Target of Rapamycin (TOR) in Nutrient Signaling and Growth Control

Abstract

TOR (Target Of Rapamycin) is a highly conserved protein kinase that is important in both fundamental and clinical biology. In fundamental biology, TOR is a nutrient-sensitive, central controller of cell growth and aging. In clinical biology, TOR is implicated in many diseases and is the target of the drug rapamycin used in three different therapeutic areas. The yeast Saccharomyces cerevisiae has played a prominent role in both the discovery of TOR and the elucidation of its function. Here we review the TOR signaling network in S. cerevisiae.

Protein kinase Ypk1 phosphorylates regulatory proteins Orm1 and Orm2 to control sphingolipid homeostasis in Saccharomyces cerevisiae

“…In the Ypk1 paralog, Ypk2, phosphorylation of S641 (in the turn motif), and T659 (in the hydrophobic motif) depends on target of rapamycin protein kinase 2 (Tor2) (11), specifically in the TORC2 complex (27,28), and absence of these modifications prevents optimal ceramide biosynthesis (6). Similarly, we (16) and others (17) found previously that a Ypk1(T662A) mutant grows normally on rich medium, but is unable to grow on the same medium containing myriocin, suggesting that phosphorylation of Ypk1 at T662 in the hydrophobic motif is critical for survival when sphingolipids become limiting.…”

“…The upstream kinases that phosphorylate these Cterminal motifs are different for different targets. For example, for yeast Sch9, like mammalian p70 S6K , TORC1 is responsible, whereas for Ypk1 (and Ypk2), like mammalian AKT and SGK, TORC2 is responsible (27,32). It is noteworthy that mutation of the hydrophobic motif in Ypk1 does not diminish its "intrinsic" catalytic activity toward a peptide substrate (16); yet, as we showed here, Ypk1(T662A) is clearly impaired in its activity toward Orm1 and Orm2 both in vitro and in vivo, consistent with the observation that, unlike cells expressing wild-type Ypk1, this mutant is unable to grow when challenged with myriocin (16,17).…”

Synergism between Inositol Polyphosphates and TOR Kinase Signaling in Nutrient Sensing, Growth Control, and Lipid Metabolism in Chlamydomonas

“…Target of Rapamycin (TOR) protein kinase is a conserved and essential regulator of eukaryotic cell growth that is thought to integrate external and internal metabolic cues to balance cell growth with energy and nutrient supplies (Menand et al, 2002;Loewith and Hall, 2011;Montané and Menand, 2013;Xiong and Sheen, 2012;Xiong et al, 2013;Rexin et al, 2015). In yeast and metazoans, TOR is found in two different complexes, TORC1 and TORC2, with distinct functions in cell growth and cytoskeletal organization, respectively, while green algae and land plants only contain the components of TORC1, namely, TOR, RAPTOR, and LST8 (Díaz-Troya et al, 2008;Loewith and Hall, 2011;Moreau et al, 2012;Maegawa et al, 2015).…”

“…In yeast and metazoans, TOR is found in two different complexes, TORC1 and TORC2, with distinct functions in cell growth and cytoskeletal organization, respectively, while green algae and land plants only contain the components of TORC1, namely, TOR, RAPTOR, and LST8 (Díaz-Troya et al, 2008;Loewith and Hall, 2011;Moreau et al, 2012;Maegawa et al, 2015). In plants, the TOR complex plays similar roles as TORC1 in animals and fungi by influencing cytoplasmic protein translation, carbon metabolism, cell growth, cell proliferation, senescence, and autophagy (Deprost et al, 2007;Liu and Bassham, 2010;Caldana et al, 2013;Xiong and Sheen, 2015;Rexin et al, 2015).…”

“…In some species, including Chlamydomonas, TOR can be inhibited by the macrolide drug rapamycin, which has proven to be a pivotal tool for investigating TOR signaling (Crespo et al, 2005;Loewith and Hall, 2011;Rexin et al, 2015). Although Chlamydomonas is sensitive to rapamycin, at saturating drug concentrations cells grow slowly but do not arrest growth completely (Crespo et al, 2005).…”