Regulation of peroxisome proliferator-activated receptor gamma activity by mitogen-activated protein kinase.
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 PPARgamma, peroxisomal proliferator-activated receptor gamma. To determine the relationship between PPARgamma activation and growth factor stimulation in adipogenesis, we investigated the effects of PDGF and EGF on PPARgamma1 activity. PDGF treatment decreased ligand-activated PPARgamma1 transcriptional activity in a transient reporter assay. In vivo [32P]orthophosphate labeling experiments demonstrated that PPARgamma1 is a phosphoprotein that undergoes EGF-stimulated MEK/mitogen-activated protein (MAP) kinase-dependent phosphorylation. Purified PPARgamma1 protein was phosphorylated in vitro by recombinant activated MAP kinase. Examination of the PPARgamma1 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 PPARgamma1 by MAP kinase contributes to the reduction of PPARgamma1 transcriptional activity by growth factor treatment.
Camp
H S
HS
Department of Cell Biology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Tafuri
S R
SR
D016475:3T3 Cells; D000409:Alanine; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D003001:Cloning, Molecular; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D008830:Microbodies / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D015345:Oligonucleotide Probes; D017354:Point Mutation; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012694:Serine; D014157:Transcription Factors / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D017931:DNA Primers; D004268:DNA-Binding Proteins; D015345:Oligonucleotide Probes; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D014157:Transcription Factors; D012694:Serine; D004815:Epidermal Growth Factor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000409:Alanine