The serine/threonine phosphatase PPM1B (PP2Cβ) selectively modulates PPARγ activity

Reversible phosphorylation is a widespread molecular mechanism to regulate the function of cellular proteins, including transcription factors. Phosphorylation of the nuclear receptor PPAR gamma (peroxisome-proliferator-activated receptor gamma) at two conserved serine residue (Ser(112) and Ser(273)) results in an altered transcriptional activity of this transcription factor. So far, only a very limited number of cellular enzymatic activities has been described which can dephosphorylate nuclear receptors. In the present study we used immunoprecipitation assays coupled to tandem MS analysis to identify novel PPAR gamma-regulating proteins. We identified the serine/threonine phosphatase PPM1B [PP (protein phosphatase), Mg2+/Mn2+ dependent, 1B; also known as PP2C beta] as a novel PPAR gamma-interacting protein. Endogenous PPM1B protein is localized in the nucleus of mature 3T3-L1 adipocytes where it can bind to PPAR gamma. Furthermore we show that PPM1B can directly dephosphorylate PPAR gamma, both in intact cells and in vitro. In addition PPM1B increases PPAR gamma-mediated transcription via dephosphorylation of Ser(112). Finally, we show that knockdown of PPM1B in 3T3-L1 adipocytes blunts the expression of some PPAR gamma target genes while leaving others unaltered. These findings qualify the phosphatase PPM1B as a novel selective modulator of PPAR gamma activity.