Rictor, a Novel Binding Partner of mTOR, Defines a Rapamycin-Insensitive and Raptor-Independent Pathway that Regulates the Cytoskeleton

Sarbassov, Dos D.; Ali, Siraj M.; Kim, Do-Hyung; Guertin, David A.; Latek, Robert; Erdjument‐Bromage, Hediye; Tempst, Paul; Sabatini, David M.

doi:10.1016/j.cub.2004.06.054

Cited by 2,432 publications

(2,465 citation statements)

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“…This also was observed for rictor, a component of mTOR complex 2 (mTORC2) which provides substrate specificity for AKT 14. Protein kinase Cα (PKCα), which is phosphorylated by mTORC2 at serine 657,15, 16 was present and phosphorylated identically in resting platelets from all horses and throughout the time course after activation with α‐thrombin (Fig 4B).…”

Section: Resultssupporting

confidence: 55%

“…Normal levels of the mTORC2 components rictor and mTOR, as well as normal phosphorylation of the mTORC2 target serine 657 of PKCα after activation, provide evidence that this complex functions normally in AET platelets 15, 16. Although recent studies have shown that pharmacological inhibition of mTORC2 does not inhibit aggregation of washed platelets, the role of this complex in fibrinogen binding and α‐granule secretion remains undefined 14, 24.…”

Section: Discussionmentioning

confidence: 99%

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Association of Factor V Secretion with Protein Kinase B Signaling in Platelets from Horses with Atypical Equine Thrombasthenia

Norris

Pombo

Shirley³

et al. 2015

Veterinary Internal Medicne

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BackgroundTwo congenital bleeding diatheses have been identified in Thoroughbred horses: Glanzmann thrombasthenia (GT) and a second, novel diathesis associated with abnormal platelet function in response to collagen and thrombin stimulation.Hypothesis/ObjectivesPlatelet dysfunction in horses with this second thrombasthenia results from a secretory defect.AnimalsTwo affected and 6 clinically normal horses.MethodsEx vivo study. Washed platelets were examined for (1) expression of the αIIb‐β3 integrin; (2) fibrinogen binding capacity in response to ADP and thrombin; (3) secretion of dense and α‐granules; (4) activation of the mammalian target of rapamycin (mTOR)‐protein kinase B (AKT) signaling pathway; and (5) cellular distribution of phosphatidylinositol‐4‐phosphate‐3‐kinase, class 2B (PIK3C2B) and SH2 containing inositol‐5′‐phosphatase 1 (SHIP1).ResultsPlatelets from affected horses expressed normal amounts of αIIb‐β3 integrin and bound fibrinogen normally in response to ADP, but bound 80% less fibrinogen in response to thrombin. α‐granules only released 50% as much Factor V as control platelets, but dense granules released their contents normally. Protein kinase B (AKT) phosphorylation was reduced after thrombin activation, but mTOR Complex 2 (mTORC2) and phosphoinositide‐dependent kinase 1 (PDK1) signaling were normal. SH2‐containing inositol‐5'‐phosphatase 1 (SHIP1) did not localize to the cytoskeleton of affected platelets and was decreased overall consistent with reduced AKT phosphorylation.Conclusions and clinical significanceDefects in fibrinogen binding, granule secretion, and signal transduction are unique to this thrombasthenia, which we designate as atypical equine thrombasthenia.

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Section: Resultssupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Association of Factor V Secretion with Protein Kinase B Signaling in Platelets from Horses with Atypical Equine Thrombasthenia

Norris

Pombo

Shirley³

et al. 2015

Veterinary Internal Medicne

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“…These complexes differ in their major binding partner: raptor (regulatory-associated protein of TOR) in mTORC1 and rictor (rapamycin-insensitive companion of mTOR) in mTORC2 (REFS 23 ,24 ) (FIG. 2).…”

