Research Topics
| Brendan ManningSummaryAffiliation: Harvard University Country: USA Publications
Research Grants
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Detail Information
Publications
A complex interplay between Akt, TSC2 and the two mTOR complexesJingxiang Huang
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA
Biochem Soc Trans 37:217-22. 2009..The present review discusses our current understanding of the increasingly complex functional interactions between Akt, the TSC1-TSC2 complex and mTOR, which are fundamentally important players in a large variety of human diseases...- Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2Brendan D Manning
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA
Genes Dev 19:1773-8. 2005..However, Pten haploinsufficiency restores Akt signaling in these tumors and dramatically enhances their severity. This study demonstrates that attenuation of the PI3K-Akt pathway in tumors lacking TSC2 contributes to their benign nature... 
Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesisBrendan D Manning
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA
J Cell Biol 167:399-403. 2004..These findings form a novel basis for improved understanding of the pathophysiology of metabolic diseases (e.g., diabetes and obesity), tumor syndromes (e.g., tuberous sclerosis complex and Peutz-Jegher's syndrome), and human cancers...
Challenges and opportunities in defining the essential cancer kinomeBrendan D Manning
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA
Sci Signal 2:pe15. 2009..Although the concept of oncogene addiction is powerful in designing therapeutic strategies to treat cancer, unbiased kinome-specific and genome-wide RNAi screens are revealing unexploited areas of potential therapeutic intervention...
Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathwayBrendan D Manning
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
Mol Cell 10:151-62. 2002..Finally, we find that a tuberin mutant lacking the major PI3K-dependent phosphorylation sites can block the activation of S6K1, suggesting a means by which the PI3K-Akt pathway regulates S6K1 activity...- Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complexJames Brugarolas
Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
Genes Dev 18:2893-904. 2004..Inhibition of mTOR function by hypoxia is likely to be important for tumor suppression as TSC2-deficient cells maintain abnormally high levels of cell proliferation under hypoxia... - The LKB1 tumor suppressor negatively regulates mTOR signalingReuben J Shaw
Department of Systems Biology, Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA
Cancer Cell 6:91-9. 2004..These findings position aberrant mTOR activation at the nexus of these germline neoplastic conditions and suggest the use of mTOR inhibitors in the treatment of Peutz-Jeghers syndrome... - Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosisUmut Ozcan
Department of Genetics and Complex Diseases, Harvard School of Public Health, Harvard University, Boston, MA 02115, USA
Mol Cell 29:541-51. 2008..These results demonstrate ER stress as a critical component of the pathologies associated with dysregulated mTOR activity and offer the possibility to exploit this mechanism for new therapeutic opportunities... - Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward RhebAndrew R Tee
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Curr Biol 13:1259-68. 2003..Tuberin and Hamartin form a tumor suppressor heterodimer that inhibits the mammalian target of rapamycin (mTOR) nutrient signaling input, but how this occurs is unclear... - Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressorsJingxiang Huang
Department of Genetics and Complex Diseases, Harvard School of Public Health, Massachusetts General Hospital, Boston, Massachusetts 02115, USA
Cancer Res 69:6107-14. 2009..These findings suggest that the TSC1-TSC2 complex plays opposing roles in tumor progression, both blocking and promoting specific oncogenic pathways through its effects on mTORC1 inhibition and mTORC2 activation, respectively... - Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signalingAndrew R Tee
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Proc Natl Acad Sci U S A 99:13571-6. 2002.... - The TSC1-TSC2 complex is required for proper activation of mTOR complex 2Jingxiang Huang
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA
Mol Cell Biol 28:4104-15. 2008..These data demonstrate that the TSC1-TSC2 complex inhibits mTORC1 and activates mTORC2, which through different mechanisms promotes Akt activation... - Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathwayHui H Zhang
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA
PLoS ONE 4:e6189. 2009.... - AKT/PKB signaling: navigating downstreamBrendan D Manning
Department of Genetics and Complex Diseases, Harvard School of Public Health, SPH2 117, Boston, MA 02115, USA
Cell 129:1261-74. 2007..In addition, we discuss 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... - S6K1 regulates GSK3 under conditions of mTOR-dependent feedback inhibition of AktHui H Zhang
