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.

Figure 1

(A) Conserved domain structure of TOR. The N-terminal half of TOR is composed of two blocks of ∼20 HEAT repeats, 40 aa that form pairs of interacting antiparallel α-helices. The ∼500-aa FAT (FRAP-ATM-TRRAP) domain contains modified HEAT repeats. Missense mutations in the ∼100-aa FRB (FKBP12-rapamycin-binding) domain confer complete resistance to rapamycin. The kinase domain phosphorylates Ser/Thr residues in protein substrates, but at the sequence level resembles the catalytic domain of phosphatidylinositol kinases. The ∼35-aa FATC domain is always found C-terminal to the FAT domain and is essential for kinase activity. (B) Composition of TOR complex 1. TORC1 is ∼2 MDa in size and contains Kog1, Tco89, Lst8, and either TOR1 or TOR2. The HEAT repeats found in Kog1 and the seven-bladed propellers of the WD-40 repeats found in Kog1 and Lst8 are depicted. The binding of Kog1 to TOR is complex, involving multiple domains on each protein. Lst8 binds to the kinase domain of TOR. Each component is likely present in two copies. (C) Composition of TOR complex 2. TORC2 is ∼2 MDa in size and contains Avo1, Avo2, Avo3, Bit61, and/or its paralog Bit2, Lst8, and TOR2 but not TOR1. The RasGEFN domain of Avo3 and the PH domain of Avo1 are indicated. Each component is likely present in two copies.

Figure 2

The EGO complex is a major regulator of TORC1. The EGO complex (EGOC) is composed of four proteins: the palmitoylated and myristolated protein Ego1, the transmembrane protein Ego3, and two Ras-family GTPases, Gtr1 and Gtr2. Like TORC1, the EGO complex is localized to the vacuolar membrane where it appears to sense/respond to intracellular leucine levels and potentially to intravacuolar amino acid levels. Vam6 has been identified as a guanine nucleotide exchange factor for Gtr1 but no other GEFs or GAPS for this GTPase system have been reported. In the Gtr1^GTP and Gtr2^GDP configuration, the EGO complex somehow activates TORC1; the reverse conformation inactivates TORC1. Activated TORC1, via its two main effector branches, the AGC kinase Sch9 and the Tap42-PP2a and PP2a-like protein phosphatases, stimulates growth by favoring anabolic processes and by antagonizing catabolic processes and stress-response programs.

Figure 3

Control of RiBi and RP gene transcription by TORC1. RiBi factors are required for the proper expression, processing, assembly, export, and maturation of rRNA and RPs into ribosomes. This energetically costly procedure is under tight regulation, particularly at the transcription level. TORC1 regulates RiBi and RP gene transcription via multiple pathways: (1) TORC1 directly phosphorylates the Split Zn-finger transcription factor Sfp1, which presumably regulates its nuclear localization and/or binding to RP and possibly RiBi gene promoters to stimulate their expression. (2) Fhl1 and Rap1 bind constitutively to RP promoters. When TORC1 is active, phosphorylated Ifh1 binds to Fhl1 to stimulate transcription, possibly by recruiting the NuA4 histone acetyltransferase. When TORC1 is inactive, Yak1 phosphorylates Crf1, which subsequently outcompetes Ifh1 for binding to Fhl1. (3) Sch9 phosphorylates and thus inhibits Stb3 and the paralogs Dot6 and Tod6. Inhibition of TORC1/Sch9 results in the dephosphorylation of these three transcription repressors, which subsequently bind to RRPE and PAC elements found in RiBi promoters. Stb3 additionally binds RP promoters. Bound to promoters, these repressors recruit the RPD3L histone deacetylase complex to repress transcription.

Figure 4

Signaling by TORC2. TORC2 directly phosphorylates the AGC kinase family member Ypk (Ypk1 and 2) and the PH domain containing protein Slm (Slm1 and -2). Downstream effectors include the phosphatase calcineurin, the transcription factor Crz1, and Pkc1. TORC2 controls organization of the actin cytoskeleton, endocytosis, sphingolipid biosynthesis, and stress-related transcription. The effector pathways by which TORC2 controls these processes are incompletely understood (see Distal readouts downstream of TORC2 for further details).