IRAK2

Summary

IRAK2 (interleukin 1 receptor associated kinase 2, HGNC:6113) is a protein-coding gene on chromosome 3p25.3, encoding Interleukin-1 receptor-associated kinase-like 2 (O43187). Binds to the IL-1 type I receptor following IL-1 engagement, triggering intracellular signaling cascades leading to transcriptional up-regulation and mRNA stabilization.

IRAK2 encodes the interleukin-1 receptor-associated kinase 2, one of two putative serine/threonine kinases that become associated with the interleukin-1 receptor (IL1R) upon stimulation. IRAK2 is reported to participate in the IL1-induced upregulation of NF-kappaB.

Source: NCBI Gene 3656 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immune dysregulation, autoimmunity, and autoinflammation (Limited, GenCC)
• GWAS associations: 8
• Clinical variants (ClinVar): 131 total — 5 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001570

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6113
Approved symbol	IRAK2
Name	interleukin 1 receptor associated kinase 2
Location	3p25.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000134070
Ensembl biotype	protein_coding
OMIM	603304
Entrez	3656

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000256458, ENST00000873196, ENST00000873197, ENST00000873198, ENST00000873199, ENST00000971361

RefSeq mRNA: 1 — MANE Select: NM_001570 NM_001570

CCDS: CCDS33697

Canonical transcript exons

ENST00000256458 — 13 exons

Exon	Start	End
ENSE00000912613	10177838	10178020
ENSE00000912614	10200369	10200515
ENSE00000912615	10209589	10209692
ENSE00000912621	10234459	10234659
ENSE00001134699	10164919	10165048
ENSE00001163909	10226371	10226433
ENSE00001163918	10222636	10222831
ENSE00001163929	10219680	10219789
ENSE00001163939	10216934	10217048
ENSE00001163947	10213484	10213548
ENSE00001163955	10213207	10213401
ENSE00001217958	10238748	10239039
ENSE00001498749	10242116	10243745

Expression profiles

Bgee: expression breadth ubiquitous, 213 present calls, max score 96.24.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.1784 / max 925.0471, expressed in 1393 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
35283	12.4398	1242
35282	1.7386	871

Top tissues by expression

238 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	96.24	gold quality
epithelial cell of pancreas	CL:0000083	91.89	gold quality
secondary oocyte	CL:0000655	88.65	gold quality
oocyte	CL:0000023	87.61	gold quality
pancreatic ductal cell	CL:0002079	84.63	silver quality
palpebral conjunctiva	UBERON:0001812	84.63	gold quality
gastrocnemius	UBERON:0001388	83.27	gold quality
tibialis anterior	UBERON:0001385	82.63	silver quality
esophagus squamous epithelium	UBERON:0006920	82.18	gold quality
muscle of leg	UBERON:0001383	81.32	gold quality
amniotic fluid	UBERON:0000173	80.71	gold quality
endothelial cell	CL:0000115	79.53	gold quality
lower esophagus mucosa	UBERON:0035834	79.50	gold quality
islet of Langerhans	UBERON:0000006	78.96	gold quality
right lobe of liver	UBERON:0001114	78.55	gold quality
urinary bladder	UBERON:0001255	78.47	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.94	gold quality
sperm	CL:0000019	77.80	gold quality
tonsil	UBERON:0002372	77.78	gold quality
granulocyte	CL:0000094	77.30	gold quality
bone marrow	UBERON:0002371	76.62	gold quality
epithelium of nasopharynx	UBERON:0001951	76.52	gold quality
bone marrow cell	CL:0002092	76.29	gold quality
liver	UBERON:0002107	75.94	gold quality
esophagus mucosa	UBERON:0002469	75.74	gold quality
upper lobe of left lung	UBERON:0008952	75.25	gold quality
vermiform appendix	UBERON:0001154	74.90	gold quality
upper lobe of lung	UBERON:0008948	74.63	gold quality
hindlimb stylopod muscle	UBERON:0004252	74.11	gold quality
adipose tissue	UBERON:0001013	73.95	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.95

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF, IRF6, NFKB, TFAP2B

miRNA regulators (miRDB)

87 targeting IRAK2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815

Literature-anchored findings (GeneRIF, showing 21)

