MAP3K8/COT

null MAP3K8, commonly called TPL2 or COT, is a MAP3K that transmits signals from Toll-like receptors, IL-1R, TNF receptors, and certain GPCRs to the MEK1/2-ERK1/2 axis. In unstimulated cells it is kept inactive within a complex containing ABIN2 and NF-kappaB1 p100; receptor engagement recruits TRAF6, p100 is degraded, and active TPL2 is released. This mechanism makes TPL2 a critical amplifier of ERK-driven production of TNF-alpha and other cytokines in macrophages and other immune cells. TPL2-deficient mice display impaired inflammatory responses, and small-molecule TPL2 inhibitors have been pursued for rheumatoid arthritis, inflammatory bowel disease, and other immune-mediated conditions.