The mammalian target of rapamycin signaling network and gene regulation

The mammalian target of rapamycin (mTOR) is a key integrator of signals from nutrients, energy and insulin. TOR is a protein kinase originally identified in yeast by the genetic selection of rapamycin-resistant mutants. Over the past decade mTOR research has progressed dramatically. Although mTOR is known as a controller of messenger RNA cap-dependent translation initiation, new advances implicate mTOR in the regulation of ribosomal protein gene transcription. The aim of this review is to highlight recent findings on mTOR regulatory networks, focusing on articles published from December 2003 to December 2004.

mTOR was recently knocked out in mice; the embryonic lethal phenotype demonstrates a critical role of mTOR in early embryo development. Intriguingly, the homozygous deletion of ribosomal protein S6 kinase 1 (S6K1), an mTOR target, in mice results in hypoinsulinemia and glucose intolerance. Despite elevated levels of plasma free fatty acids, S6K1 knockout mice are protected from the metabolic syndrome, indicating a role of S6K1 in glucose homeostasis. Current research indicates that mTOR integrates input from multiple upstream pathways, including insulin, growth factors, nutrients, mitogens and energy. Furthermore, the discovery of mTOR binding partners adds to the intricacies of mTOR as a master switch in cell signaling.

Rapamycin, an mTOR inhibitor, has emerged as an immunosuppressive and antiproliferative drug, and is considered a novel antitumor agent. A better understanding of mTOR signaling would enhance the clinical usefulness of rapamycin and inform consideration of mTOR as a target for the development of new therapies.