Figure 6. Diagram illustrating the TLR4–TPL-2–ERK–MAP kinase cascade.

Stimulation of TLR4 by LPS activates the IKK complex which phosphorylates Ser⁹²⁷ and Ser⁹³² in the p105 PEST region. This triggers p105 ubiquitination and subsequent degradation, liberating TPL-2. p105-free TPL-2 then phosphorylates and activates MEK, which in turn phosphorylates and activates ERK. In unstimulated cells, TPL-2 and p105 form a ternary complex with ABIN-2. ABIN-2 is released from p105 after LPS stimulation, but its function is currently unknown. IKK-induced p105 proteolysis also liberates associated p50 (and other Rel subunits) to translocate into the nucleus and modulate target gene expression.