Biasing the prostaglandin F2α receptor responses toward EGFR-dependent transactivation of MAPK.
The G protein-coupled prostaglandin F2α (PGF2α) receptor [F prostanoid (FP) receptor] has been implicated in many physiological events including cardiovascular, respiratory, immune, reproductive, and endocrine responses. Binding of PGF2α to FP receptor elicits inositol production and protein kinase C-dependent MAPK activation through Gα(q) coupling. Here we report that AL-8810, previously characterized as an orthosteric antagonist of PGF2α-dependent, Gα(q)-mediated signaling, potently activates ERK1/2 in a protein kinase C-independent manner. Rather, AL-8810 promoted ERK1/2 activation via an epidermal growth factor receptor transactivation mechanism in both human embryonic kidney 293 cells and in the MG-63 osteoblast-like cells, which express endogenous FP receptors. Neither AL-8810- nor PGF2α-mediated stimulation of FP receptor promoted association with β-arrestins, suggesting that MAPK activation induced by these ligands is independent of β-arrestin's signaling scaffold functions. Interestingly, the spatiotemporal activation of ERK1/2 promoted by AL-8810 and PGF2α showed almost completely opposite responses in the nucleus and the cytosol. Finally, using [(3)H]thymidine incorporation, we noted differential regulation of PGF2α- and AL-8810-induced cell proliferation in MG-63 cells. This study reveals, for the first time, the signaling biased nature of FP receptor orthosteric ligands toward MAPK signaling. Our findings on the specific patterns of ERK1/2 activation promoted by FP receptor ligands may help dissect the distinct roles of MAPK in FP receptor-dependent physiological responses.
Polypeptide Hormone Laboratory, Division of Endocrinology, Department of Medicine, McGill University Health Centre Research Institute, McGill University, Montreal, QC, Canada H3A 2B2.
Eugénie
E
Goupil
Veronica
V
Wisehart
Etienne
E
Khoury
Brandon
B
Zimmerman
Sahar
S
Jaffal
Terence E
TE
Hébert
Stéphane A
SA
Laporte
D019390:Arrestins / Q000378:metabolism; D049109:Cell Proliferation; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007294:Inositol / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D000071557:beta-Arrestins
D019390:Arrestins; D011982:Receptors, Prostaglandin; D000071557:beta-Arrestins; C034671:prostaglandin F2alpha receptor; C121227:AL 8810; D007294:Inositol; D015237:Dinoprost; D066246:ErbB Receptors; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases