Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

IRAK4 (Q9NWZ3) - Overview - Molecular Target Synopsis

Protein


IRAK4, Interleukin-1 receptor-associated kinase 4
Enzyme Classification 2.7.11.1
UniProt Q9NWZ3

Also Known as IRAK4_HUMAN, IRAK4

Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways (PubMed:17878374). Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections. Associates with MYD88 and IRAK2 to form a ternary complex called the Myddosome. Once phosphorylated, IRAK4 dissociates from the receptor complex and then associates with the TNF receptor-associated factor 6 (TRAF6), IRAK1, and PELI1; this intermediate complex is required for subsequent NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. Interacts with IL1RL1.

6EG9
IRAK4 IN COMPLEX WITH PONATINIB
RCSB/PDB
Inspect Structure
See all 3D Structures for IRAK4

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: IRAK4 is active in the following subcellular-locations: cytoplasm.
GO terms: IRAK4 is active in the following subcellular-locations: cytoplasm, cytosol, endosome membrane, extracellular space, nucleus, plasma membrane.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project IRAK4 has gain in 7 cell-lines, loss in 4 cell-lines and no signal in 994 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: K_562, MCF7, CCRF_CEM

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: DMS 53, NCI-H1930, TK

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: NHLF, SK-N-SH, AG445

(see details)

RNA Interference


IRAK4 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: PCI30, JHESOAD1. (see details)

3D Structures


For IRAK4 there are:
43 structures (129 chains) solved
40 are solved in complex with at least one small molecule ligand
1 are solved with an approved drug

IRAK4 is solved in complex with the approved drug(s):

0LI/PONATINIB (6EG9_A, 6EG9_B).

(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


IRAK4 has been screened with 2330 compounds (3066 bioactivities), 1062 compounds have bioactivities that show binding affinity of <= 500nM (1204 bioactivities). (see details)