Research Topics
Genomes and GenesSpecies | Robert AbrahamSummaryAffiliation: The Burnham Institute Country: USA Publications
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Publications
PI 3-kinase related kinases: 'big' players in stress-induced signaling pathwaysRobert T Abraham
Program in Signal Transduction Research, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92130, USA
DNA Repair (Amst) 3:883-7. 2004..This overview provides some general insights into the pharmacology, biochemistry, and function of this nonconventional group of protein kinases...- Cell biology. Guiding ATM to broken DNARobert T Abraham
Signal Transduction Program, The Burnham Institute, La Jolla, CA 92037, USA
Science 308:510-1. 2005 - Checkpoint signaling: epigenetic events sound the DNA strand-breaks alarm to the ATM protein kinaseRobert T Abraham
Program in Signal Transduction Research, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92130, USA
Bioessays 25:627-30. 2003..The new findings underscore the critical importance of epigenetic events in genome function and surveillance in mammalian cells... - Jurkat T cells and development of the T-cell receptor signalling paradigmRobert T Abraham
Program in Signal Transduction Research at The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA
Nat Rev Immunol 4:301-8. 2004 - Identification of TOR signaling complexes: more TORC for the cell growth engineRobert T Abraham
Program in Signal Transduction Research, Cancer Research Center, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Cell 111:9-12. 2002..The recent identification of novel TOR-interacting proteins has provided crucial insights into TOR regulation and function... - TOR signaling: an odyssey from cellular stress to the cell growth machineryRobert T Abraham
Signal Transduction Program, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA
Curr Biol 15:R139-41. 2005..Two recent reports have illuminated a mechanism whereby hypoxic stress dampens TOR signaling in metazoan cells... - The ATM-related kinase, hSMG-1, bridges genome and RNA surveillance pathwaysRobert T Abraham
Program in Signal Transduction Research, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92130, USA
DNA Repair (Amst) 3:919-25. 2004..In this review, we introduce a model in which hSMG-1 teams with ATM and ATR to insure the overall quality of the transcriptome in human cells... - mTOR as a positive regulator of tumor cell responses to hypoxiaR T Abraham
Program in Signal Transduction Research, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Curr Top Microbiol Immunol 279:299-319. 2004..Here we review evidence that mTOR functions as a positive regulator of HIF-1-dependent responses to hypoxic stress in human cancer cells... 
Hypoxia-induced assembly of prolyl hydroxylase PHD3 into complexes: implications for its activity and susceptibility for degradation by the E3 ligase Siah2Koh Nakayama
Signal Transduction Program, Burnham Institute for Medical Research, La Jolla, CA 92037, USA
Biochem J 401:217-26. 2007..These findings provide new insight into the mechanism underlying the regulation of PHD3 availability and activity in hypoxia by the E3 ligase Siah2...- Part-time cop nabs deviant DNARobert T Abraham
Nat Med 11:257-8. 2005 - MAPKAP kinase-2: three's company at the G(2) checkpointRobert T Abraham
Signal Transduction Program, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Mol Cell 17:163-4. 2005..Elegant studies in fission yeast by and in mammalian cells by offer new insights into the mechanism through which stress-induced p38 activation inhibits mitotic entry in eukaryotic cells... - Functional analysis of human microtubule-based motor proteins, the kinesins and dyneins, in mitosis/cytokinesis using RNA interferenceChangjun Zhu
The Burnham Institute, La Jolla, CA 92037, USA
Mol Biol Cell 16:3187-99. 2005..Using immunofluorescence analysis, time-lapse microscopy, and rescue experiments, we investigate the roles of these 12 kinesins in detail... - Interaction between human MCM7 and Rad17 proteins is required for replication checkpoint signalingCheng Chung Tsao
Program in Signal Transduction Research, Cancer Research Center, The Burnham Institute, La Jolla, CA 92037, USA
EMBO J 23:4660-9. 2004..These results demonstrate that hMCM7 plays a direct role in the transmission of DNA damage signals from active replication forks to the S-phase checkpoint machinery in human cells... - ATR functions as a gene dosage-dependent tumor suppressor on a mismatch repair-deficient backgroundYanan Fang
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
EMBO J 23:3164-74. 2004..These results demonstrate that MMR proteins and ATR functionally interact during the cellular response to genotoxic stress, and that ATR serves as a haploinsufficient tumor suppressor in MMR-deficient cells... - Dynamic recruitment of PAK1 to the immunological synapse is mediated by PIX independently of SLP-76 and Vav1Hyewon Phee
