A G protein-coupled receptor and the intracellular synthase of its agonist functionally cooperate.
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.
Service de Rhumatologie, Département de Médecine, 2 Programme d'Immunologie, Département de Pédiatrie, Faculté de Médecine et des Sciences de la Santé, and 3 Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4.
Chantal
C
Binda
Samuel
S
Génier
Andréane
A
Cartier
Jean-François
JF
Larrivée
Jana
J
Stankova
Jason C
JC
Young
Jean-Luc
JL
Parent
D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000201:enzymology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D042541:Intracellular Space / Q000201:enzymology*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D054834:Lipocalins / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D050505:Mutant Proteins / Q000378:metabolism; D021381:Protein Transport; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000819:agonists* / Q000378:metabolism*; D021601:trans-Golgi Network / Q000378:metabolism
D018841:HSP90 Heat-Shock Proteins; D054834:Lipocalins; D050505:Mutant Proteins; D043562:Receptors, G-Protein-Coupled; D011982:Receptors, Prostaglandin; C501562:prostanoid D receptor 1, human; D048049:Extracellular Signal-Regulated MAP Kinases; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase