Growth hormone modulation of EGF-induced PI3K-Akt pathway in mice liver.

DÍAZ ME; GONZÁLEZ L; MIQUET JG; MARTINEZ CS; SOTELO AI; BARTKE A; TURYN D

CELLULAR SIGNALLING

Elsevier

Año: 2011 vol. 24 p. 514 - 523

0898-6568

The epidermal growth factor (EGF) activates the phosphatidylinositol 3-kinase (PI3K)-Akt cascade amongother signaling pathways. This route is involved in cell proliferation and survival, therefore, its dysregulationcan promote cancer. Considering the relevance of the PI3K-Akt signaling in cell survival and in the pathogen-esis of cancer, and that GH was reported to modulate EGFR expression and signaling, the objective of thisstudy 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 normalsiblings. While Akt expression was increased in GH-overexpressing mice, EGF-induced phosphorylation ofAkt, 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 in-volved 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 micecompared with normal siblings. Thus, the expression and activity of phosphatases involved in the termina-tion 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 toEGFR and activation of PI3K. Rapid recruitment of SHP2, which would accelerate the termination of the pro-liferative signal induced, could be therefore contributing to the diminished EGF-induced activity of Akt in GH-overexpressing mice