Interdomain communication regulating ligand binding by PPAR-γ

Abstract

Binding to receptors in the cell nucleus is crucial for the action of lipophilic hormones and ligands. PPAR-gamma (for peroxisome proliferator-activated receptor) is a nuclear hormone receptor that mediates adipocyte differentiation and modulates insulin sensitivity, cell proliferation and inflammatory processes. PPAR-gamma ligands have been implicated in the development of atherogenic foam cells and as potential cancer treatments. Transcriptional activity of PPAR-gamma is induced by binding diverse ligands, including natural fatty acid derivatives, antidiabetic thiazolidinediones, and non-steroidal anti-inflammatory drugs. Ligand binding by PPAR-gamma, as well as by the entire nuclear-receptor superfamily, is an independent property of the carboxy-terminal ligand-binding domain (LBD) of the receptor. Here we show that ligand binding by PPAR-gamma is regulated by intramolecular communication between its amino-terminal A/B domain and its carboxy-terminal LBD. Modification of the A/B domain, for example by physiological phosphorylation by MAP kinase, reduces ligand-binding affinity, thus negatively regulating the transcriptional and biological functions of PPAR-gamma. The ability of the A/B domain to regulate ligand binding has important implications for the evaluation and mechanism of action of potentially therapeutic ligands that bind PPAR-gamma and that are likely to extend to other members of the nuclear-receptor superfamily.

p38 Mitogen-activated Protein Kinase Activates Peroxisome Proliferator-activated Receptor α

“…We have shown that PPAR␣ activity is diminished by a post-transcriptional mechanism mediated by ERK-MAPK, confirming that signal transduction cascades linked to G-protein-coupled receptors can affect the activity of PPAR␣. Similarly, the related nuclear receptor, PPAR␥, is deactivated by ERK-mediated phosphorylation through a mechanism that reduces affinity for ligand (33)(34)(35)(36). Given these previous findings, the results shown here indicating that phosphorylation of PPAR␣ by p38 MAPK leads to activation of PPAR␣ function was surprising.…”

“…p38 Activates PPAR␣A diverse array of molecular consequences have been attributed to nuclear receptor phosphorylation, including increased or decreased ligand-dependent and ligand-independent activation (reviewed in Ref. 37), enhanced recruitment of cofactors (38 -40), reduced affinity for ligand (33), increased or decreased capacity for DNA binding (reviewed in Ref. 37), enhanced or inhibited heterodimerization (41,42), and susceptibility to proteosomal degradation (43).…”

Genetic variations in peroxisome proliferator-activated receptor γ expression affect blood pressure

“…Alternatively, moderate overexpression of PPAR␥ by itself may not be sufficient to change the phenotypic outcome. This possibility also is suggested by studies in cultured cells showing that overexpression of WT PPAR␥ has only a weak adipogenic effect in the absence of ligands (18,19).…”

The Cyclopentenone-Type Prostaglandin 15-Deoxy-Δ12,14-Prostaglandin J2 Inhibits CD95 Ligand Gene Expression in T Lymphocytes: Interference with Promoter Activation Via Peroxisome Proliferator-Activated Receptor-γ-Independent Mechanisms

“…In addition, mitogen-activated protein kinase activation can strongly inhibit PPAR␥ activity, through direct phosphorylation of its amino-terminal A/B domain and a consequent negative intramolecular communication with the carboxylterminal ligand binding domain (Ref. 70 and references cited therein). These observations may then raise important questions on the specific role of PPAR␥ as immunoregulator and should lead to reconsidering its action in the context of concomitant pathways g of FasL-486Luc reporter and 4 g of pEQ176 CMV-␤-Gal expression vector as described in Materials and Methods.…”