Signaling from G Protein-coupled Receptors to ERK5/Big MAPK 1 Involves Gαq and Gα12/13 Families of Heterotrimeric G Proteins

Abstract

The regulation of gene expression by cell surface receptors often involves the stimulation of signaling pathways including one or more members of the MAPK superfamily of serine-threonine kinases. Upon their activation in the cytosol, MAPKs can translocate to the nucleus and affect the activity of a variety of transcription factors. Recently, it has been observed that a novel member of the MAPK superfamily, ERK5, can be potently activated by transforming G protein-coupled receptors (GPCRs) and that ERK5 participates in the regulation of c-jun expression through the activation of MEF2 transcription factors. How cell surface receptors, including GPCRs, stimulate ERK5 is still poorly understood. In this study, we have used transiently transfected COS-7 cells to begin delineating the biochemical route linking GPCRs to ERK5. We show that receptors that can couple to the G q and G 12/13 families of heterotrimeric G proteins, m1 and thrombin receptors, respectively, but not those coupled to G i , such as m2 receptors, are able to regulate the activity of ERK5. To investigate which heterotrimeric G proteins signal to ERK5, we used a chimeric system by which G␣ q -and G␣ 13 -mediated signaling pathways can be conditionally activated upon ligand stimulation. Using this system, as well as the expression of activated forms of G protein subunits, we show that the G␣ q and G␣ 12/13 families of heterotrimeric G proteins, but not the G␣ i , G␣ s , and ␤␥ subunits, are able to regulate ERK5. Furthermore, we provide evidence that the stimulation of ERK5 by GPCRs involves a novel signaling pathway, which is distinct from those regulated by Ras and Rho GTPases.

Gastrin Stimulates Cyclooxygenase-2 Expression in Intestinal Epithelial Cells through Multiple Signaling Pathways

“…Our study shows that activation of CCK-BR, which belongs to the G␣ q -and G␣ 12/13 -coupled receptor family (4), also stimulates the ERK5/MEF2 pathway in intestinal epithelial cells. Thus, this finding confirms and extends the previous reports (15,16,50). In addition, the signaling pathway linking CCK-BR to COX-2 expression is much more complex than initially anticipated, as it involves the integration of numerous MAPK pathways rather than a linear series of sequential events (Fig.…”

“…The muscarinic acetylcholine receptor and thrombin receptors couple with the G q and G 12/13 family of heterotrimeric G proteins. Stimulation of G q -coupled m1 muscarinic receptors by carbachol potently activates ERK5 kinase and the MEF2 transcription factor (15,16,50), but stimulation of G i -coupled m2 muscarinic receptors has no effect on ERK5 activity. In addition, activation of thrombin receptors coupled with G␣ q and G␣ 12/13 also increase ERK5 activity (50).…”

“…Stimulation of G q -coupled m1 muscarinic receptors by carbachol potently activates ERK5 kinase and the MEF2 transcription factor (15,16,50), but stimulation of G i -coupled m2 muscarinic receptors has no effect on ERK5 activity. In addition, activation of thrombin receptors coupled with G␣ q and G␣ 12/13 also increase ERK5 activity (50). These results suggest that receptors coupled with G␣ q and G␣ 12/13 may harbor the ability to transduce a signal to ERK5, whereas G i -coupled receptors do not (15,16,50).…”

“…In addition, activation of thrombin receptors coupled with G␣ q and G␣ 12/13 also increase ERK5 activity (50). These results suggest that receptors coupled with G␣ q and G␣ 12/13 may harbor the ability to transduce a signal to ERK5, whereas G i -coupled receptors do not (15,16,50). Our study shows that activation of CCK-BR, which belongs to the G␣ q -and G␣ 12/13 -coupled receptor family (4), also stimulates the ERK5/MEF2 pathway in intestinal epithelial cells.…”

“…Previous reports have shown that ERK5 and its downstream target MEF2 can be activated by GPCRs (15,16,50). The muscarinic acetylcholine receptor and thrombin receptors couple with the G q and G 12/13 family of heterotrimeric G proteins.…”