Department of Medicine, Howard Hughes Medical Institute, Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco, 94143, USA
Nat Immunol 6:608-17. 2005..These data indicate that a pathway involving the GIT-PIX-PAK1 complex has a crucial function in PAK1 activation by recruiting PAK1 to the immunological synapse... - Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinaseGary G Chiang
Program in Signal Transduction Research, The Burnham Institute, La Jolla, California 92037, USA
J Biol Chem 280:25485-90. 2005..Taken together, these results suggest that p70S6 kinase is a major effector of mTOR phosphorylation at Ser-2448 in response to both mitogen- and nutrient-derived stimuli... - A protective role for the human SMG-1 kinase against tumor necrosis factor-alpha-induced apoptosisVasco Oliveira
Department of Experimental Therapeutics, H Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida 33612, USA
J Biol Chem 283:13174-84. 2008..These results suggest that hSMG-1 plays an important role in cell survival during TNFalpha-induced stress... - A retroinhibition approach reveals a tumor cell-autonomous response to rapamycin in head and neck cancerPanomwat Amornphimoltham
Oral and Pharyngeal Cancer Branch, National Institute of Craniofacial and Dental Research, NIH, Bethesda, Maryland 20892 4330, USA
Cancer Res 68:1144-53. 2008..These findings indicate that HNSCC cells are the primary target of rapamycin in vivo, and provide evidence that its antiangiogenic effects may represent a downstream consequence of mTOR inhibition in HNSCC cells... - Discovery of lactoquinomycin and related pyranonaphthoquinones as potent and allosteric inhibitors of AKT/PKB: mechanistic involvement of AKT catalytic activation loop cysteinesLourdes Toral Barza
Oncology Research, Wyeth Research, Pearl River, NY 10965, USA
Mol Cancer Ther 6:3028-38. 2007..Moreover, lactoquinomycin reduced cellular mammalian target of rapamycin signaling and cap-dependent mRNA translation initiation. Our results highlight T-loop targeting as a new strategy for the generation of selective AKT inhibitors... - The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional culturesAmy L Howes
Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Mol Cancer Ther 6:2505-14. 2007..In addition, we propose that the use of three-dimensional tumor models is more predictive of in vivo growth inhibition by PI3K inhibitors in cancer cell lines lacking phosphatase and tensin homologue activity or expression... - SKAP55 modulates T cell antigen receptor-induced activation of the Ras-Erk-AP1 pathway by binding RasGRP1KARENA A KOSCO
Program on Inflammatory Disease Research, Infectious and Inflammatory Disease Center, The Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Mol Immunol 45:510-22. 2008..The binding of RasGRP1 to SKAP55 required the C-terminus of SKAP55 and was enhanced by tyrosine phosphorylation of SKAP55. These results suggest that SKAP55 modulates signal transduction from the TCR to Ras by binding to RasGRP1... - The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapyRobert T Abraham
Department of Oncology Discovery, Wyeth, Pearl River, New York 10960, USA
Clin Cancer Res 13:3109-14. 2007..This article highlights recent advances in our understanding of the mTOR signaling pathway and the implications of these findings for the clinical application of mTOR inhibitors in cancer patients... - The FRB domain of mTOR: NMR solution structure and inhibitor designMarilisa Leone
Cancer Research Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, California 92037, USA
Biochemistry 45:10294-302. 2006..As such, these ligands could be useful in deciphering the complex regulation of mTOR in the cell and in validating the FRB domain as a possible target for the development of novel therapeutic compounds... - The functional role of Cdc6 in S-G2/M in mammalian cellsEric Lau
The Burnham Institute, La Jolla, California 92037, USA
EMBO Rep 7:425-30. 2006..These results show that Cdc6 is not only required for G1 origin licensing, but is also crucial for proper S-phase DNA replication that is essential for DNA segregation during mitosis... - Moving out: mobilizing activated T cells from lymphoid tissuesGabriel Berstein
Nat Immunol 9:455-7. 2008 - Genotoxic stress targets human Chk1 for degradation by the ubiquitin-proteasome pathwayYou Wei Zhang
Signal Transduction Program, The Burnham Institute, La Jolla, California 92037, USA
Mol Cell 19:607-18. 2005..Proteolysis of activated Chk1 may promote checkpoint termination under normal conditions, and may play an important role in the cytotoxic effects of CPT and related anticancer drugs... - Antitumor activity of rapamycin in a transgenic mouse model of ErbB2-dependent human breast cancerMei Liu
Program in Signal Transduction Research, The Burnham Institute, La Jolla, California 92037, USA
Cancer Res 65:5325-36. 2005.... 
A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesisBoris Shor
Discovery Oncology, Wyeth Research, Pearl River, NY 10965, USA
Cancer Res 68:2934-43. 2008..This distinctive high-dose drug effect could be directly related to the antitumor activities of CCI-779 and other rapalogues in human cancer patients...- Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cellsAimee L Edinger
Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Cancer Res 63:8451-60. 2003..These results indicate that rapamycin exerts variable inhibitory actions on mTOR signaling functions and suggest that direct inhibitors of the mTOR kinase domain will display substantially broader anticancer activities than rapamycin... - Determination of the catalytic activities of mTOR and other members of the phosphoinositide-3-kinase-related kinase familyGary G Chiang
Program in Signal Transduction Research, The Burnham Institute, La Jolla, CA, USA
Methods Mol Biol 281:125-41. 2004..Here we describe, in detail, the determination of PIKK catalytic activity with a standardized immune-complex kinase assay protocol... - The rapamycin-binding domain governs substrate selectivity by the mammalian target of rapamycinLloyd P McMahon
Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA
Mol Cell Biol 22:7428-38. 2002..The findings also impose new limitations on interpreting results from experiments in which rapamycin and/or rapamycin-resistant forms of mTOR are used to investigate mTOR function in cells... - Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycinChristine C Hudson
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA
Mol Cell Biol 22:7004-14. 2002..These studies position mTOR as an upstream activator of HIF-1 function in cancer cells and suggest that the antitumor activity of rapamycin is mediated, in part, through the inhibition of cellular responses to hypoxic stress... - Pleiotropic defects in TCR signaling in a Vav-1-null Jurkat T-cell lineYoujia Cao
Department of Pharmacology and Cancer Biology and Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA
EMBO J 21:4809-19. 2002..Vav1 cells. Finally, evidence is presented to suggest that the alternative Vav family members, Vav-2 and Vav-3, are activated during TCR ligation, and partially compensate for the loss of Vav-1 in Jurkat T cells... - Distinct requirements for Ras oncogenesis in human versus mouse cellsNesrin M Hamad
Department of Pharmacology, Division of Neurology, Duke University Medical Center, Durham North Carolina 27710, USA
Genes Dev 16:2045-57. 2002..Thus, oncogenic Ras may transform murine and human cells by distinct mechanisms, and the RalGEF pathway--previously deemed to play a secondary role in Ras transformation--could represent a new target for anti-cancer therapy... - Activation of ZAP-70 through specific dephosphorylation at the inhibitory Tyr-292 by the low molecular weight phosphotyrosine phosphatase (LMPTP)Nunzio Bottini
Program of Signal Transduction, La Jolla Cancer Research Center, The Burnham Institute, La Jolla, California 92037, USA
J Biol Chem 277:24220-4. 2002..The ZAP-70 Y292F mutant was not affected by LMPTP. Our results indicate that LMPTP, like CD45, dephosphorylates a negative regulatory tyrosine site in a protein-tyrosine kinase and thereby strengthens T cell receptor signaling... 
