Table 2.

The mTOR signaling pathway

The mTOR signaling pathway integrates both intracellular and extracellular signals to regulate cell growth, proliferation, differentiation, and survival, and therefore plays an important role in several physiological and pathological settings. mTOR constitutes the basis for the formation of multi-protein complexes (mTORC1, mTORC2) that serve as crucial intermediaries to adapt physiological mechanisms to the cellular metabolic status (comprehensively reviewed in [167]). Because of the fateful downstream effects enacted through mTORC1 activation, this requires both exogenous stimulations and an abundant intracellular nutrient supply. Such examples of centrally integrated pathways are growth factors, glucose, and amino acid signaling pathways.

Growth factors activate receptor tyrosine kinases or G-protein-coupled receptors that activate PI3K/Akt (Phosphoinositide 3-kinases/ Protein kinase B (PKB), also known as Akt), which in turn phosphorylate and inhibit TSC (tuberous sclerosis complex), thereby relieving the inhibition of the small GTPase Rheb and allowing it to become activated and stimulate mTORC1 kinase activity.

The cellular glucose status is mainly sensed indirectly through AMP/ATP ratio by AMP-activated protein kinase (AMPK), which can act directly, but antagonistically, on mTORC1, as well as in a parallel signaling cascade to regulate glycolysis and mitochondrial biogenesis.

Amino acids can signal to mTORC1 through Rag GTPases by different mechanisms, including cytoplasmic sensors, such as GATORs (protein complexes that regulate the activity of RagB), amino acid transporters and the v-ATPase on the lysosomal membrane. For its activation, mTORC1 is recruited to the lysosomal surface via Ras-related small GTPases (Rag) and is allosterically activated by Rheb, a Ras homolog, in its GTP-bound, activated state

Rags are GTPases that recruit mTORC1 to the lysosomal surface. They function as obligate heterodimers consisting of RagA or RagB bound to RagC or RagD. The guanine-nucleotide-binding state of the RagA/B–RagC/D heterodimer governs mTORC1 binding, whereby in their active conformation, RagA/B is bound to GTP and RagC/D is bound to GDP. The GTP/GDP binding state of Rags is regulated by amino acid sensors, including FLCN (folliculin) [163, 164, 167]