Brendan D Manning

Summary

Affiliation: Harvard University
Country: USA

Publications

  1. pmc AKT/PKB signaling: navigating downstream
    Brendan D Manning
    Department of Genetics and Complex Diseases, Harvard School of Public Health, SPH2 117, Boston, MA 02115, USA
    Cell 129:1261-74. 2007
  2. pmc Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway
    Hui H Zhang
    Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA
    PLoS ONE 4:e6189. 2009
  3. pmc Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis
    Umut Ozcan
    Department of Genetics and Complex Diseases, Harvard School of Public Health, Harvard University, Boston, MA 02115, USA
    Mol Cell 29:541-51. 2008
  4. pmc Chronic activation of mTOR complex 1 is sufficient to cause hepatocellular carcinoma in mice
    Suchithra Menon
    Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA
    Sci Signal 5:ra24. 2012
  5. pmc The TSC1-TSC2 complex is required for proper activation of mTOR complex 2
    Jingxiang Huang
    Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA
    Mol Cell Biol 28:4104-15. 2008
  6. pmc TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1
    Christian C Dibble
    Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA
    Mol Cell 47:535-46. 2012
  7. pmc Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2
    Brendan D Manning
    Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA
    Genes Dev 19:1773-8. 2005
  8. pmc Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways
    Jessica L Yecies
    Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA
    Cell Metab 14:21-32. 2011
  9. pmc NF2/merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growth
    Marianne 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
  10. ncbi request reprint Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb
    Andrew R Tee
    Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Curr Biol 13:1259-68. 2003

Collaborators

Detail Information

Publications45

  1. pmc AKT/PKB signaling: navigating downstream
    Brendan 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...
  2. pmc Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway
    Hui H Zhang
    Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA
    PLoS ONE 4:e6189. 2009
    ....
  3. pmc Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis
    Umut 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...
  4. pmc Chronic activation of mTOR complex 1 is sufficient to cause hepatocellular carcinoma in mice
    Suchithra Menon
    Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA
    Sci Signal 5:ra24. 2012
    ..Therefore, we conclude that increased activation of mTORC1 can promote carcinogenesis and may thus represent a key molecular link between cancer risk and environmental factors, such as diet...
  5. pmc The TSC1-TSC2 complex is required for proper activation of mTOR complex 2
    Jingxiang 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...
  6. pmc TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1
    Christian C Dibble
    Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA
    Mol Cell 47:535-46. 2012
    ..Like the other TSC-TBC components, TBC1D7 knockdown results in increased mTORC1 signaling, delayed induction of autophagy, and enhanced cell growth under poor growth conditions...
  7. pmc Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2
    Brendan 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...
  8. pmc Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways
    Jessica L Yecies
    Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA
    Cell Metab 14:21-32. 2011
    ..We provide evidence that this mTORC1-independent pathway involves Akt-mediated suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2...
  9. pmc NF2/merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growth
    Marianne 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
    ....
  10. ncbi request reprint Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb
    Andrew 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...
  11. pmc Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1
    Christian 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...
  12. pmc S6K1 regulates GSK3 under conditions of mTOR-dependent feedback inhibition of Akt
    Hui 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...
  13. pmc Activation of a metabolic gene regulatory network downstream of mTOR complex 1
    Katrin 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...
  14. pmc Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling
    Andrew R Tee
    Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 99:13571-6. 2002
    ....
  15. pmc Spatial Control of the TSC Complex Integrates Insulin and Nutrient Regulation of mTORC1 at the Lysosome
    Suchithra Menon
    Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA
    Cell 156:771-85. 2014
    ..These findings provide a unifying mechanism by which independent pathways affecting the spatial recruitment of mTORC1 and the TSC complex to Rheb at the lysosomal surface serve to integrate diverse growth signals. ..
  16. pmc 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 acid
    Partha 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...
  17. ncbi request reprint Rheb fills a GAP between TSC and TOR
    Brendan 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
    ....
  18. pmc The TSC1-TSC2 complex: a molecular switchboard controlling cell growth
    Jingxiang 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...
  19. pmc Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors
    Jingxiang 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...
  20. ncbi request reprint The LKB1 tumor suppressor negatively regulates mTOR signaling
    Reuben 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...
  21. pmc Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex
    James 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...
  22. pmc Phosphatidylcholine transfer protein interacts with thioesterase superfamily member 2 to attenuate insulin signaling
    Baran A Ersoy
    Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Sci Signal 6:ra64. 2013
    ..These findings reveal a phospholipid-dependent mechanism that suppresses insulin signaling downstream of its receptor. ..
  23. pmc Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1
    Issam Ben-Sahra
    Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA
    Science 339:1323-8. 2013
    ..Growth signaling through mTORC1 thus stimulates the production of new nucleotides to accommodate an increase in RNA and DNA synthesis needed for ribosome biogenesis and anabolic growth...
  24. ncbi request reprint Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways
    David 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...
  25. pmc Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors
    Thomas De Raedt
    Genetics Division, Department of Medicine, Brigham and Women s Hospital, Boston, MA, 02115, USA
    Cancer Cell 20:400-13. 2011
    ..Notably, the mechanism by which these agents cooperate reveals a therapeutic paradigm that can be expanded to develop additional combinations...
  26. doi request reprint A growing role for mTOR in promoting anabolic metabolism
    Jessica J Howell
    Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, SPH2 117, Boston, MA 02115, USA
    Biochem Soc Trans 41:906-12. 2013
    ..As mTORC1 is aberrantly activated in a number of tumour syndromes and up to 80% of human cancers, we also discuss the importance of this mTORC1-driven biosynthetic programme in tumour growth and progression. ..
  27. doi request reprint mTOR links oncogenic signaling to tumor cell metabolism
    Jessica L Yecies
    Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA
    J Mol Med (Berl) 89:221-8. 2011
    ..Here, we focus on the molecular mechanisms of metabolic regulation by mTORC1 and the potential consequences for anabolic tumor growth and therapeutic strategies...
  28. pmc A complex interplay between Akt, TSC2 and the two mTOR complexes
    Jingxiang 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...
  29. pmc Signal integration by mTORC1 coordinates nutrient input with biosynthetic output
    Christian C Dibble
    Division of Signal Transduction, Beth Israel Deaconess Medical Center, Systems Biology Department, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nat Cell Biol 15:555-64. 2013
    ..Our expanding understanding of the regulatory network upstream of mTORC1 provides molecular insights into the integrated sensing mechanisms by which diverse cellular signals converge to control cell physiology...
  30. pmc Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis
    Brendan 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...
  31. pmc mTOR couples cellular nutrient sensing to organismal metabolic homeostasis
    Jessica J Howell
    Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA
    Trends Endocrinol Metab 22:94-102. 2011
    ..In this review, we detail the current knowledge of the physiological functions of mTORC1 in controlling systemic metabolism, with a focus on advances obtained through genetic mouse models...
  32. pmc The TSC-mTOR pathway regulates macrophage polarization
    Vanessa Byles
    1 Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA 2
    Nat Commun 4:2834. 2013
    ....
  33. doi request reprint mTORC1 status dictates tumor response to targeted therapeutics
    Ilana Kelsey
    Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA
    Sci Signal 6:pe31. 2013
    ..Studies are now suggesting that to effectively target the major oncogenic signaling pathway in a given tumor, mTORC1 must be inhibited, and that its sustained activation is a major mechanism of resistance to such targeted therapies. ..
  34. pmc Metabolic and functional genomic studies identify deoxythymidylate kinase as a target in LKB1-mutant lung cancer
    Yan Liu
    Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
    Cancer Discov 3:870-9. 2013
    ..Thus, LKB1-mutant lung cancers have deficits in nucleotide metabolism that confer hypersensitivity to DTYMK inhibition, suggesting that DTYMK is a potential therapeutic target in this aggressive subset of tumors. ..
  35. pmc Transcriptional control of cellular metabolism by mTOR signaling
    Jessica L Yecies
    Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts, USA
    Cancer Res 71:2815-20. 2011
    ..As mTORC1 signaling is aberrantly elevated in the majority of genetic tumor syndromes and sporadic cancers, this pathway is poised to be a major driver of the metabolic conversion of tumor cells...
  36. doi request reprint Challenges and opportunities in defining the essential cancer kinome
    Brendan 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...
  37. doi request reprint A molecular link between AKT regulation and chemotherapeutic response
    Christian 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...
  38. pmc The multifaceted role of mTORC1 in the control of lipid metabolism
    Stéphane J H Ricoult
    Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, SPH2 117, Boston, Massachusetts 02115, USA
    EMBO Rep 14:242-51. 2013
    ..Defining the role of mTORC1 signalling in these metabolic processes is crucial to understanding the pathophysiology of obesity and its relationship to complex diseases, including diabetes and cancer...
  39. ncbi request reprint Hitting the target: emerging technologies in the search for kinase substrates
    Brendan 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...
  40. ncbi request reprint Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway
    Brendan 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...
  41. pmc Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis
    Pengda Liu
    Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    Nat Cell Biol 15:1340-50. 2013
    ....
  42. doi request reprint Adaptation to starvation: translating a matter of life or death
    Brendan D Manning
    Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, SPH2 117, Boston, MA 02115, USA
    Cancer Cell 23:713-5. 2013
    ..In a recent issue of Cell, Leprivier and colleagues demonstrate that eEF2K, which can inhibit translation elongation acutely during protein synthesis, is a critical switch in the survival versus death fate of starved cancer cells...
  43. doi request reprint Chewing the fat on tumor cell metabolism
    Jessica 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...
  44. ncbi request reprint Targeting the PI3K-Akt pathway in human cancer: rationale and promise
    Ji Luo
    Howard Hughes Medical Institute, USA
    Cancer Cell 4:257-62. 2003
  45. ncbi request reprint The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor
    Akrit 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...