Interleukin-1 receptor-associated kinases (IRAKs) are a unique family of death domain containing protein kinases that play a key role in initiating innate immune response against foreign pathogens. They are involved in Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways. IRAK1 is the first member of this kinase family. Upon ligand binding to TLR/IL-1R, IRAK1 is recruited by MYD88 to the receptor-signaling complex, the association leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. Hyper-phosphorylated IRAK1 then disengages from the receptor complex, and forms a cytosolic IRAK1-TRAF6 complex. TRAF6 then interacts with TAK and TAB, resulting in eventual activation of the NF-κB and MAPK pathways. Phosphorylated IRAK1 also undergoes ubiquitin-mediated degradation or sumoylation, which results in nuclear translocation and transcriptional activation of inflammatory target genes. (PMID: 17890055; 12620219)