Mammalian TPL-2 kinase (MAP3K8) mediates Toll-like receptor activation of ERK1/2 and p38α MAP kinases and is critical for regulating immune responses to pathogens. TPL-2 also has an important adaptor function, maintaining stability of associated ABIN-2 ubiquitin-binding protein. Consequently, phenotypes detected in Map3k8 mice can be caused by lack of TPL-2, ABIN-2, or both proteins. Recent studies show that increased inflammation of Map3k8 mice in allergic airway inflammation and colitis results from reduced ABIN-2 signaling, rather than blocked TPL-2 signaling. However, Map3k8 mice have been employed extensively to evaluate the potential of TPL-2 as an anti-inflammatory drug target. We posit that Map3k8 mice, expressing catalytically inactive TPL-2 and physiologic ABIN-2, should be used to evaluate the potential effects of TPL-2 inhibitors in disease.
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