Author
Robbie Loewith
Other affiliations: University of Basel, University of Calgary
Bio: Robbie Loewith is an academic researcher from University of Geneva. The author has contributed to research in topics: TOR complex & Phosphorylation. The author has an hindex of 40, co-authored 76 publications receiving 17289 citations. Previous affiliations of Robbie Loewith include University of Basel & University of Calgary.
Papers published on a yearly basis
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TL;DR: The physiological consequences of mammalianTORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders.
5,553 citations
TL;DR: Two distinct TOR complexes constitute a primordial signalling network conserved in eukaryotic evolution to control the fundamental process of cell growth.
Abstract: The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of cell growth. In budding yeast, TOR is found in structurally and functionally distinct protein complexes: TORC1 and TORC2. A mammalian counterpart of TORC1 (mTORC1) has been described, but it is not known whether TORC2 is conserved in mammals. Here, we report that a mammalian counterpart of TORC2 (mTORC2) also exists. mTORC2 contains mTOR, mLST8 and mAVO3, but not raptor. Like yeast TORC2, mTORC2 is rapamycin insensitive and seems to function upstream of Rho GTPases to regulate the actin cytoskeleton. mTORC2 is not upstream of the mTORC1 effector S6K. Thus, two distinct TOR complexes constitute a primordial signalling network conserved in eukaryotic evolution to control the fundamental process of cell growth.
2,059 citations
TL;DR: Two functionally distinct TOR complexes account for the diversity, specificity, and selective rapamycin inhibition of TOR signaling.
1,769 citations
TL;DR: It is found that p110alpha is the primary insulin-responsive PI3-K in cultured cells, whereas p110beta is dispensable but sets a phenotypic threshold for p110 alpha activity, which illustrates systematic target validation using a matrix of inhibitors that span a protein family.
1,152 citations
TL;DR: This work uses two novel and specific mTOR kinase domain inhibitors (PP242 and PP30) to show that pharmacological inhibition of mTOR blocks the phosphorylation of Akt at S473 and prevents its full activation, and shows that the TORKinib PP242 is a more effective mTORC1 inhibitor than rapamycin.
Abstract: The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals These signaling functions are distributed between at least two distinct mTOR protein complexes: mTORC1 and mTORC2 mTORC1 is sensitive to the selective inhibitor rapamycin and activated by growth factor stimulation via the canonical phosphoinositide 3-kinase (PI3K)-->Akt-->mTOR pathway Activated mTORC1 kinase up-regulates protein synthesis by phosphorylating key regulators of mRNA translation By contrast, mTORC2 is resistant to rapamycin Genetic studies have suggested that mTORC2 may phosphorylate Akt at S473, one of two phosphorylation sites required for Akt activation; this has been controversial, in part because RNA interference and gene knockouts produce distinct Akt phospho-isoforms The central role of mTOR in controlling key cellular growth and survival pathways has sparked interest in discovering mTOR inhibitors that bind to the ATP site and therefore target both mTORC2 and mTORC1 We investigated mTOR signaling in cells and animals with two novel and specific mTOR kinase domain inhibitors (TORKinibs) Unlike rapamycin, these TORKinibs (PP242 and PP30) inhibit mTORC2, and we use them to show that pharmacological inhibition of mTOR blocks the phosphorylation of Akt at S473 and prevents its full activation Furthermore, we show that TORKinibs inhibit proliferation of primary cells more completely than rapamycin Surprisingly, we find that mTORC2 is not the basis for this enhanced activity, and we show that the TORKinib PP242 is a more effective mTORC1 inhibitor than rapamycin Importantly, at the molecular level, PP242 inhibits cap-dependent translation under conditions in which rapamycin has no effect Our findings identify new functional features of mTORC1 that are resistant to rapamycin but are effectively targeted by TORKinibs These potent new pharmacological agents complement rapamycin in the study of mTOR and its role in normal physiology and human disease
1,129 citations
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01 Apr 2012
TL;DR: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis as mentioned in this paper, and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration.
Abstract: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation.
6,268 citations
TL;DR: Recent advances in understanding of the mTOR pathway are reviewed and pharmacological approaches to treat human pathologies linked to mTOR deregulation are discussed.
5,792 citations
TL;DR: The physiological consequences of mammalianTORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders.
5,553 citations
TL;DR: Those Akt substrates that are most likely to contribute to the diverse cellular roles of Akt, which include cell survival, growth, proliferation, angiogenesis, metabolism, and migration are discussed.
5,505 citations
TL;DR: In this paper, the rictor-mTOR complex was used to identify compounds which modulate Akt activity mediated by the Rictor mTOR complex and methods for treating or preventing a disorder that is associated with aberrant Akt activation.
Abstract: In certain aspects, the invention relates to methods for identifying compounds which modulate Akt activity mediated by the rictor-mTOR complex and methods for treating or preventing a disorder that is associated with aberrant Akt activity.
5,430 citations