Section: Mtor Kinase Complexes and Their Activitiesmentioning

confidence: 99%

The TORrid affairs of viruses: effects of mammalian DNA viruses on the PI3K–Akt–mTOR signalling pathway

et al. 2008

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The successful replication of mammalian DNA viruses requires that they gain control of key cellular signalling pathways that affect broad aspects of cellular macromolecular synthesis, metabolism, growth and survival. The phosphatidylinositol 3′-kinase-Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway is one such pathway. Mammalian DNA viruses have evolved various mechanisms to activate this pathway to obtain the benefits of Akt activation, including the maintenance of translation through the activation of mTOR. In addition, viruses must overcome the inhibition of this pathway that results from the activation of cellular stress responses during viral infection. This Review will discuss the range of mechanisms that mammalian DNA viruses use to activate this pathway, as well as the multiple mechanisms these viruses have evolved to circumvent inhibitory stress signalling.The successful replication of mammalian DNA viruses, such as polyomaviruses (also called papovaviruses), adenoviruses, herpesviruses and poxviruses, requires viral adaptation of the host cell to establish an environment that can accommodate the increased demands for nutrients, energy and macromolecular synthesis that accompany viral infection. All DNA viruses must gain control of key cellular signalling pathways that affect broad aspects of cellular macromolecular synthesis, metabolism, growth and survival. The phosphatidylinositol 3′-kinase-Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway is one such pathway. Virtually all mammalian viruses, both DNA and RNA, must regulate this pathway, either by activating or inactivating some aspect of it 1 . In general, mammalian DNA viruses activate this pathway at some point in their life cycle to benefit from the growth, metabolic, anti-apoptotic and translational functions that the pathway controls. However, a viral mechanism for activating this pathway is not enough; to maintain control, viruses must also overcome the many controls that are used to inhibit this pathway when cellular stress responses are activated during viral infection.Correspondence to J.C.A., e-mail: alwine@mail.med.upenn.edu. * These authors contributed equally to this work. DATABASES NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe substantial alterations in cellular physiology that are induced by a viral lytic infectionas a result of nutrient depletion, energy depletion, hypoxia and endoplasmic reticulum stress -activate cellular stress responses that alert the cell to problems with metabolic and synthetic processes. The resulting stress signalling activates mechanisms that either alleviate the problems or, if this is not possible, induce apoptosis. Stress signalling has many effects that can be either beneficial or detrimental to viral growth. One example of a detrimental effect is inhibition of translation, which is among the most common consequences of cellular stress responses 2-6 . Although the inhibition of this energy-intensive process permits the cell to recover from stress,...

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“…mTOR is an evolutionarily conserved serine/threonine protein kinase which is constituted by two signaling complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Both complexes have specific effects on distinct cellular functions, such as controlling mRNA translation, ribosome biogenesis, autophagy and metabolism (4)(5)(6). mTORC2 phosphorylates AGC kinases such as AKT, serum-and glucocorticoid-induced protein kinase-1 (SGK1) and protein kinase C-alpha (PKCα) (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax

Espona-Fiedler

Soto‐Cerrato

Hosseini

et al. 2012

Biochemical Pharmacology

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The PI3K/AKT/mTOR signaling pathway regulates cell proliferation, survival and angiogenesis. The mammalian target of rapamycin (mTOR) is a protein kinase ubiquitously expressed within cells that regulates cell growth and survival by integrating nutrient and hormonal signals. mTOR exists in two complexes, mTORC1 and mTORC2. Hyperactivation of the mTOR protein has been linked to development of cancer, raising mTOR as an attractive target for cancer therapy. Prodigiosin (PG) and Obatoclax (OBX), two members of the prodiginines family, are small molecules with anticancer properties which are currently under clinical trials. In the present paper, we demonstrate that mTOR is a molecular target of both prodiginines in melanoma, a highly drug-resistant cancer model. The inhibition of mTORC1 and mTORC2 complexes by PG or OBX resulted in a loss of AKT phosphorylation at S473, preventing its full activation, with no significant effect on T308. The strongest activity inhibition (89%) was induced by PG on mTORC2. Binding assays using Surface Plasmon Resonance (SPR) provide kinetic and affinity data of the interaction of these small molecules with mTOR. In addition, in silico modelling produced a detailed atomic description of the binding modes. These results provide new data to understand the mechanism of action of these molecules, and provide new structural data that will allow the development of more specific mTOR inhibitors for cancer treatment.3

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Rictor, a Novel Binding Partner of mTOR, Defines a Rapamycin-Insensitive and Raptor-Independent Pathway that Regulates the Cytoskeleton

Cited by 2,432 publications

References 21 publications

Association of Factor V Secretion with Protein Kinase B Signaling in Platelets from Horses with Atypical Equine Thrombasthenia

Association of Factor V Secretion with Protein Kinase B Signaling in Platelets from Horses with Atypical Equine Thrombasthenia

The TORrid affairs of viruses: effects of mammalian DNA viruses on the PI3K–Akt–mTOR signalling pathway

Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax

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