Fig. 3.

Schematic representation of PI3K and MAPK signaling to mTORC1. Insulin, growth factors and other stimuli activate mTORC1 signaling through binding and activating RTKs located at the membrane, following which PI3K/AKT and RAS-MAPK integrate these extracellular stimulating signals and convert them into intracellular signals. TSC consists of TSC2 and the scaffolding protein TSC1. The major target of AKT, ERK and RSK involved in the regulation of mRNA translation is TSC2, which is a GAP towards Rheb, and converts Rheb from its active GTP-bound form to the inactive GDP-bound form. Rheb is a small GTPase that stimulates the activation of mTORC1 in its GTP-bound active form. The phosphorylation of TSC2 by AKT, ERK and RSK impedes its GAP activity towards Rheb, resulting in increased Rheb-GTP levels and mTORC1 activation. The major targets of RAS-ERK and RAS-p38 MAPK are RSKs and MNKs. MNKs directly phosphorylate eIF4E on Ser209 which is thought to be the only post-translational modification of eIF4E, this phosphorylation of eIF4E enhances its ability to stimulate mRNA translation. In addition to TSC2, eIF4B, PDCD4 and eEF2K are also the major substrates of RSKs, as illustrated in Fig. 2 and in the text. Black arrows and red T-bars represent stimulatory and inhibitory signals, respectively