CAMKK2 Protein

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CAMKK2 Protein

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CAMKK2 Protein

Overview

CAMKK2 (Calcium/Calmodulin-Dependent Protein Kinase Kinase 2) is a serine/threonine kinase that activates AMPK and CaMK1.

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4ea;">CAMKK2 (Calcium/Calmodulin-Dependent Protein Kinase Kinase 2)</th></tr>
<tr><td><strong>Gene</strong></td><td>[CAMKK2](/genes/camkk2)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q96MP8](https://www.uniprot.org/uniprot/Q96MP8)</td></tr>
<tr><td><strong>PDB Structure</strong></td><td>4AFE, 5U6J, 6QVK (kinase domain)</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>65 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Cytosol, nucleus, plasma membrane</td></tr>
<tr><td><strong>Protein Family</strong></td><td>CaM kinase family (Ser/Thr protein kinase)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/autoimmune" style="color:#ef9a9a">Autoimmune</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">42 edges</a></td>
</tr>
</table>
</div>

Structure

CAMKK2 is a calcium/calmodulin-dependent protein kinase that functions as a serine/threonine protein kinase[@harwood2005]. The protein contains:

...

CAMKK2 Protein

Overview

CAMKK2 (Calcium/Calmodulin-Dependent Protein Kinase Kinase 2) is a serine/threonine kinase that activates AMPK and CaMK1.

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4ea;">CAMKK2 (Calcium/Calmodulin-Dependent Protein Kinase Kinase 2)</th></tr>
<tr><td><strong>Gene</strong></td><td>[CAMKK2](/genes/camkk2)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q96MP8](https://www.uniprot.org/uniprot/Q96MP8)</td></tr>
<tr><td><strong>PDB Structure</strong></td><td>4AFE, 5U6J, 6QVK (kinase domain)</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>65 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Cytosol, nucleus, plasma membrane</td></tr>
<tr><td><strong>Protein Family</strong></td><td>CaM kinase family (Ser/Thr protein kinase)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/autoimmune" style="color:#ef9a9a">Autoimmune</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">42 edges</a></td>
</tr>
</table>
</div>

Structure

CAMKK2 is a calcium/calmodulin-dependent protein kinase that functions as a serine/threonine protein kinase[@harwood2005]. The protein contains:

N-terminal catalytic domain (~300 aa) with typical kinase fold
Regulatory segment with autoinhibitory sequence
Calmodulin-binding domain at the C-terminus
Multiple phosphorylation sites for regulation[@tokumitsu2003]

Normal Function

CAMKK2 is a central integrator of calcium signaling in [neurons](/entities/neurons):

Upstream Kinase: Phosphorylates and activates [CAMK1](/genes/camk1), [CAMK4](/genes/camk4), [AMPK](/entities/prkaa1), and [SIRT1](/entities/sirt1)[@woods2005]
Calcium Signaling: Responds to elevated intracellular calcium via calmodulin binding
Energy Metabolism: Activates [AMPK](/therapeutics/metformin-neurodegeneration) to regulate cellular energy homeostasis
Synaptic Plasticity: Regulates gene expression through transcription factor phosphorylation
Neuroprotection: Activates [mTOR](/therapeutics/rapamycin-tauopathy) and [autophagy](/entities/autophagy) pathways[@racioppi2012]

Role in Neurodegeneration

Alzheimer's Disease

CAMKK2 plays complex roles in [Alzheimer's disease](/diseases/alzheimers-disease):

Synaptic Dysfunction: Reduced CAMKK2 expression in AD [hippocampus](/brain-regions/hippocampus) contributes to synaptic plasticity deficits[@liu2012]
[AMPK](/therapeutics/metformin-neurodegeneration) Dysregulation: Impaired CAMKK2-AMPK signaling affects [tau](/proteins/tau) phosphorylation and [autophagy](/mechanisms/autophagy-lysosomal-pathway)
Calcium Homeostasis: Altered neuronal calcium signaling is an early AD feature linked to CAMKK2 dysfunction[@berridge2010]
Therapeutic Target: CAMKK2 activators being explored to enhance AMPK activity in AD[@asadbegi2016]

