Mammalian TOR signaling to the AGC kinases

Abstract

The mechanistic (or mammalian) target of rapamycin (mTOR), an evolutionarily conserved protein kinase, orchestrates cellular responses to growth, metabolic and stress signals. mTOR processes various extracellular and intracellular inputs as part of two mTOR protein complexes, mTORC1 or mTORC2. The mTORCs have numerous cellular targets but members of a family of protein kinases, the protein kinase (PK)A/PKG/PKC (AGC) family are the best characterized direct mTOR substrates. The AGC kinases control multiple cellular functions and deregulation of many members of this family underlies numerous pathological conditions. mTOR phosphorylates conserved motifs in these kinases to allosterically augment their activity, influence substrate specificity, and promote protein maturation and stability. Activation of AGC kinases in turn triggers the phosphorylation of diverse, often overlapping, targets that ultimately control cellular response to a wide spectrum of stimuli. This review will highlight recent findings on how mTOR regulates AGC kinases and how mTOR activity is feedback regulated by these kinases. We will discuss how this regulation can modulate downstream targets in the mTOR pathway that could account for the varied cellular functions of mTOR.

Figure 1. Schematic structure of human mTORprotein

Human mTOR is a 2549 amino acid protein. It contains multiple HEAT repeats, a helix turn helix (HTH) motif, and a Golgi/ER localization signal sequence (LS) at its N-terminus. Its catalytic domain is flanked by a FAT and FATC sequences. Immediate upstream to the catalytic domain is the FKBP12-rapamycin binding (FRB) motif. A phosphomimetic residue Asp (E2363) at its putative activation loop, three known phosphorylation sites, T2446, S2448, and S2481, and three other less characterized phosphorylation sites, S1261, S2159, T2164, are shown.

Figure 2. Two mTOR complexes in activation of AGC kinases and cellular functions

In response to amino acids and growth factors, mTORC1 and mTORC2 phosphorylate several AGC kinases at conserved motifs in their carboxyl-terminal tail. Phosphorylation at these sites, in conjunction with PDK1 phosphorylation of the AGC kinase activation loop, confers optimal activities to these kinases. In turn, the activated AGC kinases could serve to positively or negatively regulate mTORC signaling to control various cellular functions as indicated.