Signaling from G protein-coupled receptors to ERK5/Big MAPK 1 involves Galpha q and Galpha 12/13 families of heterotrimeric G proteins. Evidence for the existence of a novel Ras AND Rho-independent pathway.
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 Galpha(q)- and Galpha(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 Galpha(q) and Galpha(12/13) families of heterotrimeric G proteins, but not the Galpha(i), Galpha(s), and betagamma 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.
Fukuhara
S
S
Oral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892-4330, USA.
Marinissen
M J
MJ
Chiariello
M
M
Gutkind
J S
JS
D000818:Animals; D019556:COS Cells; D002217:Carbachol / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019204:GTP-Binding Proteins / Q000378:metabolism*; D017930:Genes, Reporter; D016758:Genes, jun; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D007700:Kinetics; D064326:MEF2 Transcription Factors; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018006:Myogenic Regulatory Factors; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000502:physiology*; D011976:Receptors, Muscarinic / Q000502:physiology; D018179:Receptors, Thrombin / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013917:Thrombin / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism
D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D011956:Receptors, Cell Surface; D011976:Receptors, Muscarinic; D018179:Receptors, Thrombin; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D002217:Carbachol; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases; D013917:Thrombin; D019204:GTP-Binding Proteins; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins; D018631:ras Proteins