• CTCF plays a major role in IRAK2 transcription; EMSA revealed a CTCF-binding site within the mouse Irak2 promoter (PMID:15670593)
• IRAK-2 plays a more central role than IRAK-1 in TLR signaling to NFkappaB through TRAF6 ubiquitination (PMID:17878161)
• TRAF6 and interleukin receptor-associated kinase 2 are novel binding partners for PS1, and IL-1R1 is a new substrate for presenilin-dependent gamma-secretase cleavage (PMID:18996842)
• Our data show that interleukin-1R-associated kinase 2 is a novel and critical component of TGFbeta signaling. (PMID:20332216)
• the crystal structure of the MyD88-IRAK4-IRAK2 death domain (DD) complex, which surprisingly reveals a left-handed helical oligomer that consists of 6 MyD88, 4 IRAK4 and 4 IRAK2 DDs (PMID:20485341)
• analysis of differential regulation of interleukin-1 receptor-associated kinase-1 (IRAK-1) and IRAK-2 by microRNA-146a and NF-kappaB in stressed human astroglial cells and in Alzheimer disease (PMID:20937840)
• Human interleukin-1 receptor-associated kinase-2 is essential for Toll-like receptor-mediated transcriptional and post-transcriptional regulation of tumor necrosis factor alpha. (PMID:21606490)
• These findings demonstrate an unexpected linkage of the innate immunity machinery to unfolded protein response signaling, revealing IRAK2 as a novel amplifier of the IRE1 pathway. (PMID:23724040)
• Results suggest that D431E-IRAK2 (interleukin-1 receptor-associated kinase-2) increases NF-kappaB activation by promoting TRAF6 ubiquitination by enhancing TNF Receptor-Associated Factor 6 (TRAF6)-IRAK2 interaction. (PMID:24662294)
• This for the first time implicates human IRAK2 in a human disease and highlights the R214G IRAK2 variant as a potential novel and broadly applicable biomarker for disease or as a therapeutic intervention point. (PMID:24973222)
• Human miR-373 is silenced by histone modification in lung cancer cells and is a negative regulator of the mesenchymal phenotype through downstream IRAK2 and LAMP1 target genes. (PMID:25063738)
• IRAK2 L392V showed intact binding to, but impaired ubiquitination of, tumor necrosis factor receptor-associated factor 6, a vital step in signal transduction (PMID:26250868)
• This study for the first time ever reports the association of IRAK2 rs3844283, IRAK2 rs708035, and the corresponding haplotypes with rheumatoid arthritis. (PMID:29129009)
• these findings demonstrate a novel mechanism of interplays for the different branches of ER stress signaling network and highlight IRAK2 as a potential tumor suppressor to counterbalance oncogenic Smurf1. (PMID:29753111)
• Authors identified IRAK2 rs779901 C > T as a predictor of NSCLC OS, with a variant-allele (T) attributed hazards ratio (HR) of 0.78 [95% confidence interval (CI) = 0.67-0.91, P = 0.001] in the PLCO dataset, 0.84 (0.72-0.98, 0.031) in the Harvard dataset, and 0.81 (0.73-0.90, 1.08x10(-4) ) in the meta-analysis of these two GWAS datasets. (PMID:29978465)
• Both IRAK2 and TLR10 play important roles in the onset and development of Hashimoto’s disease. (PMID:31073143)
• IRAK2 is associated with systemic lupus erythematosus risk. (PMID:31650390)
• MyD88 Death-Domain Oligomerization Determines Myddosome Architecture: Implications for Toll-like Receptor Signaling. (PMID:31995744)
• The extreme C-terminus of IRAK2 assures full TRAF6 ubiquitination and optimal TLR signaling. (PMID:33799071)
• IRAK2 Has a Critical Role in Promoting Feed-Forward Amplification of Epidermal Inflammatory Responses. (PMID:33864770)
• Multi-locus SNP analyses of interleukin 1 receptor associated kinases 2 gene polymorphisms with the susceptibility to rheumatoid arthritis. (PMID:35588430)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
mus_musculus	Irak2	ENSMUSG00000060477
rattus_norvegicus	Irak2	ENSRNOG00000021817
drosophila_melanogaster	pll	FBGN0010441
drosophila_melanogaster	Haspin	FBGN0046706
caenorhabditis_elegans		WBGENE00004029
caenorhabditis_elegans	hasp-1	WBGENE00007258
caenorhabditis_elegans		WBGENE00012159
caenorhabditis_elegans	hasp-2	WBGENE00021214

Paralogs (4): IRAK3 (ENSG00000090376), HASPIN (ENSG00000177602), IRAK1 (ENSG00000184216), IRAK4 (ENSG00000198001)

Protein

Protein identifiers

Interleukin-1 receptor-associated kinase-like 2 — O43187 (reviewed: O43187)

All UniProt accessions (1): O43187

UniProt curated annotations — full annotation on UniProt →

Function. Binds to the IL-1 type I receptor following IL-1 engagement, triggering intracellular signaling cascades leading to transcriptional up-regulation and mRNA stabilization.

