Target of Rapamycin (TOR), a giant protein kinase expressed by all eucaryotic 
cells, controls cell size in response to nutrient signals. In metazoans, cell 
and organismal growth is controlled by nutrients and the insulin/insulin-like 
growth factor (IGF) system, and the understanding of how these inputs 
coordinately regulate TOR signaling has advanced greatly in the past 5 years. In 
single-cell eucaryotes and Caenorhabditis elegans, TOR is a dominant regulator 
of overall mRNA translation, whereas in higher metazoans, TOR controls the 
expression of a smaller fraction of mRNAs that is especially important to cell 
growth. TOR signals through two physically distinct multiprotein complexes, and 
the control of cell growth is mediated primarily by TOR complex 1 (TORC1), which 
contains the polypeptides raptor and LST8. Raptor is the substrate binding 
element of TORC1, and the ability of raptor to properly present substrates, such 
as the translational regulators 4E-BP and p70 S6 kinase, to the TOR catalytic 
domain is essential for their TOR-catalysed phosphorylation, and is inhibited by 
the Rapamycin/FKBP-12 complex. The dominant proximal regulator of TORC1 
signaling and kinase activity is the ras-like small GTPase Rheb. Rheb binds 
directly to the mTOR catalytic domain, and Rheb-GTP enables TORC1 to attain an 
active configuration. Insulin/IGF enhances Rheb GTP charging through the ability 
of activated Akt to inhibit the Rheb-GTPase-activating function of the tuberous 
sclerosis heterodimer (TSC1/TSC2). Conversely, energy depletion reduces Rheb-GTP 
charging through the ability of the adenosine monophosphate-activated protein 
kinase to phosphorylate TSC2 and stimulate its Rheb-GTPase activating function, 
as well as by HIFalpha-mediated transcriptional responses that act upstream of 
the TSC1/2 complex. Amino-acid depletion inhibits TORC1 acting predominantly 
downstream of the TSC complex, by interfering with the ability of Rheb to bind 
to mTOR. The components of the insulin/IGF pathway to TORC1 are now well 
established, whereas the elements mediating the more ancient and functionally 
dominant input of amino acids remain largely unknown.