Parkinson's Disease

Dopaminergic Neuroprotection: CAMKK2 activates [AMPK](/entities/prkaa1) which protects dopaminergic neurons[@timmons2009]
Mitochondrial Function: CAMKK2-AMPK axis regulates [mitochondrial biogenesis](/mechanisms/mitochondrial-dynamics-alzheimers) and quality control
Autophagy: CAMKK2-mediated AMPK activation enhances [mitophagy](/mechanisms/autophagy-lysosomal-pathway) in PD models[@wu2011]

Amyotrophic Lateral Sclerosis

Motor neuron survival requires functional CAMKK2 signaling[@van2012]
Dysregulated calcium handling in [ALS](/diseases/amyotrophic-lateral-sclerosis) involves CAMKK2 pathway alterations
Therapeutic potential of CAMKK2 activators being investigated[@martinez2017]

Stroke and Ischemia

CAMKK2-AMPK pathway activated during cerebral ischemia[@mccullough2005]
Neuroprotective role in stroke models
Potential therapeutic target for acute brain injury

Therapeutic Targeting

CAMKK2 Activators: STO-609 (selective CAMKK inhibitor - for research), natural compounds

AMPK Activators: [Metformin](/therapeutics/metformin-neurodegeneration), [AICAR](/therapeutics/aicar-neurodegeneration)[@salminen2016]

Calcium Channel Modulators: Target upstream calcium dysregulation

Combination Therapy: CAMKK2 activators with [autophagy](/therapeutics/rapamycin-tauopathy) enhancers

External Links

[UniProt: camkk2](https://www.uniprot.org/)
[PubMed: camkk2](https://pubmed.ncbi.nlm.nih.gov/?term=camkk2+neurodegeneration)

References

[Harwood, G. et al., (2005). Structure of CaMKK2 Reveals a Novel Kinase Fold (2005)](https://pubmed.ncbi.nlm.nih.gov/16216572/)

[Tokumitsu, H. et al., (2003). CaM-Kinase Kinase: A Unique Neuronal Signaling Kinase (2003)](https://pubmed.ncbi.nlm.nih.gov/12944368/)

[Woods, A. et al., (2005). CaM-Kinase Activates AMPK (2005)](https://pubmed.ncbi.nlm.nih.gov/16213825/)

[Unknown, Racioppi, L. & Means, A.R. (2012). Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (2012)](https://pubmed.ncbi.nlm.nih.gov/21835167/)

[Liu, F. et al., (2012). CaMKII and CaMKK2 in Alzheimer's Disease (2012)](https://pubmed.ncbi.nlm.nih.gov/22453954/)

[Unknown, Berridge, M.J. (2010). Calcium Hypothesis of Alzheimer's Disease (2010)](https://pubmed.ncbi.nlm.nih.gov/19795146/)

[Asadbegi, M. et al., (2016). AMPK Activation in Alzheimer's Disease (2016)](https://pubmed.ncbi.nlm.nih.gov/27666982/)

[Timmons, S. et al., (2009). CaM Kinase Kinase in Parkinsonism (2009)](https://pubmed.ncbi.nlm.nih.gov/19543767/)

[Wu, Y. et al., (2011). AMPK and Autophagy in α-Synuclein Toxicity (2011)](https://pubmed.ncbi.nlm.nih.gov/21508683/)

[Van Hoecke, A. et al., (2012). CaMKK2 Contributes to Motor Neuron Degeneration (2012)](https://pubmed.ncbi.nlm.nih.gov/22647597/)

[Martinez, A. et al., (2017). Kinase Targets for Neurodegenerative Diseases (2017)](https://pubmed.ncbi.nlm.nih.gov/28378924/)

[McCullough, L.D. et al., (2005). AMPK Activation in Stroke (2005)](https://pubmed.ncbi.nlm.nih.gov/15647739/)

[Salminen, A. et al., (2016). AMPK Activation in Aging and Neurodegeneration (2016)](https://pubmed.ncbi.nlm.nih.gov/26850212/)

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Related Entities

CAMKK2PROTEIN

▸Metadataorigin_type: v1_polymorphic_backfill

slug	proteins-camkk2-protein
kg_node_id	CAMKK2PROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-c87f2b5b8f61
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-camkk2-protein'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

50%

Debates

0

Incoming

10

Outgoing

13

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

CAMKK2 Protein

CAMKK2 Protein

Overview

Structure

CAMKK2 Protein

Overview

Structure

Normal Function

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis

Stroke and Ischemia

Therapeutic Targeting

See Also

External Links

References

💬 Discussion