EGF receptor transactivation is obligatory for protein synthesis stimulation by G protein-coupled receptors.
The epidermal growth factor receptor (EGFR) was recently identified as a signal transducer of G protein-coupled receptors (GPCRs). In this study, we have examined the contribution of EGFR transactivation to the growth-promoting effect of GPCRs on vascular smooth muscle cells. Activation of the G(q)-coupled ANG II receptor or G(i)-coupled lysophosphatidic acid receptor resulted in increased tyrosine phosphorylation and activation of EGFR. Specific inhibition of EGFR kinase activity by tyrphostin AG-1478 or expression of a dominant-negative EGFR mutant abolished this response. Importantly, inhibition of EGFR function strongly attenuated the global stimulation of protein synthesis by GPCR agonists in vitro in cultured aortic smooth muscle cells and in vivo in the rat aorta and in small resistance arteries. The growth inhibition was associated with a marked reduction of extracellular signal-regulated kinase and phosphoinositide 3-kinase pathway activity and the resulting suppression of eukaryotic translation initiation factor 4E and 4E binding protein 1 phosphorylation. Our results demonstrate that EGFR transactivation is a physiologically relevant action of GPCRs linked to translational control and protein synthesis.
Voisin
Laure
L
Institut de recherches cliniques de Montréal, Montreal H2W 1R7, Canada.
Foisy
Sylvain
S
Giasson
Edith
E
Lambert
Chantal
C
Moreau
Pierre
P
Meloche
Sylvain
S
D000818:Animals; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000235:genetics*; D039561:Eukaryotic Initiation Factor-4E; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019204:GTP-Binding Proteins / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000096:biosynthesis*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D010448:Peptide Initiation Factors / Q000378:metabolism; D051381:Rats; D011945:Receptors, Angiotensin / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology*
D039561:Eukaryotic Initiation Factor-4E; D009124:Muscle Proteins; D010448:Peptide Initiation Factors; D011945:Receptors, Angiotensin; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D066246:ErbB Receptors; D019204:GTP-Binding Proteins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins