CA : A Cancer Journal for Clinicians

http://dipbsf.uninsubria.it/monti/BFPN%202009/mTOR.pdf

Defining the Role of mTOR in Cancer

The multiprotein mTORC1 protein kinase complex is the central component of a pathway that promotes growth in response to insulin, energy levels, and amino acids and is deregulated in common cancers. We find that the Rag proteins--a family of four related small guanosine triphosphatases (GTPases)--interact with mTORC1 in an amino acid-sensitive manner and are necessary for the activation of the mTORC1 pathway by amino acids. A Rag mutant that is constitutively bound to guanosine triphosphate interacted strongly with mTORC1, and its expression within cells made the mTORC1 pathway resistant to amino acid deprivation. Conversely, expression of a guanosine diphosphate-bound Rag mutant prevented stimulation of mTORC1 by amino acids. The Rag proteins do not directly stimulate the kinase activity of mTORC1, but, like amino acids, promote the intracellular localization of mTOR to a compartment that also contains its activator Rheb.

/pdf/the-rag-gtpases-bind-raptor-and-mediate-amino-acid-signaling-4jmorq20z2.pdf

The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1

Endoplasmic Reticulum Stress and the Inflammatory Basis of Metabolic Disease

One of the central regulators of cellular and organismal metabolism in eukaryotes is AMP-activated protein kinase (AMPK), which is activated when intracellular ATP production decreases. AMPK has critical roles in regulating growth and reprogramming metabolism, and has recently been connected to cellular processes such as autophagy and cell polarity. Here we review a number of recent breakthroughs in the mechanistic understanding of AMPK function, focusing on a number of newly identified downstream effectors of AMPK.

The AMPK signalling pathway coordinates cell growth, autophagy and metabolism

Targeting mammalian target of rapamycin (mTOR) for health and diseases.

Yeast Tor1 is dynamically distributed in the cytoplasm and nucleus, and its association with the rDNA promoter is important for 35S rRNA synthesis and cell growth. TOR is the target of the immunosuppressant rapamycin and a key regulator of cell growth. It modulates diverse cellular processes in the cytoplasm and nucleus1,2,3,4,5, including the expression of amino acid transporters, ribosomal RNAs and ribosomal proteins. Despite considerable recent progress, little is known about the spatial and temporal regulation of TOR signalling, particularly that leading into the nucleus. Here we show that Tor1 is dynamically distributed in the cytoplasm and nucleus in yeast. Tor1 nuclear localization is nutrient dependent and rapamycin sensitive: starvation or treatment with rapamycin causes Tor1 to exit from the nucleus. Tor1 nuclear localization is critical for 35S rRNA synthesis, but not for the expression of amino acid transporters and ribosomal protein genes. We show further that Tor1 is associated with 35S ribosomal DNA (rDNA) promoter chromatin in a rapamycin- and starvation-sensitive manner; this association is necessary for 35S rRNA synthesis and cell growth. These results indicate that the spatial regulation of TOR complex 1 (TORC1) might be involved in differential control of its target genes. TOR is known as a classic cytoplasmic kinase that mediates the cytoplasm-to-nucleus signalling by controlling the localization of transcription factors. Our data indicate that TOR might be more intimately involved in gene regulation than previously thought.

Nutrient regulates Tor1 nuclear localization and association with rDNA promoter

Tripartite regulation of Gln3p by TOR, Ure2p, and phosphatases.

Rab1A Is an mTORC1 Activator and a Colorectal Oncogene

The target of rapamycin protein (TOR) is a highly conserved ataxia telangiectasia-related protein kinase essential for cell growth. Emerging evidence indicates that TOR signaling is highly complex and is involved in a variety of cellular processes. To understand its general functions, we took a chemical genomics approach to explore the genetic interaction between TOR and other yeast genes on a genomic scale. In this study, the rapamycin sensitivity of individual deletion mutants generated by the Saccharomyces Genome Deletion Project was systematically measured. Our results provide a global view of the rapamycin-sensitive functions of TOR. In contrast to conventional genetic analysis, this approach offers a simple and thorough analysis of genetic interaction on a genomic scale and measures genetic interaction at different possible levels. It can be used to study the functions of other drug targets and to identify novel protein components of a conserved core biological process such as DNA damage checkpoint/repair that is interfered with by a cell-permeable chemical compound.

https://www.pnas.org/content/pnas/97/24/13227.full.pdf

X. F.Steven Zheng

Papers

Targeting mammalian target of rapamycin (mTOR) for health and diseases.

Nutrient regulates Tor1 nuclear localization and association with rDNA promoter

Tripartite regulation of Gln3p by TOR, Ure2p, and phosphatases.

Rab1A Is an mTORC1 Activator and a Colorectal Oncogene

A chemical genomics approach toward understanding the global functions of the target of rapamycin protein (TOR)