A G protein-coupled receptor and the intracellular synthase of its agonist functionally cooperate

• Published in: The Journal of cell biology Vol. 204; no. 3; pp. 377 - 393
• Main Authors: Binda, Chantal, Génier, Samuel, Cartier, Andréane, Larrivée, Jean-François, Stankova, Jana, Young, Jason C, Parent, Jean-Luc
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 03.02.2014; The Rockefeller University Press
• Subjects: Cell Membrane - metabolism; Cell Nucleus - enzymology; Cells; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases - metabolism; HEK293 Cells; HeLa Cells; HSP90 Heat-Shock Proteins - metabolism; Humans; Intracellular Space - enzymology; Intramolecular Oxidoreductases - metabolism; Lipocalins - metabolism; MAP Kinase Signaling System; Mutant Proteins - metabolism; Protein Transport; Proteins; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - metabolism; Receptors, Prostaglandin - agonists; Receptors, Prostaglandin - metabolism; Signal transduction; trans-Golgi Network - metabolism
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201304015

Export of newly synthesized G protein-coupled receptors (GPCRs) remains poorly characterized. We show in this paper that lipocalin-type prostaglandin D2 (PGD2) synthase (L-PGDS) interacts intracellularly with the GPCR DP1 in an agonist-independent manner. L-PGDS promotes cell surface expression of DP1, but not of other GPCRs, in HEK293 and HeLa cells, independent of L-PGDS enzyme activity. In addition, formation of a DP1-Hsp90 complex necessary for DP1 export to the cell surface is dependent on the interaction between L-PGDS and the C-terminal MEEVD residues of Hsp90. Surprisingly, PGD2 synthesis by L-PGDS is promoted by coexpression of DP1, suggesting a possible intracrine/autocrine signaling mechanism. In this regard, L-PGDS increases the formation of a DP1-ERK1/2 complex and increases DP1-mediated ERK1/2 signaling. Our findings define a novel cooperative mechanism in which a GPCR (DP1) promotes the activity of the enzyme (L-PGDS) that produces its agonist (PGD2) and in which this enzyme in turn acts as a cofactor (of Hsp90) to promote export and agonist-dependent activity of the receptor.