Department of Genetics and Complex Diseases, Harvard School of Public Health, Harvard Medical School, Boston, Massachusetts 02115, USA
Mol Cell 24:185-97. 2006..We find that GSK3 can also be regulated downstream of mTORC1 in a HepG2 model of cellular insulin resistance. Therefore, we define conditions in which S6K1, rather than Akt, is the predominant GSK3 regulatory kinase... - Rheb fills a GAP between TSC and TORBrendan D Manning
Department of Cell Biology, Harvard Medical School, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Rm 1028, 4 Blackfan Circle, Boston, MA 02115, USA
Trends Biochem Sci 28:573-6. 2003.... - Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathwaysDavid J Kwiatkowski
Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, One Blackfan Circle, 6th Floor, Room 216, Boston, MA 02115, USA
Hum Mol Genet 14:R251-8. 2005..As a specific inhibitor of mTOR, rapamycin has therapeutic potential for the treatment of TSC hamartomas... - NF2/merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growthMarianne F James
Center for Human Genetic Research, Massachusetts General Hospital, Richard B Simches Research Building, 185 Cambridge St, Boston, MA 02114, USA
Mol Cell Biol 29:4250-61. 2009.... - The mammalian target of rapamycin complex 1 regulates leptin biosynthesis in adipocytes at the level of translation: the role of the 5'-untranslated region in the expression of leptin messenger ribonucleic acidPartha Chakrabarti
Boston University School of Medicine, Boston, Massachusetts 02118, USA
Mol Endocrinol 22:2260-7. 2008..It appears, therefore, that mTORC1 controls translation of leptin mRNA via a novel mechanism that does not require the presence of either the 5'-terminal oligopyrimidine tract or the 5'-UTR... - The TSC1-TSC2 complex: a molecular switchboard controlling cell growthJingxiang Huang
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA
Biochem J 412:179-90. 2008..In the present review we focus on the molecular details of TSC1-TSC2 complex regulation and function as it relates to the control of Rheb and mTORC1... - Activation of a metabolic gene regulatory network downstream of mTOR complex 1Katrin Düvel
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA
Mol Cell 39:171-83. 2010..Therefore, in addition to promoting protein synthesis, mTORC1 activates specific bioenergetic and anabolic cellular processes that are likely to contribute to human physiology and disease... - A molecular link between AKT regulation and chemotherapeutic responseChristian C Dibble
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA
Cancer Cell 16:178-80. 2009..In this issue of Cancer Cell, Pei et al. show that FKBP51 negatively regulates AKT through the phosphatase PHLPP. This regulation appears to be a determinant of chemosensitivity in cancer cells... - Hitting the target: emerging technologies in the search for kinase substratesBrendan D Manning
Department of Cell Biology, Harvard Medical School, Division of Signal Transduction, Beth Israel Deaconess Medical Center, 4 Blackfan Circle, Boston, MA 02115, USA
Sci STKE 2002:PE49. 2002..We describe these approaches and discuss their utility and inherent caveats... - Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1Christian C Dibble
Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Ave, SPH2 117, Boston, MA 02115, USA
Mol Cell Biol 29:5657-70. 2009..We provide evidence that Rictor-T1135 phosphorylation acts in parallel with other mTORC1-dependent feedback mechanisms, such as those affecting IRS-1 signaling to PI3K, to regulate the response of Akt to insulin... - Chewing the fat on tumor cell metabolismJessica L Yecies
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA
Cell 140:28-30. 2010..Nomura et al. (2010) now demonstrate that an increase in monoacylglycerol lipase (MAGL) drives tumorigenesis through the lipolytic release and remodeling of free fatty acids... - The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptorAkrit Sodhi
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA
Cancer Cell 10:133-43. 2006..Collectively, these results implicate mTOR in KS initiation and suggest that the sarcomagenic potential of KSHV may be a direct consequence of the profound sensitivity of endothelial cells to vGPCR dysregulation of the TSC2/mTOR pathway... - Targeting the PI3K-Akt pathway in human cancer: rationale and promiseJi Luo
Howard Hughes Medical Institute, USA
Cancer Cell 4:257-62. 2003
Research Grants
- Pathologic and therapeutic implications of Akt attenuation in TSC cells and tumorBrendan Manning; Fiscal Year: 2007....
- Pathologic and therapeutic implications of Akt attenuation in TSC cells and tumorBrendan Manning; Fiscal Year: 2009....
- Regulatory mechanisms and role of the PI3K-TSC-mTOR signaling network in tumorsBrendan D Manning; Fiscal Year: 2010..Under this proposal, a particular emphasis will be put on the role of this signaling network in the development, progression, and treatment of glioblastoma. ..