Figure 7.

Simplified model of signaling pathways regulating protein synthesis and degradation. Arrows denote activating events, whereas perpendicular lines denote inhibitory events. The solid lines indicate direct activation. The dashed lines indicate indirect activation, whereby intermediate steps are involved but are not specified in this schematic. Protein synthesis is regulated by protein kinase B (Akt), p44/42 MAPK (ERK) and AMP-activated protein kinase (AMPK), resulting in activation of the downstream targets mammalian target of rapamycin (mTOR), glycogen synthase kinase-3β (GSK3β), MAPK-interacting kinases 1/2 (MNK1/2), p70S6 kinase (p70S6K), eIF4E-binding protein 1 (4EBP1), and eukaryotic initiation factors 2B and 4E (eIF2B and eIF4E). Conversely, Akt is responsible for the phosphorylation status of forkhead box protein (FoxO). Upon phosphorylation by Akt, FoxO leaves the nucleus and becomes inactive, thus preventing protein degradation. If Akt activity is suppressed, FoxO becomes dephosphorylated, translocates to the nucleus, and exerts its transcriptional effects on atrogenes to induce protein degradation through the ubiquitin-proteasome pathway. Figure from Argadine et al. (4), with permission.