Mammalian target of rapamycin (mTOR): conducting the cellular signaling symphony

Abstract

The mammalian target of rapamycin (mTOR) protein kinase responds to diverse environmental cues to control a plethora of cellular processes. mTOR forms the catalytic core of at least two distinct signaling complexes known as mTOR complexes 1 and 2. Differing sensitivities to the mTOR inhibitor rapamycin, unique partner proteins, distinct substrates, and unique cellular functions distinguish the complexes. Here, we review recent progress in our understanding of the regulation and function of mTOR signaling networks in cellular physiology.

FIGURE 1.

mTORC1 versus mTORC2. Distinct rapamycin sensitivities, partner proteins, substrates, and cellular functions distinguish the two known mTOR signaling complexes, mTORC1 and mTORC2.

FIGURE 2.

Regulation of mTORC signaling networks. Growth factors/mitogens (insulin, EGF) and nutrients (e.g. amino acids, energy) promote mTORC1 signaling via phosphorylation cascades that converge on TSC and the mTORCs themselves. Insulin signals via its receptor (Insulin-R) to activate the PI3K/Akt/TSC/Rheb pathway; EGF signals via its receptor (EGF-R) to activate the Ras/MEK/MAPK/RSK pathway; amino acid sufficiency signals via hVps34 and the RAG and RalA GTPases; and energy sufficiency suppresses AMPK. Insulin/PI3K signaling likely promotes mTORC2 signaling via an unknown pathway. An mTORC1/S6K1-mediated negative feedback loop signals via two pathways to suppress PI3K/mTORC2/Akt signaling. Arrows versus blocked lines indicate activation or inhibition of protein function, respectively, by an upstream regulator. Phosphorylation events (denoted by circled yellow P) known to modulate protein function are shown. The kinases responsible for phosphorylation events are also indicated, with (+) or (−) denoting activation or inhibition of protein function, respectively.