Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Facultad de Farmacia y Bioquímica, Junín 956 (1113) Buenos Aires, Argentina.
Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Facultad de Farmacia y Bioquímica, Junín 956 (1113) Buenos Aires, Argentina.
Cell Signal. 2012 Feb;24(2):514-523. doi: 10.1016/j.cellsig.2011.10.001. Epub 2011 Oct 14.
The epidermal growth factor (EGF) activates the phosphatidylinositol 3-kinase (PI3K)-Akt cascade among other signaling pathways. This route is involved in cell proliferation and survival, therefore, its dysregulation can promote cancer. Considering the relevance of the PI3K-Akt signaling in cell survival and in the pathogenesis of cancer, and that GH was reported to modulate EGFR expression and signaling, the objective of this study was to analyze the effects of increased GH levels on EGF-induced PI3K-Akt signaling. EGF-induced signaling was evaluated in the liver of GH-overexpressing transgenic mice and in their normal siblings. While Akt expression was increased in GH-overexpressing mice, EGF-induced phosphorylation of Akt, relative to its protein content, was diminished at Ser473 and inhibited at Thr308; consequently, mTOR, which is a substrate of Akt, was not activated by EGF. However, the activation of PDK1, a kinase involved in Akt phosphorylation at Thr308, was not reduced in transgenic mice. Kinetics studies of EGF-induced Akt phosphorylation showed that it is rapidly and transiently induced in GH-overexpressing mice compared with normal siblings. Thus, the expression and activity of phosphatases involved in the termination of the PI3K-Akt signaling were studied. In transgenic mice, neither PTEN nor PP2A were hyperactivated; however, EGF induced the rapid and transient association of SHP-2 to Gab1, which mediates association to EGFR and activation of PI3K. Rapid recruitment of SHP2, which would accelerate the termination of the proliferative signal induced, could be therefore contributing to the diminished EGF-induced activity of Akt in GH-overexpressing mice.
表皮生长因子 (EGF) 通过激活磷脂酰肌醇 3-激酶 (PI3K)-Akt 级联反应等信号通路发挥作用。该途径参与细胞增殖和存活，因此其失调可促进癌症的发生。鉴于 PI3K-Akt 信号通路在细胞存活和癌症发病机制中的重要性，以及 GH 被报道可调节 EGFR 表达和信号转导，本研究旨在分析 GH 水平升高对 EGF 诱导的 PI3K-Akt 信号转导的影响。通过 GH 过表达转基因小鼠及其正常同窝仔鼠的肝脏，评估 EGF 诱导的信号转导。在 GH 过表达小鼠中，Akt 表达增加，但 EGF 诱导的 Akt 磷酸化相对于其蛋白含量，在 Ser473 处减少，在 Thr308 处受到抑制；因此，Akt 的底物 mTOR 未被 EGF 激活。然而，PDK1 的激活并未在转基因小鼠中降低，PDK1 是参与 Akt 在 Thr308 处磷酸化的激酶。EGF 诱导的 Akt 磷酸化动力学研究表明，与正常同窝仔鼠相比，其在 GH 过表达小鼠中被快速短暂诱导。因此，研究了参与 PI3K-Akt 信号转导终止的磷酸酶的表达和活性。在转基因小鼠中，PTEN 和 PP2A 均未过度激活；然而，EGF 诱导 SHP-2 与 Gab1 的快速和短暂结合，后者介导 EGFR 的结合和 PI3K 的激活。SHP2 的快速募集会加速诱导的增殖信号的终止，因此可能导致 GH 过表达小鼠中 EGF 诱导的 Akt 活性降低。
