Molecular mechanisms through which amino acids mediate signaling through the mammalian target of rapamycin.

The purpose of this review is to provide a summary of the current state of knowledge concerning one of the intracellular signal transduction pathways through which amino acids, and in particular leucine, regulate the initiation phase of mRNA translation. The primary focus is on a protein kinase, termed the mammalian target of rapamycin (mTOR), that is a point of convergence between amino acid and growth factor signaling to mRNA translation and thereby to cell growth. Until recently the pathway through which amino acids signal to mTOR was completely undefined. Several recent reports, however, describe the identification of proteins that modulate amino acid signaling through mTOR, that is the tuberous sclerosis complex proteins 1 and 2 and the Ras homolog enriched in brain (Rheb) protein. Tuberous sclerosis complex protein 2 is a GTPase activator protein for Rheb that is inhibited by amino acids, allowing Rheb to activate mTOR through a mechanism still to be delineated. In addition, two proteins that interact with mTOR to target it to two important substrates, eukaryotic initiation factor 4E binding protein 1 and ribosomal protein S6 kinase, have been identified. Both proteins, that is the regulatory associated protein of mTOR and G protein beta-subunit-like protein, are required for optimal signaling through mTOR by amino acids. Studies reported in the past 18 months have greatly expanded our knowledge of one of the signaling pathways through which amino acids act to regulate mTOR and also the molecular interactions that mediate the interaction between mTOR and two downstream substrates, eukaryotic initiation factor 4E binding protein 1 and ribosomal protein S6 kinase.