IκB kinase regulation of the TPL‐2/ERK MAPK pathway

Summary: Nuclear factor‐κB (NF‐κB) and mitogen‐activated protein kinase (MAPK) activation play central roles in the induction of gene expression in innate immune cells following pathogen recognition. TPL‐2 (tumor progression locus 2) is the MAP 3‐kinase component of an ERK‐1/2 (extracellular signal‐regulated kinase 1/2) MAPK pathway activated by Toll‐like receptor and tumor necrosis factor receptor family stimulation. In this review, we discuss results obtained from our laboratory and others that show that TPL‐2 signaling function is directly controlled by the inhibitor of NF‐κB (IκB) kinase (IKK) complex. Significantly, this means that IKK controls both NF‐κB and ERK activation. TPL‐2 is stoichiometrically complexed with the NF‐κB inhibitory protein, NF‐κB1 p105, and the ubiquitin‐binding protein ABIN‐2, both of which are required to maintain TPL‐2 protein stability. Binding to p105 also prevents TPL‐2 from phosphorylating MEK (MAPK/ERK kinase), its downstream target. Agonist stimulation releases TPL‐2 from p105‐inhibition by IKK‐mediated phosphorylation of p105, which triggers degradation of p105 by the proteasome. This facilitates TPL‐2 phosphorylation of MEK, in addition to liberating p105‐associated Rel subunits to translocate into the nucleus. We also examine evidence that TPL‐2 is critical for the induction of inflammation and may play a role in development and/or progression of certain types of cancer. Finally, we consider the potential of TPL‐2 as an anti‐inflammatory drug target for treatment of certain types of inflammatory disease and cancer.