MYD88 signaling. After stimulation of the TLRs by pathogen-associated molecular pattern, MYD88 is recruited to the activated receptor complex as a homodimer via its TIR domain and forms complexes with IRAK1 and IRAK4. IRAK1 is then phosphorylated by IRAK4, separates from MYD88, and interacts with the tumor necrosis factor (TNF) R-associated factor 6 (TRAF6) E3 ubiquitin ligase. Active TRAF6 catalyzes polyubiquitination of a complex comprising transforming growth factor β (TGF-β)-activated kinase 1 (TAK1) and TAK1-binding proteins (TAB1, TAB2, and TAB3), which in turns phosphorylate both the inhibitor of kappaB kinase beta (IKBKB) and the mitogen-activated protein kinase 6 (MAP2K6). Active IKBKB phosphorylates IκBα, leading to its degradation by the proteasome and the release of NF-κB. On the other side, MAP2K6 activates MAPK including c-Jun N-terminal kinase 1/2 (JNK1/2), p38 and extracellular signal-regulated kinase 1/2 (ERK1/2) to stimulate AP-1 activity. Active NF-κB and AP-1 translocate into the nucleus to turn on the expression of their target genes. Molecular targets of ibrutinib and idelalisib are highlighted.