Up and Downstream of TOR

There is little conservation among TOR effectors. In budding yeast, TORC1 triggers growth by promoting ribosomal assembly and inhibiting autophagy, largely by mediating the phosphorylation-sensitive subcellular localization of transcription factors—reviewed in Inoki and Guan (2006). Many of these transcription factors govern ribosomal components or autophagy promoting proteins. Active TORC1 simultaneously triggers the nuclear accumulation of transcription factors governing ribosomal components while inhibiting nuclear localization of transcription factors for autophagy-promoting genes. In the absence of nutrients or upon rapamycin treatment, TORC1 is inactive, ri-bosomal component transcription factors are retained in the cytoplasm, and autophagy-promoting transcription is localized to the nucleus.

Mammalian mTORC1 similarly promotes protein synthesis, but through very different effectors. TORC1 phosphorylates S6K and 4E-BP (Hara et al. 1998). S6K (ribosomal protein rpS6 kinase) phosphorylates the ribosomal regulatory component rpS6; S6K activity requires activating phosphoryla-tion by TORC1. Phosphorylated rpS6 increases ribosomal processivity. 4E-BP (eukaryotic initiation factor 4E binding protein) inhibits mRNA recruitment to the ribosome. TORC1 phosphorylated 4E-BP is inactive, thus increasing mRNA translation.

TORC2 defects can be suppressed by overexpression of the AGC kinase Ypk2 (Kamada et al. 2005), implicating this kinase as a major budding yeast TORC2 effector. mTORC2 is known to phosphorylate the Ser/Thr kinase Akt/PKB (Sarbassov et al. 2005). Akt is also an AGC kinase but not the mammalian homologue of yeast Ypk2.

Like TOR effectors, regulatory elements upstream of TOR are not well conserved. mTORC1 is regulated by amino acid levels, hormonal signals, and cellular AMP levels (Schmelzle and Hall 2000). Budding yeast TORC1 is similarly regulated by amino acid levels and AMP levels, but the specific amino acids sensed are different and the mechanism of sensing is unclear (Crespo and Hall 2002; Wullschleger et al. 2006). AMP concentration, as a measure of cellular energy levels, is sensed by AMPK in yeast and mammals, and perhaps in all eukaryotes (Hardie 2005); however, intermediates that transfer signals from AMPK to TORC1 are not conserved.

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