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Review
. 2005 Mar;69(1):79-100.
doi: 10.1128/MMBR.69.1.79-100.2005.

Signaling by target of rapamycin proteins in cell growth control

Ken Inoki  1 , Hongjiao Ouyang, Yong Li, Kun-Liang Guan
Affiliations
Review

Signaling by target of rapamycin proteins in cell growth control

Ken Inoki et al. Microbiol Mol Biol Rev. 2005 Mar.

Abstract

Target of rapamycin (TOR) proteins are members of the phosphatidylinositol kinase-related kinase (PIKK) family and are highly conserved from yeast to mammals. TOR proteins integrate signals from growth factors, nutrients, stress, and cellular energy levels to control cell growth. The ribosomal S6 kinase 1 (S6K) and eukaryotic initiation factor 4E binding protein 1(4EBP1) are two cellular targets of TOR kinase activity and are known to mediate TOR function in translational control in mammalian cells. However, the precise molecular mechanism of TOR regulation is not completely understood. One of the recent breakthrough studies in TOR signaling resulted in the identification of the tuberous sclerosis complex gene products, TSC1 and TSC2, as negative regulators for TOR signaling. Furthermore, the discovery that the small GTPase Rheb is a direct downstream target of TSC1-TSC2 and a positive regulator of the TOR function has significantly advanced our understanding of the molecular mechanism of TOR activation. Here we review the current understanding of the regulation of TOR signaling and discuss its function as a signaling nexus to control cell growth during normal development and tumorigenesis.

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Figures

FIG. 1.
FIG. 1.
TOR complexes in yeast and mammalian cells. TOR complex 1 (TORC1) contains either Tor1p or Tor2p with Kog1p, Lst8p, and Tco89p. TORC1 regulates a variety of functions including transcription, mRNA turnover, protein turnover, and translation. All of these TORC1 functions are rapamycin sensitive. TORC2 consists of Tor2p, Avo1-3p, Bit61p, and Lst8p. TORC2 regulates cytoskeleton organization. This function is specific for TORC2 and rapamycin insensitive (left panel). Mammalian TOR also forms two complexes. mTORC1 consists of mTOR, Raptor, and GβL (mLst8). The identified function of mTORC1 complex is similar to that of yeast TORC1. Recently, Rictor/mammalian AVO3 has been identified as a component of mTORC2. Rictor/mAVO3 and GβL are involved in regulating cytoskeleton organization in a rapamycin-insensitive manner.
FIG. 2.
FIG. 2.
Structural domains of mTOR and TOR-associated proteins. mTOR consists of HEAT, FAT, FATC, FRB, and kinase domains. All of them are evolutionarily conserved in TOR orthologs. Raptor-Kog1p consists of RNC, HEAT, and WD40 domains. All domains are also conserved in raptor orthologs. Avo1p has homologies to the Ras-binding domain in the middle of the protein (amino acids [a.a.] 843 to 919) and to the SIN1 gene product. Sin1p is implicated in regulating transcriptional processes and chromatin assembly and is also characterized as the Sapkp (stress activated-protein kinase)-interacting protein. Avo2p has four ankyrin repeats in the N-terminal region. Rictor-Avo3p, also known as Tsc11p, has homology to the Ras GEF N terminus in the middle of the protein (a.a. 990 to 1046). Tco89p and Bit61p are novel yeast TOR-interacting proteins. Abbreviations: HEAT, Huntingtin, elongation factor 3, A subunit of PP2A, TOR; FAT, FRAP, ATM, TRRAP; FATC, FAT carboxyl terminal; FRB, FKBP12-rapamycin binding; RNC, raptor N-terminal conserved; WD, WD40.
FIG. 3.
FIG. 3.
Regulation of PP2A by TOR in yeast.
FIG. 4.
FIG. 4.
Transcriptional regulation by TOR. In yeast, TOR regulates multiple transcription factors through its inactivation of PP2A activity. Recently, a study of yeast has indicated that the regulation of ribosomal protein (RP) genes expression is independent of Tap42p. TOR-dependent regulation of UBF, TIF-1A, and URI has been demonstrated in mammalian system.
FIG. 5.
FIG. 5.
Structural domains and phosphorylation sites of TSC1 and TSC2. TSC1 (hamartin) has transmembrane and coiled-coil domains at the N- and C-terminal regions, respectively. Thr447, Ser584, and Thr1047 are cdc2-dependent phosphorylation sites, and these phosphorylations negatively regulate TSC1-TSC2 complex activity (8). TSC2 (tuberin) consists of a leucine zipper domain, two coiled-coils domains, and a Rheb-GAP domain. It has been reported that the N-terminal coiled-coil domain is critical for its association with TSC1. Ser939, Ser1130, Ser1132, and Thr1462 are Akt-dependent phosphorylation sites (57, 122, 161, 194), and Ser1254 is a MAPKAP-K2 phophorylation site (149). Phosphorylation of TSC2 by Akt and MAPKAP-K2 inactivates TSC1-TSC2 complex activity. Thr1271 and Ser1387 are sites of phosphorylation by AMPK, and AMPK phosphorylation activates the TSC1-TSC2 complex (123).
FIG. 6.
FIG. 6.
TOR functions as a multiple-channel sensor for a variety of upstream signals. Multiple signaling cascades impinge on the TSC1-TSC2 complex-Rheb-mTOR complex to regulate translational machinery. LKB1 complex consists of LKB1 kinase, STRAD, and Mo25. STRAD and Mo25 (12, 26) are required for full activation of LKB1 kinase and are important for cytosolic localization of LKB1. It has been reported that LKB1 complex activates not only AMPK but also another 12 AMPK-related kinases (153). Whether these AMPK members participate in the regulation of translation machinery has not yet been determined. Protein X represents a putative amino acid-sensing molecule.
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