MEK1 Inhibits Cardiac PPAR alpha Activity by Direct Interaction and Prevents Its Nuclear Localization

Background: The response of the postnatal heart to growth and stress stimuli includes activation of a network of signal transduction cascades, including the stress activated protein kinases such as p38 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase (JNK) and the extracellular signal-regulated kinase (ERK1/2) pathways. In response to increased workload, the mitogen-activated protein kinase kinase (MAPKK) MEK1 has been shown to be active. Studies embarking on mitogen-activated protein kinase (MAPK) signaling cascades in the heart have indicated peroxisome-proliferators activated-receptors (PPARs) as downstream effectors that can be regulated by this signaling cascade. Despite the importance of PPAR alpha in controlling cardiac metabolism, little is known about the relationship between MAPK signaling and cardiac PPAR alpha signaling. Methodology/Principal Finding: Using co-immunoprecipitation and immunofluorescence approaches we show a complex formation of PPAR alpha with MEK1 and not with ERK1/2. Binding of PPAR alpha to MEK1 is mediated via a LXXLL motif and results in translocation from the nucleus towards the cytoplasm, hereby disabling the transcriptional activity of PPAR alpha. Mice subjected to voluntary running-wheel exercise showed increased cardiac MEK1 activation and complex formation with PPAR alpha, subsequently resulting in reduced PPAR alpha activity. Inhibition of MEK1, using U0126, blunted this effect. Conclusion: Here we show that activation of the MEK1-ERK1/2 pathway leads to specific inhibition of PPAR alpha transcriptional activity. Furthermore we show that this inhibitory effect is mediated by MEK1, and not by its downstream effector kinase ERK1/2, through a mechanism involving direct binding to PPAR alpha and subsequent stimulation of PPAR alpha export from the nucleus.