Cooperative mitogenic signaling by G protein-coupled receptors and growth factors is dependent on G(q/11).
Previously we reported that the G protein-coupled receptor (GPCR) agonist thrombin potentiated the mitogenic effect of epidermal growth factor (EGF) on human airway smooth muscle (ASM) by promoting sustained late-phase activation of PI3K and p70S6K via a pathway dependent on Gbetagamma subunits of heterotrimeric G proteins. Here, we provide additional mechanistic insight and reveal the robustness of this phenomenon by demonstrating that H1 histamine and thromboxane receptors utilize the same mechanism to augment ASM growth via specific activation of the heterotrimeric G protein G(q/11). Thrombin, histamine, and U46619 all enhanced EGF-stimulated [3H]-thymidine incorporation as well as late-phase Akt and p70S6K phosphorylation in ASM cultures. Heterologous expression of Gbetagamma sequestrants (GRK2CT-GFP or Galpha(i)G203A), as well as GRK2NT-GFP (an RGS protein for G(q/11)) but neither p115RhoGEFRGS-GFP (an RGS for G(12/13)) nor pertussis toxin pretreatment (inactivating G(i/o)), attenuated the effects on both signaling and growth. Inhibition of Rho, Rho kinase, or Src, or modulation of arrestin expression did not significantly affect the cooperative signaling by EGF and any of the GPCR agonists. Thus, G(q/11)-coupled receptors are the principal GPCR subfamily mediating cooperative mitogenic signaling in ASM, acting through Gbetagamma-dependent, and Src/arrestin-independent activation of PI3K and p70S6K.
Kong
Kok Choi
KC
Department of Internal Medicine and Center for Human Genomics, Wake Forest University Health Sciences, Medical Center Blvd., Winston-Salem, North Carolina 27157, USA.
Billington
Charlotte K
CK
Gandhi
Uma
U
Panettieri
Reynold A
RA
Penn
Raymond B
RB
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology*; D006133:Growth Substances / Q000502:physiology*; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013917:Thrombin / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D006133:Growth Substances; D043562:Receptors, G-Protein-Coupled; D014662:Vasoconstrictor Agents; D004815:Epidermal Growth Factor; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D006632:Histamine; D013917:Thrombin; D043802:GTP-Binding Protein alpha Subunits, Gq-G11