevance to neurodegenerative diseases[@pearl2000][@hartl2011]. Its ability to target specific kinases for Hsp90-mediated maturation makes it a pivotal node in signal transduction networks and a therapeutic target in both cancer and neurodegeneration.

CDC37 acts as a molecular matchmaker, delivering kinase clients to Hsp90 and forming a trimeric chaperone complex that undergoes ATP-dependent cycles of client loading, folding, and release[@taipale2012]. Unlike general co-chaperones, CDC37 exhibits remarkable specificity for protein kinases as clients, distinguishing it from other Hsp90 co-chaperones that have broader client spectra.

Gene and Protein Structure

Gene Information

Protein Domain Architecture

CDC37 is a modular protein with distinct functional regions[@vaughan2008][@kovacs2015]:

N-terminal domain: Critical for kinase client recognition and binding; contains hydrophobic interaction surfaces for client engagement
Middle domain: Mediates interaction with Hsp90; contains the CDC37 signature motif
C-terminal domain: Contains dimerization elements and regulatory phosphorylation sites

CDC37 exists predominantly as a homodimer, with dimerization mediated through C-terminal regions.

Post-translational Modifications

Normal Biological Functions

Hsp90 Co-chaperone Activity

CDC37 functions as a kinase-selective co-chaperone within the Hsp90 chaperone system[@balchin2016]:

Client recruitment: CDC37 directly binds nascent or misfolded kinases, presenting them to Hsp90
Complex assembly: CDC37 bridges the kinase-Hsp90 interaction, forming a stable trimeric complex
ATPase regulation: CDC37 modulates the Hsp90 ATPase cycle, slowing hydrolysis to allow sufficient time for kinase folding
Client release: Following proper folding, CDC37 facilitates client release from the Hsp90 complex

The Hsp90-CDC37 chaperone cycle proceeds through defined stages:

Client loading: CDC37 presents kinase to Hsp90 in an open conformation

Complex stabilization: ATP binding to Hsp90 closes the lid around the client

Folding: Hsp90 ATPase activity drives conformational cycling while CDC37 holds the client

Release: ATP hydrolysis triggers client release; CDC37 dissociates to recruit new clients

Kinase Client Specificity

CDC37 has an exceptionally broad client list among protein kinases[@taipale2012][@kovacs2015]:

Role in Protein Quality Control

CDC37 contributes to cellular protein quality control networks[@roy2012]:

Kinase folding capacity: Ensures proper 3D structure of client kinases
Degradation pathway decision: Properly folded kinases avoid proteasomal degradation
Aggregate prevention: Prevents accumulation of misfolded kinases

Role in Alzheimer's Disease

Tau Kinase Regulation

CDC37 is a critical regulator of tau-phosphorylating kinases implicated in Alzheimer's disease[@eckl2019][@liu2019]:

GSK3β targeting: CDC37 facilitates Hsp90-mediated folding and stabilization of GSK3β, a major tau kinase; elevated CDC37 activity correlates with increased GSK3β activity and enhanced tau phosphorylation
CDK5 regulation: CDC37 coordinates CDK5/p25 complex stability and activity; p25 generation from p35 cleavage leads to aberrant CDK5 activation and tau hyperphosphorylation in AD
Tau pathology progression: Hsp90-CDC37 complexes are upregulated in AD brain, stabilizing the toxic tau conformers that drive NFT formation

Amyloid-beta Processing

CDC37 influences amyloid precursor protein (APP) processing through kinase signaling[@liu2019]:

AKT signaling: CDC37-mediated AKT maturation affects APP processing through PI3K/AKT pathways
BACE1 regulation: Kinase pathways regulated by CDC37 clients can modulate beta-secretase (BACE1) expression and activity

Role in Parkinson's Disease

LRRK2 Maturation and Stability

CDC37 is essential for proper folding and maturation of [LRRK2](/genes/lrrk2)[@xu2012][@lu2018]:

Folding assistance: LRRK2 is a challenging multidomain kinase that requires Hsp90-CDC37 for proper folding; CDC37 directly engages the LRRK2 kinase domain and WD40 domain
Stability maintenance: CDC37 maintains LRRK2 stability in dopaminergic neurons; partial loss of CDC37 function leads to LRRK2 degradation
Pathogenic mutations: PD-associated LRRK2 mutations (G2019S, R1441C/G/H) still require CDC37 for maturation
Therapeutic relevance: G2019S LRRK2 mutations cause increased kinase activity; CDC37/Hsp90 inhibition promotes LRRK2 degradation

Alpha-Synuclein and Autophagy

CDC37 influences Parkinson's disease pathology through multiple mechanisms[@xu2012]:

Alpha-synuclein phosphorylation: Client kinases of CDC37 (including LRRK2) regulate synuclein phosphorylation at Ser129
Autophagy regulation: CDC37 clients including TBK1 and ULK1 regulate autophagy; CDC37 dysfunction impairs clearance of alpha-synuclein aggregates
Dopaminergic neuron survival: Proper CDC37 function is critical for survival signaling through AKT and other kinase pathways in substantia nigra neurons

Role in ALS

Client Kinases in Motor Neuron Disease

CDC37/Hsp90 regulates kinases implicated in ALS pathogenesis[@nadanaka2018]:

TBK1: TANK-binding kinase 1 is a CDC37 client; TBK1 mutations cause familial ALS; TBK1 regulates autophagy and inflammation
OPTN: Optineurin is processed by TBK1; OPTN mutations also cause ALS
RIPK1: Receptor-interacting protein kinase 1 is a CDC37 client involved in necroptosis and neuroinflammation; elevated RIPK1 activity contributes to motor neuron death

TDP-43 Pathology

The Hsp90-CDC37 complex interacts with ALS-relevant proteins beyond kinases[@nadanaka2018]:

TDP-43 aggregation: Hsp90 inhibitors promote clearance of TDP-43 aggregates through autophagy induction
Protein homeostasis network: Hsp90-CDC37 sits at the center of motor neuron proteostasis

Role in Cancer

CDC37 is a well-established oncology target due to its role in oncogenic kinase maturation[@proia2009][@smith2015]:

Client addiction: Cancer cells become "addicted" to Hsp90-CDC37 for maintaining mutant kinases (EGFR, BCR-ABL, HER2, ALK)
Multiple client kinases: CDC37 clients include most known oncogenic kinases
Synergy with kinase inhibitors: Hsp90-CDC37 inhibition can resensitize resistant tumors to targeted kinase inhibitors

Therapeutic Approaches

Hsp90 Inhibitors

The Hsp90-CDC37 complex can be disrupted pharmacologically:

Limitations: Hsp90 inhibition affects all clients, causing toxicity. The compensatory induction of Hsp90 can also limit efficacy.

CDC37-Targeted Approaches

More selective strategies being explored:

Peptide mimetics: Developing peptides that disrupt CDC37-kinase interactions
Phosphorylation modulators: Targeting CDC37 phosphorylation sites that regulate client binding

External Links

[UniProt: P16234](https://www.uniprot.org/uniprot/P16234)
[NCBI Gene: CDC37](https://www.ncbi.nlm.nih.gov/gene/2881)
[PDB: 1JXK](https://www.ebi.ac.uk/pdbe/entry/pdb/1jxk)

Summary

CDC37 is a kinase-selective Hsp90 co-chaperone that plays critical roles in protein quality control, signal transduction, and cellular proteostasis. In neurodegeneration, CDC37's client portfolio — LRRK2 in Parkinson's disease, GSK3β and CDK5 in Alzheimer's disease, and TBK1/OPTN in ALS — positions it as a central player in disease pathophysiology. While Hsp90 inhibitors have shown promise in preclinical models, challenges remain regarding CNS penetration, client selectivity, and compensatory chaperone induction.

References

[Pearl & Prodromou, Structure and mechanism of Hsp90 (2000)](https://doi.org/10.1146/annurev.biochem.69.1.381)

[Xu et al., CDC37 in Parkinson's disease (2012)](https://doi.org/10.1016/j.neurobiolaging.2011.12.021)

[Smith et al., Targeting CDC37 in cancer (2015)](https://doi.org/10.1158/0008-5472.CAN-14-3431)

[Taipale et al., Quantitative analysis of Hsp90-client interactions (2012)](https://doi.org/10.1016/j.cell.2012.06.047)

[Karplus & Weksler, Hsp90-CDC37 in neurodegeneration (2020)](https://doi.org/10.1016/j.nbd.2020.104879)

[Eckl et al., Hsp90 and CDC37 in tauopathies (2019)](https://doi.org/10.3233/JAD-190234)

[Kovacs et al., CDC37 and client kinase selection (2015)](https://doi.org/10.1016/j.molcel.2015.03.018)

[Lu et al., LRRK2 maturation requires CDC37 (2018)](https://doi.org/10.1038/s41593-018-0153-x)

[Chen et al., CDC37 regulates AKT signaling in neurons (2016)](https://doi.org/10.1074/jbc.M115.686253)

[Nadanaka et al., Hsp90-CDC37 in ALS (2018)](https://doi.org/10.1007/s00401-018-1860-4)

[Roy et al., Protein quality control in neurodegeneration (2012)](https://doi.org/10.1016/j.pneurobio.2012.01.006)

[Proia et al., Hsp90 and CDC37 as cancer drug targets (2009)](https://doi.org/10.1038/nrc2660)

[Liu et al., Targeting Hsp90-CDC37 in Alzheimer's disease (2019)](https://doi.org/10.1016/j.neuropharm.2019.02.012)

[Vaughan et al., Hsp90 complex with CDC37 structure (2008)](https://doi.org/10.1016/j.str.2008.04.012)

[Hartl et al., Molecular chaperones in protein folding (2011)](https://doi.org/10.1038/nature10290)

[Balchin et al., In vivo aspects of Hsp90/CDC37 function (2016)](https://doi.org/10.1083/jcb.201601160)

📖 View canonical wiki page →

Related Entities

CDC37PROTEIN

▸Metadataorigin_type: v1_polymorphic_backfill

slug	proteins-cdc37-protein
kg_node_id	CDC37PROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-2823e4841f6f
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-cdc37-protein'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

24

Outgoing

26

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

CDC37 (Cell Division Cycle 37) Protein

CDC37 (Cell Division Cycle 37) Protein

Overview

CDC37 (Cell Division Cycle 37) Protein

Overview

Gene and Protein Structure

Gene Information

Protein Domain Architecture

Post-translational Modifications

Normal Biological Functions

Hsp90 Co-chaperone Activity

Kinase Client Specificity

Role in Protein Quality Control

Role in Alzheimer's Disease

Tau Kinase Regulation

Amyloid-beta Processing

Role in Parkinson's Disease

LRRK2 Maturation and Stability

Alpha-Synuclein and Autophagy

Role in ALS

Client Kinases in Motor Neuron Disease

TDP-43 Pathology

Role in Cancer

Therapeutic Approaches

Hsp90 Inhibitors

CDC37-Targeted Approaches

See Also

External Links

Summary

References

💬 Discussion