MAPK kinases as nucleo-cytoplasmic shuttles for PPARγ

Peroxisome proliferator - activated receptor - gamma ( PPAR.) is a ligand - activated transcription factor of the nuclear receptor superfamily that regulates genes involved in differentiation, metabolism and immunity. PPAR. - ligands are used for therapy of type 2 diabetes and hold the promise for treatment of inflammation and cancer. As a central regulatory component, PPAR. activity is well regulated during various cellular processes, and indeed mitogenic stimulation often suppresses PPAR gamma's s genomic activity. This downregulation is mediated largely by the extracellular signal - regulated kinase 1/ 2 ( ERKs)/mitogen - activated protein kinases ( MAPKs) signaling cascade, which attenuates PPAR gamma' s transactivation function either by an inhibitory phosphorylation or by modulating PPAR gamma' s nucleo - cytoplasmic compartmentalization. The latter is achieved by the mitogen - induced nuclear export of PPAR gamma through its direct interaction with the ERK cascade component MAPK/ ERK - kinases 1/ 2 ( MEKs). Upon mitogenic stimulation, MEKs translocate into the nucleus, but are rapidly exported from this location by their N - terminal nuclear export signal ( NES), in a process that is accompanied by the export of their inter acting nuclear PPAR gamma molecules. Interestingly, it was recently demonstrated that PPAR gamma has cytoplasmatic activities, and therefore, the MEK - dependent shuttle may also represent a mechanism for control of the extra - nuclear/ nongenomic actions of PPAR gamma. Because of the similarity within nuclear receptor docking motifs, it is possible that the same mechanism may control the nuclear and cytoplasmatic activity of other receptors. The changes in the subcellular localization of PPAR. may also represent novel targets for selective interfer ence in patients with chronic inflammatory or proliferation - related diseases.