Role of Peroxisome Proliferator-Activated Receptor Gamma and Its Ligands in the Treatment of Hematological Malignancies

Figure 2

Reversible posttranslational modifications of PPAR. The superfamily of nuclear hormone receptors possesses conserved structural and functional domains including PPAR. The A/B domain is the hypervariable region containing the putative activation function-1 (AF-1) domain. Human PPAR2 contains a 28 amino acid amino terminal region that arises from differential promoter use and splicing (see Figure 1). The primary structure of the C-domain is the most conserved and contains the DNA binding domain (DBD). The D-domain (Hinge) allows for conformational change following ligand binding to promote coregulator (coactivator or corepressor) docking; binding of ERK5 to the hinge helix 1 region potentiates ligand-dependent PPAR1 activity. The E/F region contains the ligand binding domain (LBD) of PPAR and the activation function-2 (AF-2) domain that participates in ligand-dependent degradation mediated by the ubiquitin-proteasome pathway. PPAR heterodimerizes with its binding partners, RXR family members, through the E/F domain as well. Reversible posttranslational modifications of PPAR regulate its activation. In addition to proteasome-mediated degradation, PPAR can be phosphorylated by MAP kinases at S^84/112 (position of serine in PPAR1/PPAR2) or SUMO-1 modification. Two SUMOylation consensus motifs have been described. Whereas SUMOylation at a conserved ψKXEXXSP (where ψ is a hydrophobic amino acid and X can be any residue) is linked to serine phosphorylation events, SUMOylation at ψKXE/D motifs are not generally linked to MAPK phosphorylation. The lysine residues of the three SUMOylation motifs identified on PPAR1/2 are depicted in red. The serine residue phosphorylated by MAPKs is depicted in yellow. Both serine phosphorylation and SUMOylation negatively regulate PPAR activity.