A G protein–coupled receptor and the intracellular synthase of its agonist functionally cooperate
| Autor: | Jean-Luc Parent, Jason C. Young, Andréane Cartier, Jean-François Larrivée, Jana Stankova, Samuel Génier, Chantal Binda |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Agonist
Intracrine Physiology medicine.drug_class MAP Kinase Signaling System Receptors Prostaglandin Intracellular Space Biology Article Receptors G-Protein-Coupled 03 medical and health sciences Enzyme activator 0302 clinical medicine medicine Humans HSP90 Heat-Shock Proteins Autocrine signalling Receptor Extracellular Signal-Regulated MAP Kinases Research Articles 030304 developmental biology G protein-coupled receptor Cell Nucleus 0303 health sciences integumentary system HEK 293 cells Cell Membrane Cell Biology Lipocalins Cell biology Enzyme Activation Intramolecular Oxidoreductases Protein Transport HEK293 Cells lipids (amino acids peptides and proteins) Mutant Proteins Signal transduction 030217 neurology & neurosurgery HeLa Cells trans-Golgi Network |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| Popis: | The GPCR DP1 promotes the activity of L-PGDS, the enzyme that produces the DP1 agonist PGD2, while at the same time L-PGDS promotes the export and activity of DP1 in response to PGD2. 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. |
| Databáze: | OpenAIRE |
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