Subunit / interactions. Interacts with MYD88. IL-1 stimulation leads to the formation of a signaling complex which dissociates from the IL-1 receptor following the binding of PELI1.

Tissue specificity. Expressed in spleen, thymus, prostate, lung, liver, skeletal muscle, kidney, pancreas and peripheral blood leukocytes.

Domain organisation. The protein kinase domain is predicted to be catalytically inactive.

Similarity. Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily.

RefSeq proteins (1): NP_001561* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000488	Death_dom	Domain
IPR000719	Prot_kinase_dom	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR042151	Death_IRAK2	Domain

Pfam: PF00069, PF00531

Enzyme classification (BRENDA):

• EC 2.7.10.2 — non-specific protein-tyrosine kinase (BRENDA: 41 organisms, 396 substrates, 479 inhibitors, 43 Km, 32 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.014–17.64	12
[KDSRC KINASE]-L-TYROSINE	0.0057–0.24	12
POLY(GLU4-TYR)	0.018–0.659	10
EEEEYIQ[DP]-8-HYDROXY-5-(N,N-DIMETHYLSULFONAMIDO	0.057	1
S1 PEPTIDE	0.037	1
EEEEY	—	0

UniProt features (38 total): sequence variant 14, helix 8, turn 5, binding site 3, domain 2, region of interest 2, compositionally biased region 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3MOP	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43187-F1	68.76	0.28

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (3): 216–224; 237; 337–340

Post-translational modifications (1): 144

Function

Pathways and Gene Ontology

Reactome pathways

42 pathways

ID	Pathway
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane
R-HSA-168638	NOD1/2 Signaling Pathway
R-HSA-445989	TAK1-dependent IKK and NF-kappa-B activation
R-HSA-450302	activated TAK1 mediates p38 MAPK activation
R-HSA-450321	JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1
R-HSA-9020702	Interleukin-1 signaling
R-HSA-937042	IRAK2 mediated activation of TAK1 complex
R-HSA-937072	TRAF6-mediated induction of TAK1 complex within TLR4 complex
R-HSA-9692916	SARS-CoV-1 activates/modulates innate immune responses
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses
R-HSA-975138	TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation
R-HSA-975155	MyD88 dependent cascade initiated on endosome
R-HSA-975163	IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation
R-HSA-975871	MyD88 cascade initiated on plasma membrane
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1643685	Disease
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade
R-HSA-166166	MyD88-independent TLR4 cascade
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade
R-HSA-168142	Toll Like Receptor 10 (TLR10) Cascade
R-HSA-168164	Toll Like Receptor 3 (TLR3) Cascade
R-HSA-168176	Toll Like Receptor 5 (TLR5) Cascade
R-HSA-168179	Toll Like Receptor TLR1:TLR2 Cascade
R-HSA-168181	Toll Like Receptor 7/8 (TLR7/8) Cascade
R-HSA-168188	Toll Like Receptor TLR6:TLR2 Cascade
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168643	Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways
R-HSA-168898	Toll-like Receptor Cascades
R-HSA-181438	Toll Like Receptor 2 (TLR2) Cascade

MSigDB gene sets: 297 (showing top): REACTOME_TRAF6_MEDIATED_INDUCTION_OF_TAK1_COMPLEX_WITHIN_TLR4_COMPLEX, TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_6HR_DN, LEE_SP4_THYMOCYTE, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_NOD1_2_SIGNALING_PATHWAY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, REACTOME_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_NLR_SIGNALING_PATHWAYS, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY

GO Biological Process (15): regulation of cytokine-mediated signaling pathway (GO:0001959), MyD88-dependent toll-like receptor signaling pathway (GO:0002755), protein phosphorylation (GO:0006468), inflammatory response (GO:0006954), canonical NF-kappaB signal transduction (GO:0007249), Toll signaling pathway (GO:0008063), lipopolysaccharide-mediated signaling pathway (GO:0031663), toll-like receptor 4 signaling pathway (GO:0034142), intracellular signal transduction (GO:0035556), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), interleukin-1-mediated signaling pathway (GO:0070498), response to interleukin-1 (GO:0070555), signal transduction (GO:0007165), non-canonical NF-kappaB signal transduction (GO:0038061)

GO Molecular Function (8): protein kinase activity (GO:0004672), ATP binding (GO:0005524), signaling adaptor activity (GO:0035591), protein homodimerization activity (GO:0042803), protein heterodimerization activity (GO:0046982), molecular adaptor activity (GO:0060090), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), endosome membrane (GO:0010008)

Reactome top-level categories

Rollup of top-21 pathways:

Category	Pathways
Toll-like Receptor Cascades	3
Toll Like Receptor 4 (TLR4) Cascade	2
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	2
TRIF (TICAM1)-mediated TLR4 signaling	2
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	2
MyD88 cascade initiated on plasma membrane	2
MAP kinase activation	2
Toll Like Receptor TLR1:TLR2 Cascade	1
Toll Like Receptor TLR6:TLR2 Cascade	1
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1
Toll Like Receptor 3 (TLR3) Cascade	1
Interleukin-1 signaling	1
Interleukin-1 family signaling	1
SARS-CoV-1-host interactions	1
SARS-CoV-2-host interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytokine-mediated signaling pathway	2
intracellular signaling cassette	2
cell surface receptor signaling pathway	2
intracellular anatomical structure	2
canonical NF-kappaB signal transduction	2
regulation of canonical NF-kappaB signal transduction	2
protein dimerization activity	2
binding	2
cellular anatomical structure	2
regulation of signal transduction	1
regulation of response to cytokine stimulus	1
toll-like receptor signaling pathway	1
phosphorylation	1
protein modification process	1
defense response	1
cellular response to lipopolysaccharide	1
cell surface toll-like receptor signaling pathway	1
signal transduction	1
positive regulation of intracellular signal transduction	1
negative regulation of intracellular signal transduction	1
cellular response to interleukin-1	1
response to cytokine	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein-macromolecule adaptor activity	1
identical protein binding	1
molecular_function	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
membrane	1

Protein interactions and networks

STRING

1912 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IRAK2	MYD88	P78397	998
IRAK2	TRAF6	Q9Y4K3	998
IRAK2	IRAK4	Q9NWZ3	989
IRAK2	IRAK1	P51617	987
IRAK2	IRAK3	Q9Y616	974
IRAK2	IL1R1	P14778	925
IRAK2	TIRAP	P58753	904
IRAK2	TAB2	Q9NYJ8	879
IRAK2	TLR4	O00206	862
IRAK2	TLR3	O15455	823
IRAK2	TAB1	Q15750	800
IRAK2	TLR2	O60603	772
IRAK2	IL1A	P01583	761
IRAK2	TLR7	Q9NYK1	708
IRAK2	TOLLIP	Q9H0E2	690

IntAct

42 interactions, top by confidence:

A	B	Type	Score
IRAK2	TRAF6	psi-mi:“MI:0915”(physical association)	0.810
TRAF6	IRAK2	psi-mi:“MI:0915”(physical association)	0.810
TIRAP	TLR4	psi-mi:“MI:0914”(association)	0.810
IRAK4	IRAK2	psi-mi:“MI:0914”(association)	0.710
IRAK2	IRAK4	psi-mi:“MI:0915”(physical association)	0.710
IRAK2	SESTD1	psi-mi:“MI:0914”(association)	0.640
IRAK2	MYD88	psi-mi:“MI:0915”(physical association)	0.580
IRAK2	MYD88	psi-mi:“MI:0914”(association)	0.580
IRAK1	IRAK2	psi-mi:“MI:0915”(physical association)	0.560
IRAK2	IRAK1	psi-mi:“MI:0915”(physical association)	0.560
IRAK2	IRAK3	psi-mi:“MI:0915”(physical association)	0.560
IRAK3	IRAK2	psi-mi:“MI:0915”(physical association)	0.560
IRAK2	TIRAP	psi-mi:“MI:0915”(physical association)	0.560
IRAK3	IRAK2	psi-mi:“MI:0914”(association)	0.560
OPG044	IRAK2	psi-mi:“MI:0915”(physical association)	0.520
IRAK2	OPG044	psi-mi:“MI:0915”(physical association)	0.520
TOLLIP	IRAK2	psi-mi:“MI:0914”(association)	0.500
IRAK2	ARAF	psi-mi:“MI:0915”(physical association)	0.500
TOLLIP	IRAK2	psi-mi:“MI:0915”(physical association)	0.500
IRAK2	STT3A	psi-mi:“MI:0915”(physical association)	0.500
IRAK2	TARDBP	psi-mi:“MI:0915”(physical association)	0.500
ZC3H12A	IRAK2	psi-mi:“MI:0915”(physical association)	0.500
IRAK2	Sarm1	psi-mi:“MI:0915”(physical association)	0.500
	IRAK2	psi-mi:“MI:0915”(physical association)	0.400
IRAK2	MYD88	psi-mi:“MI:0915”(physical association)	0.400
IRAK2	IRAK2	psi-mi:“MI:0915”(physical association)	0.400
TICAM2	IRAK2	psi-mi:“MI:0915”(physical association)	0.400
IRAK2	RBBP4	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (79): TRAF6 (Affinity Capture-Western), TRAF6 (Affinity Capture-MS), SESTD1 (Affinity Capture-MS), TUBA4A (Affinity Capture-MS), N4BP2L2 (Affinity Capture-MS), IRAK2 (Affinity Capture-RNA), IRAK2 (Affinity Capture-Western), IRAK2 (Affinity Capture-Western), RNF152 (Affinity Capture-Western), SESTD1 (Affinity Capture-MS), TRAF6 (Affinity Capture-MS), SENP1 (Affinity Capture-MS), IRAK2 (Phenotypic Suppression), IRAK2 (Phenotypic Suppression), IRAK2 (Affinity Capture-Western)

