Cooperative mitogenic signaling by G protein-coupled receptors and growth factors is dependent on Gq/11
Cooperative mitogenic signaling by G protein-coupled receptors and growth factors is dependent on Gq/11
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DOI：
10.1096/fj.05-5622fje
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发表时间：
2006-07-01
期刊：
影响因子：
4.8
通讯作者：
Penn, Raymond B.
中科院分区：
文献类型：
--
作者：
Kong, Kok Choi;Billington, Charlotte K.;Penn, Raymond B.
先前我们报道了G蛋白偶联受体激动剂凝血酶通过依赖于异源三聚体G蛋白Gβγ亚基的途径，促进PI3K和p70S6K的持续晚期激活，从而增强了表皮生长因子(EGF)对人气道平滑肌(ASM)的促有丝分裂作用。在这里，我们提供了额外的机制洞察力，并通过证明H1组胺和血栓烷受体通过异源三聚体G蛋白G(Q/11)的特异性激活利用相同的机制来促进ASM生长，揭示了这一现象的稳健性。凝血酶、组胺和U46619均可增强表皮生长因子刺激的ASM细胞[H-3]-胸腺嘧啶核苷掺入以及晚期Akt和p70S6K的磷酸化。异源表达GRK2CT-GFP或Gα(I)G203A以及GRK2NT-GFP(G(Q/11)的RGS蛋白)，但既不能减弱p115RhoGEFRGS-GFP(G(12/13)的RGS)，也不能减弱百日咳毒素预处理(灭活G(I/o))对信号和生长的影响。抑制Rho、Rho激酶或Src，或调节arrestin的表达，对EGF和任何一种GPCR激动剂的协同信号没有显著影响。因此，G(Q/11)偶联受体是介导ASM中协同有丝分裂信号的主要GPCR亚家族，它通过依赖于Gβ-γ和非依赖于Src/arrestin激活PI3K和p70S6K来发挥作用。
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 G beta gamma 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 [H-3]-thymidine incorporation as well as late-phase Akt and p70S6K phosphorylation in ASM cultures. Heterologous expression of G beta gamma sequestrants (GRK2CT-GFP or G alpha(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 G beta gamma-dependent, and Src/arrestin-independent activation of PI3K and p70S6K.