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


RESULTS
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.


CONCLUSIONS
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.
Kimball
Scot R
SR
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Jefferson
Leonard S
LS
D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D004330:Drosophila / Q000378:metabolism; D029721:Drosophila Proteins; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D000076205:Ras Homolog Enriched in Brain Protein; D012097:Repressor Proteins / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
D000596:Amino Acids; D029721:Drosophila Proteins; D039561:Eukaryotic Initiation Factor-4E; D006133:Growth Substances; D009479:Neuropeptides; D012333:RNA, Messenger; D000076205:Ras Homolog Enriched in Brain Protein; D012097:Repressor Proteins; C490212:Rheb protein, Drosophila; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins