Abstract
The target of rapamycin (TOR) protein kinase is at the core of growth factor- and nutrient-dependent signaling pathways that are well-known for their regulation of metabolism, growth, and proliferation. However, TOR is also involved in the regulation of gene expression, genomic and epigenomic stability. TOR affects nuclear functions indirectly through its activity in the cytoplasm, but also directly through active nuclear TOR pools. The mechanisms by which TOR regulates its nuclear functions are less well-understood compared with its cytoplasmic activities. TOR is an important pharmacological target for several diseases, including cancer, metabolic and neurological disorders. Thus, studies of the nuclear functions of TOR are important for our understanding of basic biological processes, as well as for clinical implications.
Highlights
Signal transduction pathways act to communicate extracellular and intracellular signals to effector proteins that control a range of fundamental cellular processes
This study showed that mTORC2 activity localized to the plasma membrane, mitochondria, and endosomal vesicles; it did not test for localization of mTORC2 to the nucleus [88]
Additional studies in mammalian cells demonstrated that both mammalian TOR (mTOR) and Raptor interact with the DNA binding factor TFIIIC to induce Pol III-dependent transcription of 5S and tRNA genes (Figure 2A) [91]
Summary
Signal transduction pathways act to communicate extracellular and intracellular signals to effector proteins that control a range of fundamental cellular processes. As detailed below, TOR and its closely associated protein interactors and direct downstream effectors localize to the nucleus where they regulate critical nuclear activities involved in gene expression. The role of TOR in the regulation of protein synthesis, one of the most energy-demanding cellular processes, is in accord with its function as a master regulator of cellular growth. Other anabolic processes, such as transcription and lipid and nucleotide synthesis, are critical downstream mTORC1-regulated processes. The role of TORC2 in the activation of downstream AGC kinases is conserved in yeast cells. Certain cellular activities are oppositely regulated by TORC1 and TORC2, while others are coordinated to result in the same cellular output [17,53,54]
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