Regulation of peroxisome proliferator-activated receptor γ activity by mitogen-activated protein kinase

Abstract

Adipocyte differentiation is regulated both positively and negatively by external growth factors such as insulin, platelet-derived growth factor (PDGF), and epidermal growth factor (EGF). A key component of the adipocyte differentiation process is PPARγ, peroxisomal proliferator-activated receptor γ. To determine the relationship between PPARγ activation and growth factor stimulation in adipogenesis, we investigated the effects of PDGF and EGF on PPARγ1 activity. PDGF treatment decreased ligand-activated PPARγ1 transcriptional activity in a transient reporter assay. In vivo [32P]orthophosphate labeling experiments demonstrated that PPARγ1 is a phosphoprotein that undergoes EGF-stimulated MEK/mitogen-activated protein (MAP) kinase-dependent phosphorylation. Purified PPARγ1 protein was phosphorylated in vitro by recombinant activated MAP kinase. Examination of the PPARγ1 sequence revealed a single MAP kinase consensus recognition site at Ser82. Mutation of Ser82 to Ala inhibited both in vitro and in vivo phosphorylation and growth factor-mediated transcriptional repression. Therefore, phosphorylation of PPARγ1 by MAP kinase contributes to the reduction of PPARγ1 transcriptional activity by growth factor treatment.