ESM2 similar proteins: A0A140LI67, B5KFD7, D4A7V9, M0R4F8, O08774, O35827, O43187, O70167, O70173, O88866, O88900, O95398, O95704, P0C5Y8, Q0P5I2, Q13322, Q14449, Q4QQS0, Q5BIW4, Q5ICW4, Q5JV73, Q5PQS0, Q5R810, Q60760, Q68DX3, Q6IFT4, Q6IRN0, Q6P4K6, Q6REY9, Q6S5L8, Q6TXD4, Q7TSI1, Q80TQ5, Q80VA5, Q8BW88, Q8CFA1, Q8IWE5, Q8R1C9, Q8R2S1, Q8VCC8

Diamond homologs: A2XW02, B8BB68, C0LGD9, C0LGH3, C0LGI2, C0LGQ7, C0LGT1, C0LGT5, C0LGU1, C0LGW6, G5ECP4, O22476, O24585, O43187, O48837, O64483, O64793, O65468, O80623, P0C5E2, Q09092, Q0P5I2, Q0WRY5, Q1PDV6, Q2R560, Q39086, Q4QQS0, Q5R810, Q658G7, Q67X31, Q6I5Q6, Q6K4T4, Q6R2J8, Q6XAT2, Q6Z4U4, Q75J39, Q7F8Q9, Q7G768, Q7XR88, Q7XV05

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
IRAK2	“up-regulates activity”	IL1R1	binding
IRAK2	“down-regulates activity”	SRSF1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 29 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	7	56.1×	5e-09
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	5	50.1×	1e-06
MyD88 dependent cascade initiated on endosome	5	50.1×	1e-06
Toll Like Receptor 4 (TLR4) Cascade	6	41.5×	4e-07
Interleukin-1 signaling	6	39.2×	4e-07
Toll-like Receptor Cascades	5	32.7×	1e-05
Cytokine Signaling in Immune system	5	10.7×	8e-04
Innate Immune System	6	8.1×	7e-04

GO biological processes:

GO term	Partners	Fold	FDR
MyD88-dependent toll-like receptor signaling pathway	7	273.1×	6e-14
interleukin-1-mediated signaling pathway	6	200.6×	3e-11
toll-like receptor 4 signaling pathway	7	153.6×	3e-12
lipopolysaccharide-mediated signaling pathway	6	131.7×	4e-10
obsolete positive regulation of NF-kappaB transcription factor activity	5	42.8×	4e-06
positive regulation of canonical NF-kappaB signal transduction	9	27.2×	1e-09
cellular response to lipopolysaccharide	5	20.4×	9e-05
inflammatory response	5	7.8×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

131 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	0
Uncertain significance	92
Likely benign	10
Benign	1

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
3246834	NC_000003.11:g.(?10183598)(10206573_?)del	Pathogenic
997749	NC_000003.11:g.10182212_10212738del	Pathogenic
997751	NC_000003.11:g.10188005_10207561del	Pathogenic
997756	NC_000003.11:g.10184086_10218542del	Pathogenic
997763	NC_000003.11:g.10190033_10209132del	Pathogenic

SpliceAI

1987 predictions. Top by Δscore:

Variant	Effect	Δscore
3:10165044:GTTCG:G	donor_gain	1.0000
3:10177836:A:AG	acceptor_gain	1.0000
3:10177837:G:GT	acceptor_gain	1.0000
3:10177837:GC:G	acceptor_gain	1.0000
3:10177837:GCC:G	acceptor_gain	1.0000
3:10177837:GCCT:G	acceptor_gain	1.0000
3:10177837:GCCTC:G	acceptor_gain	1.0000
3:10178016:GAACT:G	donor_gain	1.0000
3:10178017:AACT:A	donor_gain	1.0000
3:10178017:AACTG:A	donor_loss	1.0000
3:10178018:ACT:A	donor_gain	1.0000
3:10178019:CT:C	donor_gain	1.0000
3:10178020:TG:T	donor_loss	1.0000
3:10178021:G:GC	donor_loss	1.0000
3:10178021:G:GG	donor_gain	1.0000
3:10178022:T:G	donor_loss	1.0000
3:10178023:GAGTA:G	donor_loss	1.0000
3:10178024:A:AC	donor_loss	1.0000
3:10178024:A:AG	donor_gain	1.0000
3:10178025:G:GG	donor_gain	1.0000
3:10200367:A:AG	acceptor_gain	1.0000
3:10200367:A:C	acceptor_loss	1.0000
3:10200367:AG:A	acceptor_gain	1.0000
3:10200367:AGG:A	acceptor_gain	1.0000
3:10200368:G:GG	acceptor_gain	1.0000
3:10200368:GG:G	acceptor_gain	1.0000
3:10200368:GGG:G	acceptor_gain	1.0000
3:10200368:GGGA:G	acceptor_gain	1.0000
3:10200368:GGGAA:G	acceptor_gain	1.0000
3:10200473:G:GT	donor_gain	1.0000

AlphaMissense

4091 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:10165046:T:C	F31S	0.995
3:10177964:T:C	L74P	0.995
3:10177922:T:C	L60P	0.994
3:10165038:G:C	W28C	0.993
3:10165038:G:T	W28C	0.993
3:10177933:T:A	W64R	0.993
3:10177933:T:C	W64R	0.993
3:10165036:T:A	W28R	0.991
3:10165036:T:C	W28R	0.991
3:10177913:C:A	T57K	0.991
3:10165045:T:C	F31L	0.990
3:10165047:C:A	F31L	0.990
3:10165047:C:G	F31L	0.990
3:10177838:C:A	A32D	0.990
3:10165015:G:C	D21H	0.989
3:10177871:G:C	R43P	0.989
3:10177991:T:C	L83P	0.989
3:10177868:T:C	L42P	0.988
3:10177906:A:C	S55R	0.988
3:10177908:C:A	S55R	0.988
3:10177908:C:G	S55R	0.988
3:10177973:T:C	L77P	0.988
3:10177925:T:C	L61P	0.987
3:10165046:T:G	F31C	0.985
3:10177913:C:G	T57R	0.985
3:10177976:T:C	L78P	0.984
3:10165001:T:C	L16P	0.983
3:10177943:G:C	R67P	0.983
3:10219788:A:C	S338R	0.983
3:10222636:C:A	S338R	0.983

dbSNP variants (sampled 300 via entrez): RS1000048316 (3:10188951 G>C), RS1000050180 (3:10227447 CAAAAA>C,CAAAA,CAAAAAA), RS1000055181 (3:10216563 A>C), RS1000116747 (3:10181490 C>G), RS1000156346 (3:10221100 GT>G,GTT,GTTTT), RS1000160259 (3:10224679 C>A), RS1000192658 (3:10182621 G>C), RS1000201566 (3:10209794 G>A), RS1000248896 (3:10165138 C>T), RS1000303239 (3:10176522 G>A), RS1000311090 (3:10226889 T>C), RS1000334498 (3:10214765 C>A,T), RS1000343513 (3:10239241 C>A), RS1000356837 (3:10199060 G>A), RS1000413057 (3:10169705 A>G)

Disease associations

OMIM: gene MIM:603304 | disease phenotypes: MIM:193300, MIM:263400

GenCC curated gene-disease

Disease	Classification	Inheritance
immune dysregulation, autoimmunity, and autoinflammation	Limited	Autosomal dominant

Mondo (3): von Hippel-Lindau disease (MONDO:0008667), Chuvash polycythemia (MONDO:0009892), immune dysregulation, autoimmunity, and autoinflammation (MONDO:0957790)

