mTOR

mTOR

The mechanistic target of rapamycin (mTOR), also known as mammalian target of rapamycin and FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a protein that in humans is encoded by the MTOR gene. mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases. mTOR functions as a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription. mTOR also functions as a tyrosine protein kinase that promotes the activation of insulin receptors and insulin-like growth factor 1 receptors.

Rapamycin is an Food and Drug Administration (FDA) approved drug used for immunosuppression in organ transplants, prevention of restenosis post-angioplasty, and chemotherapy for soft-tissue and bone sarcomas. The target of rapamycin (TOR) is a highly conserved phosphatidylinositol kinase-related serine/threonine protein kinase that regulates cell growth, proliferation, morphology, and survival. The functions of TOR in translation and cell size control have been well characterized due to the availability of rapamycin, a highly specific TOR inhibitor.

TOR forms two distinct structural and functional complexes (TORC1 and TORC2). TORC1 and TORC2 were initially identified in S. cerevisiae, which has two TOR genes, while higher eukaryotes have only one TOR gene. Yeast TORC1 consists of either Tori or Tor2, Kogl, Lst8 and Tco89, while yeast TORC2 contains Tor2, Lst8, Avol, Avo2, Avo3, and Bit61. Biochemical studies show that TORC1 activity is inhibited by rapamycin. In contrast, TORC2 activity is insensitive to rapamycin inhibition. Recently, both TORC1 and TORC2 have also been identified in higher eukaryotes. Mammalian TORC1 (mTORCl) consists of mTOR, Raptor (homolog of Kogl) and mLST8 (also known as GDL). mTORCl regulates translation and cell growth by phosphorylating ribosomal S6 kinase (S6K) and eukaryote initiation factor 4E-binding protein 1 (4EBP1) in a rapamycin-sensitive manner. Much of the current knowledge about mTOR in literature is associated with mTORCl, because of the wide utilization of rapamycin in biochemical studies. The identification of these two distinct TOR complexes ties together many yeast and mammalian studies and has significantly advanced the understanding of TOR biology.

The mammalian target of rapamycin (mTOR) has drawn much attention recently because of its essential role in cell growth control and its involvement in human tumorigenesis. Great endeavors have been made to elucidate the functions and regulation of mTOR in the past decade. The current prevailing view is that mTOR regulates many fundamental biological processes, such as cell growth and survival, by integrating both intracellular and extracellular signals, including growth factors, nutrients, energy levels, and cellular stress. The significance of mTOR has been highlighted most recently by the identification of mTOR-associated proteins. Amazingly, when bound to different proteins, mTOR forms distinctive complexes with very different physiological functions. These findings not only expand the roles that mTOR plays in cells, but also further complicate the regulation network. Thus it is now even more critical that we precisely understand the underlying molecular mechanisms in order to directly guide the development and usage of anti-cancer drugs targeting the mTOR signaling pathway.

Despite its humble beginning two decades ago, mTOR is now recognized as a central regulator in a diverse array of vital cellular processes, including proliferation, growth, differentiation, and survival. The physiological functions of mTOR continue to expand. The regulation of mTOR has progressed from a signaling pathway to a network. In recent years, many outstanding research groups have dedicated their efforts to elucidating mTOR functions and regulations. Exciting progress has been achieved, and the discoveries have begun to show promising clinical implications. Nevertheless, our understanding of mTOR, especially regarding mTORC2, is far from complete. How is mTORC2 activated and regulated? What are the undiscovered functions of mTORC2? How do mTORCl and mTORC2 coordinate with each other to regulate distinct cellular processes? What are the relationships between the signaling cascades upstream or downstream of mTOR complexes? The answers to these questions will not only advance our understanding of many vital physiological processes but also help us develop new strategies for treating cancer and improving the quality of human life.

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