IRAK

The IRAKs (Interleukin-1 receptor-associated kinases) are serine-threonine kinases, EC 2.7.11.1, that are essential regulators of IL-1R and TLR-mediated signaling. Four IRAK isoforms have been identified to date, IRAK1, IRAK2, IRAK3 (IRAK-M) and IRAK4.

Products
Background
Gene Data

IRAK Inhibitors

Cat. No. Product Name / Activity
5430 AS 2444697
Potent and selective IRAK4 inhibitor
7546 C28
Potent IRAK4 inhibitor; also inhibits LMTK3
5665 IRAK1/4 Inhibitor I
IRAK4 and IRAK1 inhibitor
6373 PF 06650833
Potent and selective IRAK4 inhibitor

Degraders

Cat. No. Product Name / Activity
7983 IRAK3 Degrader 23
IRAK3 Degrader (PROTAC®)
8029 JNJ 1013
Interleukin 1 Receptor Associated Kinase 1 (IRAK1) PROTAC®

The IRAK (Interleukin-1 receptor-associated kinases) family of serine-threonine kinases, EC 2.7.11.1, consists of four members, IRAK1, IRAK2, IRAK3 (IRAK-M) and IRAK4. IRAK1/2 have ubiquitous tissue expression, whereas IRAK3 is expressed by monocytes and macrophages, and IRAK4 is predominantly localized to the liver and kidney. Despite being labelled as serine-threonine kinases, IRAK2/3 have inactive kinase domains.

IRAKs are key regulators of interleukin-1 receptor (IL-1R) and Toll-like receptor (TLR)-mediated signaling, and are thus important in physiological processes such as inflammation, apoptosis and cellular differentiation. Upon ligand binding to IL-1R or TLR, adapter proteins are recruited to the receptor, which results in the formation of the Myddosome, a complex created by the association of IRAK2 and IRAK4 with the adapter protein Myd88. Myddosome formation leads to the recruitment of IRAK1 to the complex, where it binds Myd88 before being phosphorylated by IRAK4. Phosphorylated IRAK1 dissociates from the Myddosome and binds to the ubiquitin E3 ligase TRAF6, which in turn activates IKK/NF-κB, JNK and p38 signaling and transcription. IRAK1 is then degraded by the ubiquitin/proteasome system to regulate IL-1R/TLR signaling. In monocytes and macrophages IL-1R and TLR signaling is also regulated by IRAK3, which inhibits signaling by preventing the dissociation of IRAK1 from the Myddosome and inhibiting the formation of the IRAK1-TRAF6 complex.

The IRAKs have been implicated in the pathogenesis of atherosclerosis, with IRAK1 being shown to associate with STAT3 in the nucleus enhancing IL-10 expression, a hallmark of atherosclerosis. IRAKs are a potential target for cancer researchers, as overexpression and activation of IRAKs have been associated with acute myeloid leukemia and melanoma. IRAK4 inhibitors have also been proposed as treatment for chronic inflammatory diseases, due to their role in mediating NF-κB-induced expression of proinflammatory cytokines.

External sources of pharmacological information for IRAK :

DYRK Gene Data

Gene Species Gene Symbol Gene Accession No. Protein Accession No.
IRAK1 Human IRAK1 XM_005274668 P51617
Mouse Irak1 NM_001177973 Q62406
Rat Irak1 NM_001127555 NP_001121027
IRAK2 Human IRAK2 NM_001570 O43187
Mouse Irak2 NM_172161 Q8CFA1
Rat Irak2 NM_001025422 NP_001020593
IRAK3 (IRAK-M) Human IRAK3 NM_001142523 Q9Y616
Mouse Irak3 NM_028679 Q8K4B2
Rat Irak3 NM_001108101 NP_001101571
IRAK4 Human IRAK4 XM_011538431 Q9NWZ3
Mouse Irak4 NM_029926 Q8R4K2
Rat Irak4 NM_001106791 NP_001100261