IRAK

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 :

• IUPHAR Receptor Code

• BJP Guide

DYRK Gene Data