Mechanisms of activation of PI3K/Akt signaling in adaptive versus maladaptive hypertrophy. In adaptive hypertrophy, binding of growth factors to their cognate receptors triggers translocation of the PI3K isoform p110α to the cell membrane, a process triggered by the interaction of the p85 subunit of PI3K with specific tyrosine phosphorylated residues in the growth factor receptor. p110α then phosphorylates phosphatidylinositols in the membrane at the 3′ position of the inositol ring. The pleckstrin homology (PH) domains of both Akt and its activator, PDK1, associate with the 3′ phosphorylated lipids, allowing PDK1 to activate Akt. Full activation of Akt requires phosphorylation by a second kinase, PDK2 (not shown), that may be the DNA-dependent protein kinase (DNA-PK). Activation of Akt then leads to activation of mTOR, a central regulator of protein synthesis, via its effects on both ribosome biogenesis and activation of the protein translation machinery. Akt also phosphorylates and inhibits a kinase, GSK-3 (of which there are 2 isoforms, α and β). Since GSK-3 inhibits a key component of the protein translation machinery, as well as a number of transcription factors believed to play roles in the induction of the hypertrophic program of gene expression, inhibition of GSK-3 promotes both protein synthesis and gene transcription. Maladaptive hypertrophy, triggered by neurohormonal mediators and biomechanical stress, also activates Akt, but the mechanism involves activation of heterotrimeric G-protein–coupled receptors coupled to the G-protein family Gq/G11. The PI3K isoform p110γ associates with the βγ subunits of Gq and phosphorylates membrane phosphatidylinositols, which leads to the recruitment of PDK1 and Akt. Maladaptive hypertrophy also recruits alternative pathways to activation of mTOR and Akt. Also shown is the phosphatase, PTEN, which, by dephosphorylating the 3′ position of phosphatidylinositol trisphosphate (PIP₃), shuts off signaling down the pathway.