Orphanet (2): Chuvash erythrocytosis (Orphanet:238557), Von Hippel-Lindau disease (Orphanet:892)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST004600_184	Eosinophil percentage of white cells	6.000000e-11
GCST004606_104	Eosinophil count	1.000000e-10
GCST004617_78	Eosinophil percentage of granulocytes	3.000000e-10
GCST004624_35	Sum eosinophil basophil counts	6.000000e-09
GCST90002381_134	Eosinophil count	2.000000e-14
GCST90002381_135	Eosinophil count	4.000000e-09
GCST90002382_551	Eosinophil percentage of white cells	4.000000e-10
GCST90002382_99	Eosinophil percentage of white cells	9.000000e-17

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0005090	basophil count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D006623	von Hippel-Lindau Disease	C10.562.925; C14.907.077.925; C16.131.077.245.750; C16.320.184.750
C563918	Erythrocytosis, Familial, 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105759 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Interleukin-1 receptor-associated kinase (IRAK) family

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.77	Kd	170	nM	CHEMBL4064608

PubChem BioAssay actives

1 with measured affinity, of 1 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-(4-morpholin-4-ylcyclohexyl)-5-(oxan-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine	1471966: Binding affinity wild type human IRAK2 (T180 to T519) expressed in mammalian expression system	kd	0.1700	uM

CTD chemical–gene interactions

97 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	4
Benzo(a)pyrene	affects expression, affects methylation, increases methylation	3
Estradiol	affects cotreatment, increases expression	3
Lipopolysaccharides	affects cotreatment, increases expression, affects response to substance	3
Asbestos, Crocidolite	affects expression, increases expression	3
Particulate Matter	increases abundance, increases expression	3
zinc sulfide	increases expression, decreases expression, affects cotreatment	2
Acetaminophen	affects cotreatment, increases expression	2
Cadmium	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	increases expression	2
Cyclosporine	increases expression	2
Aflatoxin B1	increases expression, increases methylation	2
beta-Naphthoflavone	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
2-anisidine	affects expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
titanium dioxide	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	increases expression	1
zinc chromate	increases abundance, increases expression	1
cupric chloride	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
diallyl trisulfide	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4027010	Binding	Binding affinity wild type human IRAK2 (T180 to T519) expressed in mammalian expression system	Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88L265P Diffuse Large B-Cell Lymphoma. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SS85	HAP1 IRAK2 (-) 1	Cancer cell line	Male
CVCL_XP84	HAP1 IRAK2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

47 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT07405164	PHASE3	RECRUITING	Extension Study for Participants in Studies That Include Belzutifan (MK-6482-043/LITESPARK-043)
NCT00052013	PHASE2	COMPLETED	Treatment of Von Hippel-Lindau (VHL)-Related Hemangioblastoma With PTK787/ZK 222584
NCT00330564	PHASE2	TERMINATED	Evaluation of Sunitinib Malate in Patients With Von Hippel-Lindau Syndrome (VHL) Who Have VHL Lesions to Follow
NCT01168440	PHASE2	COMPLETED	Study of Sunitinib in Patients With Von Hippel-Lindau (VHL) Disease
NCT01266070	PHASE2	TERMINATED	TKI 258 in Von Hippel-Lindau Syndrome (VHL)
NCT01436227	PHASE2	COMPLETED	Pazopanib Hydrochloride in Treating Patients With Von Hippel-Lindau Syndrome
NCT01967537	PHASE2	COMPLETED	Evaluation of 68Gallium-DOTATATE PET/CT for Detecting Neuroendocrine Tumors
NCT03108066	PHASE2	COMPLETED	MK-3795 (PT2385) for the Treatment of Von Hippel-Lindau Disease-Associated Clear Cell Renal Cell Carcinoma (MK-3795-003)
NCT03401788	PHASE2	ACTIVE_NOT_RECRUITING	A Phase 2 Study of Belzutifan (PT2977, MK-6482) for the Treatment of Von Hippel Lindau (VHL) Disease-Associated Renal Cell Carcinoma (RCC) (MK-6482-004)
NCT04074135	PHASE2	RECRUITING	Natural History and Management of Von Hippel-Lindau (VHL) Associated Pancreatic Neuroendocrine Tumors
NCT04924075	PHASE2	RECRUITING	Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL) Disease-Associated Tumors, Advanced Gastrointestinal Stromal Tumor (wt GIST), or Solid Tumors With HIF-2α Related Genetic Alterations (MK-6482-015)
NCT05810246	PHASE2	UNKNOWN	68Ga-NY104 PET/CT in Von Hippel-Lindau Disease
NCT07167329	PHASE2	RECRUITING	Real-World Effectiveness and Pharmacogenetics of Belzutifan in VHL Syndrome: The BELIEVE-VHL Trial
NCT00089765	PHASE1	COMPLETED	Ranibizumab Injections to Treat Retinal Tumors in Patients With Von Hippel-Lindau Syndrome
NCT02108002	PHASE1	COMPLETED	Effect of Vorinostat on Nervous System Hemangioblastomas in Von Hippel-Lindau Disease (Missense Mutation Only)
NCT05843305	PHASE1	UNKNOWN	A Study of BPI-452080 in Subjects With Solid Tumors
NCT00470977	PHASE1/PHASE2	COMPLETED	Treatment of Exudative and Vasogenic Chorioretinal Diseases Including Variants of AMD and Other CNV Related Maculopathy
NCT00673816	PHASE1/PHASE2	TERMINATED	Sunitinib Malate to Treat Advanced Eye Disease in Patients With Von Hippel-Lindau Syndrome
NCT02859441	PHASE1/PHASE2	COMPLETED	A Phase I/II Trial for Intravitreous Treatment of Severe Ocular Von Hippel-Lindau Disease Using a Combination of the PDGF Antagonist E10030 and the VEGF Antagonist Ranibizumab
NCT01015300	EARLY_PHASE1	TERMINATED	Bevacizumab (Avastin) in Unresectable/Recurrent Hemangioblastoma From Von-Hippel-Lindau Disease
NCT03001349	EARLY_PHASE1	TERMINATED	68Ga-DOTA-TOC PET/CT in Imaging Participants With Neuroendocrine Tumors
NCT00001803	Not specified	TERMINATED	Von Hippel-Lindau Disease Genetic Epidemiology Study
NCT00062166	Not specified	COMPLETED	Natural History and Management of Pancreatic Lesions in Von Hippel-Lindau Disease
NCT00075348	Not specified	COMPLETED	Genetic Study to Identify Gene Mutations in Participants Previously Enrolled in Clinical Trial NCI-99-C-0053 Who Have Von Hippel-Lindau Syndrome or Are at Risk for Von Hippel-Lindau Syndrome
NCT00102544	Not specified	ENROLLING_BY_INVITATION	Use of Tracking Devices to Locate Abnormalities During Invasive Procedures
NCT00970970	Not specified	COMPLETED	Visualizing Vascular Endothelial Growth Factor (VEGF) Producing Lesions in Von Hippel-Lindau Disease
NCT01496625	Not specified	RECRUITING	National Eye Institute Biorepository for Retinal Diseases
NCT02420067	Not specified	RECRUITING	Screening for Endolymphatic Sac Tumours (ELSTs) in Von Hippel-Lindau (vHL) Patients
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03749980	Not specified	RECRUITING	MyVHL: Patient Natural History Study
NCT03979833	Not specified	UNKNOWN	Drivers of Hypoxia-induced Angiogenesis in Tumor Development
NCT04458935	Not specified	ACTIVE_NOT_RECRUITING	Retrospective Case Series of Trans-scleral Cryotherapy for Retinal Hemangioblastoma
NCT05424016	Not specified	RECRUITING	Propranolol and Von Hippel-Lindau Disease
NCT05534854	Not specified	UNKNOWN	Frequency, Clinical Phenotype and Genetic Analysis of Heritable Kidney Cancer Syndromes
NCT05737602	Not specified	ENROLLING_BY_INVITATION	Promoting Stress Management and Resilience Among Individuals With Von Hippel- Lindau Disease
NCT05941637	Not specified	NO_LONGER_AVAILABLE	An Expanded Access Program to Axitinib is Available for Patients With Advanced Forms of Kidney Cancer (Ductal; Papillary; Chromophobic; Oncocytic) With Mutations in VHL, PBRM1 / BAP1, SETD2, VEGF)
NCT05955014	Not specified	RECRUITING	Data Collection Protocol for Patients With Von Hippel Lindau Disease
NCT06194669	Not specified	RECRUITING	Mechanisms of Somatic Mutation and Tumor Initiation in Pre-malignant Kidney Tubule Cells
NCT06195150	Not specified	ACTIVE_NOT_RECRUITING	Overtaking Intra and Inter Tumoral Heterogeneity In Von Hippel-Lindau Related Renal Cancer
NCT06391879	Not specified	UNKNOWN	Establishment of a Multidimensional Prediction Model for the Natural Course of VHL Disease-related Renal Cell Carcinoma