Figure 2

The mitogen-activated protein kinase (MAPK) signaling cascade. The MAPKs form an interacting cascade of signaling enzymes that orchestrate responses to extracellular stress, such as inflammation, infection, and tissue damage. The three main families (ERK, JNK, and p38) have overlapping functions but tend to regulate cell growth, matrix turnover, and cytokine production, respectively. The cascade generally has three levels (shown on the left), including the MAP kinase kinase kinases (MAP3Ks), which activate the MAP kinase kinases (MAPKKs or MKKs), which, in turn, activate the MAPKs. Drug development efforts thus far have focused on p38 and MEK1/2 for rheumatic diseases. JNK inhibitors are effective in preclinical models and are also being developed for cancer. ATF2, activating transcription factor-2; ERK, extracellular signal related kinases; JNK, c-Jun N-terminal kinase; MAPKAPK, mitogen-activated protein kinase-activated protein kinase; MEK1/2, mitogen-activated protein kinase kinases.