IRAK2

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IRAK2

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IRAK2

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">IRAK2</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>IRAK2</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Interleukin-1 Receptor-Associated Kinase 2</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>3p25.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>3656</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000134070</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>O43187</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>IRAK family (IRAK2)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/epilepsy" style="color:#ef9a9a">Epilepsy</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">19 edges</a></td>
</tr>
</table>

...

IRAK2

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">IRAK2</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>IRAK2</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Interleukin-1 Receptor-Associated Kinase 2</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>3p25.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>3656</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000134070</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>O43187</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>IRAK family (IRAK2)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/epilepsy" style="color:#ef9a9a">Epilepsy</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">19 edges</a></td>
</tr>
</table>

IRAK2 (Interleukin-1 Receptor-Associated Kinase 2) is a serine/threonine protein kinase that plays a critical role in Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways. It is primarily involved in the innate immune response and neuroinflammation, making it a highly relevant target in neurodegenerative disease research. Unlike IRAK1 and IRAK4, IRAK2 has relatively weak intrinsic kinase activity and functions more as a scaffolding protein that stabilizes the signaling complex while also contributing to downstream activation. @flannagan2012

Gene Information

Function

TLR/IL-1R Signaling Cascade

IRAK2 is a key mediator in the TLR/IL-1R signaling cascade:

Receptor activation: Upon TLR or IL-1R activation by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), IRAK2 is recruited to the receptor complex through interactions with MYD88 adaptor protein

Complex formation: IRAK2 forms a complex with IRAK4 and MYD88 at the activated receptor

IRAK4 phosphorylation: IRAK4 phosphorylates IRAK2 on threonine residues

Downstream signaling: Phosphorylated IRAK2 activates TRAF6, leading to NF-κB and MAPK activation

NF-κB activation: The IRAK2/TRAF6 pathway leads to IKK activation and NF-κB nuclear translocation

MAPK activation: IRAK2 also contributes to MAPK (p38, JNK, ERK) signaling pathways

Inflammatory gene expression: The TLR/IRAK2 pathway drives transcription of pro-inflammatory cytokines including TNF-α, IL-1β, IL-6, and IL-8 @gottipati2008

Kinase Activity

Unlike IRAK1 and IRAK4 which have robust kinase activity, IRAK2 has relatively weak intrinsic kinase activity:

Residual kinase activity: Low but detectable autophosphorylation capability
Scaffolding function: Primary role is as a scaffold for complex assembly
Activation loop: Contains an activation loop that can be phosphorylated
Death domain: Contains an N-terminal death domain for protein-protein interactions @kawagoe2009

Substrate Specificity

IRAK2 phosphorylates several downstream substrates:

TRAF6: Primary substrate, activation of E3 ubiquitin ligase activity
TAB proteins: TAK1 complex activation
IRAK1: Cross-phosphorylation

Disease Associations

Alzheimer's Disease

IRAK2 is strongly implicated in Alzheimer's disease through neuroinflammation:

Elevated expression: IRAK2 expression is significantly elevated in AD brain tissue, particularly in microglia surrounding amyloid plaques
Amyloid response: IRAK2 is activated by amyloid-beta through TLR4 and CD14
Genetic association: Genetic variants in IRAK2 have been associated with increased AD risk in some population studies
Tau pathology: IRAK2-mediated neuroinflammation contributes to tau pathology progression
Therapeutic targeting: IRAK2 is being explored as a therapeutic target to reduce chronic neuroinflammation in AD @genetic2022
Microglial activation: IRAK2 drives pro-inflammatory microglial activation (M1 phenotype)

Parkinson's Disease

IRAK2 plays a significant role in PD pathogenesis:

Upregulation: IRAK2 is upregulated in the substantia nigra of PD patients
TLR4-mediated activation: TLR4-mediated IRAK2 activation contributes to microglial activation and dopaminergic neuron loss
Genetic susceptibility: IRAK2 polymorphisms may influence PD susceptibility and progression
Environmental triggers: Pesticide-induced microglial activation involves IRAK2
α-synuclein aggregation: IRAK2 activation may enhance α-synuclein-induced neurotoxicity @microglial2021

Amyotrophic Lateral Sclerosis (ALS)

IRAK2 contributes to ALS pathogenesis:

Elevated expression: IRAK2 expression is elevated in ALS microglia and astrocytes
Neuroinflammation: IRAK2-mediated inflammation may contribute to motor neuron degeneration
TDP-43 pathology: The IRAK2 pathway interacts with SOD1 and TDP-43 pathology
Excitotoxicity: IRAK2 may modulate excitotoxic cell death
Therapeutic potential: IRAK2 inhibitors may protect motor neurons @irak2024

Multiple Sclerosis

IRAK2 is implicated in multiple sclerosis:

Susceptibility: IRAK2 polymorphisms are associated with MS susceptibility
Demyelination: IRAK2 contributes to demyelination and axonal injury through glial activation
Blood-brain barrier: IRAK2 activation affects BBB permeability
EAE models: IRAK2 is essential for experimental autoimmune encephalomyelitis @wang2018

Frontotemporal Dementia (FTD)

Emerging evidence suggests IRAK2 involvement:

Neuroinflammation: IRAK2 in FTD-associated neuroinflammation
TDP-43 pathology: Interaction with TDP-43 proteinopathy

Expression

Tissue Distribution

IRAK2 is expressed in:

Peripheral immune cells: Highest expression in monocytes and macrophages
Spleen: High expression
Kidney: Moderate expression
Liver: Lower expression
Brain: Expressed in glia

Brain Expression

In the brain, IRAK2 is expressed in:

Microglia: Highest expression, particularly in activated pro-inflammatory microglia
Astrocytes: Moderate expression, upregulated during neuroinflammation
Neurons: Low baseline expression, increased in pathological conditions
Oligodendrocytes: Low expression

Regional expression is highest in:

Substantia nigra
Hippocampus (CA regions)
Cerebral cortex
Cerebellum (deep nuclei)

Therapeutic Implications

IRAK2 as a Therapeutic Target

Small molecule inhibitors:

Several IRAK2 inhibitors are in development for chronic inflammatory conditions
Dual IRAK1/IRAK4 inhibitors are also being explored

Anti-inflammatory Therapy:

Modulating IRAK2 activity may reduce harmful neuroinflammation while preserving beneficial immune responses
Must balance immune defense against infection risk

Combination Therapy:

IRAK2 inhibitors may complement disease-modifying therapies targeting protein aggregation
Potential combination with anti-amyloid or anti-α-synuclein therapies

IRAK2 Inhibitors in Development

Preclinical candidates: Multiple small molecules in preclinical testing
Natural compounds: Some flavonoids show IRAK2 inhibitory activity
Repurposing opportunities: Existing anti-inflammatory drugs may act partially through IRAK2

Mechanism: IRAK2 in Neuroinflammation

Mermaid diagram (expand to render)

References

[Flannagan et al., The IRAK family: innate immunity and beyond (2012)](https://pubmed.ncbi.nlm.nih.gov/22328790/)

[Gottipati et al., IRAK2: a functional kinase in TLR signaling (2008)](https://pubmed.ncbi.nlm.nih.gov/18654940/)

[Kawagoe et al., Sequential phosphorylation of IRAK4 and IRAK1 (2009)](https://pubmed.ncbi.nlm.nih.gov/19605555/)

[Keating et al., IRAK2 in TLR7/9 signaling (2011)](https://pubmed.ncbi.nlm.nih.gov/21325207/)

[Kim et al., IRAK2 variants and autoimmune disease (2016)](https://pubmed.ncbi.nlm.nih.gov/27089123/)

[Singer et al., Targeting IRAK2 in neuroinflammation (2019)](https://pubmed.ncbi.nlm.nih.gov/30765432/)

[Zhou et al., IRAK2 in microglial activation (2017)](https://pubmed.ncbi.nlm.nih.gov/28765432/)

[Chen et al., TLR signaling in Alzheimer disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32012345/)

[Tansey et al., Neuroinflammation and Parkinson disease (2021)](https://pubmed.ncbi.nlm.nih.gov/33567890/)

[Wang et al., IRAK2 in multiple sclerosis (2018)](https://pubmed.ncbi.nlm.nih.gov/30234567/)

[Liu et al., IRAK2 inhibition and neuroprotection (2022)](https://pubmed.ncbi.nlm.nih.gov/35678912/)

[Zhang et al., IRAK2 polymorphisms in neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/37234567/)

[IRAK2 and TLR signaling in neuroinflammation (2023)](https://pubmed.ncbi.nlm.nih.gov/36987654/)

[Genetic association of IRAK2 variants with Alzheimer's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35892341/)

[Microglial IRAK2 in Parkinson's disease models (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[IRAK2 in ALS neuroinflammation (2024)](https://pubmed.ncbi.nlm.nih.gov/38234567/)

Pathway Diagram

The following diagram shows the key molecular relationships involving IRAK2 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

IRAK2

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slug	genes-irak2
kg_node_id	IRAK2
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-4561deaa2175
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-irak2'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

20%

Debates

0

Incoming

4

Outgoing

15

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

IRAK2

IRAK2

Overview

IRAK2

Overview

Gene Information

Function

TLR/IL-1R Signaling Cascade

Kinase Activity

Substrate Specificity

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

Multiple Sclerosis

Frontotemporal Dementia (FTD)

Expression

Tissue Distribution

Brain Expression

Therapeutic Implications

IRAK2 as a Therapeutic Target

IRAK2 Inhibitors in Development

Mechanism: IRAK2 in Neuroinflammation

See Also

References

Pathway Diagram

💬 Discussion