Translocation of PKC[theta] in T cells is mediated by a nonconventional, PI3-K- and Vav-dependent pathway, but does not absolutely require phospholipase CMartin Villalba
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA
J Cell Biol 157:253-63. 2002..These results provide evidence that a nonconventional PI3-K- and Vav-dependent pathway mediates the selective membrane recruitment and, possibly, activation of PKCtheta in T cells...- Hypoxia links ATR and p53 through replication arrestEster M Hammond
Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA 94303 5152, USA
Mol Cell Biol 22:1834-43. 2002.... - Novel pyrrolo-quinoline derivatives as potent inhibitors for PI3-kinase related kinasesHairuo Peng
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA
Bioorg Med Chem 10:167-74. 2002.... - Tyrosine phosphorylation of VHR phosphatase by ZAP-70Andres Alonso
Program of Signal Transduction, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Nat Immunol 4:44-8. 2003..These results suggest that VHR is a target for ZAP-70 and tempers activation of the Erk2 pathway in a ZAP-70-controlled manner... - Mechanism of recruitment of WASP to the immunological synapse and of its activation following TCR ligationYoji Sasahara
Division of Immunology, Children s Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
Mol Cell 10:1269-81. 2002..These results suggest that the ZAP-70-CrkL-WIP pathway and PKCtheta link TCR to WASP activation... - Differential regulation of TCR-mediated gene transcription by Vav family membersShaheen Zakaria
Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
J Exp Med 199:429-34. 2004..These data indicate that, although both Vav proteins are biochemically coupled to the TCR, they regulate distinct molecular pathways leading to defined gene transcriptional events... - SLP-76 coordinates Nck-dependent Wiskott-Aldrich syndrome protein recruitment with Vav-1/Cdc42-dependent Wiskott-Aldrich syndrome protein activation at the T cell-APC contact siteRong Zeng
Department of Pathology, University of Chicago, Chicago, IL 60637, USA
J Immunol 171:1360-8. 2003..Taken together, these findings reconstruct the signaling pathway leading from TCR ligation to localized WASP activation... - Requirement of protein phosphatase 5 in DNA-damage-induced ATM activationAmbereen Ali
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA
Genes Dev 18:249-54. 2004..Together our findings indicate that PP5 plays an essential role in the activation and checkpoint signaling functions of ATM in cells that have suffered DNA double-strand breaks... - The mRNA surveillance protein hSMG-1 functions in genotoxic stress response pathways in mammalian cellsKathryn M Brumbaugh
Program in Signal Transduction Research, The Burnham Institute, La Jolla, CA 92037, USA
Mol Cell 14:585-98. 2004..Finally, NMD is suppressed in hSMG-1- but not ATM-deficient cells. These results indicate that hSMG-1 plays important roles in the maintenance of both genome and transcriptome integrity in human cells... - Vav-1 and the IKK alpha subunit of I kappa B kinase functionally associate to induce NF-kappa B activation in response to CD28 engagementEnza Piccolella
Department of Cellular and Developmental Biology, University of Rome La Sapienza, Rome, Italy
J Immunol 170:2895-903. 2003..Taken together, these data evidence that Vav-1 plays a key role in the control of NF-kappa B pathway by targeting IKK alpha in the T cell membrane and favoring its activation in response to CD28 stimulation... - Antigen receptors rap to integrin receptorsRobert T Abraham
Nat Immunol 3:212-3. 2002 - Isoform-specific phosphoinositide 3-kinase inhibitors from an arylmorpholine scaffoldZachary A Knight
Program in Chemistry and Chemical Biology, University of California-San Francisco, San Francisco, CA 94143, USA
Bioorg Med Chem 12:4749-59. 2004..13 microM, p110delta=0.63 microM). We also identify trends that suggest certain PI3-K isoforms may be more sensitive to potent inhibition by arylmorpholines, thereby guiding future drug design based on this pharmacophore... - Protein tyrosine phosphorylation in T cell signalingTomas Mustelin
Program of Signal Transduction, Cancer Research Center, The Burnham Institute, La Jolla, CA 92037, USA
Front Biosci 7:d918-69. 2002..Finally, we briefly review the key substrates for tyrosine phosphorylation and their role in coupling the kinases and phosphatases to gene transcription and other aspects of the T lymphocyte response to antigen... - Targeting the mTOR signaling network in cancerGary G Chiang
Program in Signal Transduction, Burnham Institute for Medical Research, 10901 N Torrey Pines Road, La Jolla, CA 92037, USA
Trends Mol Med 13:433-42. 2007..In this review, we discuss the regulatory pathways that govern mTOR activity, and highlight clinical results obtained with the first generation of mTOR inhibitors to reach the oncology clinics... - Mammalian target of rapamycin as a therapeutic target in oncologyRobert T Abraham
Oncology Discovery Research, Wyeth, 401 N Middletown Road, Pearl River, NY 10965, USA
Expert Opin Ther Targets 12:209-22. 2008..The mammalian target of rapamycin (mTOR) has emerged as a validated therapeutic target in cancer and mTOR inhibitors alter tumor cell responses to mitogenic signals and microenvironmental stress... - Checkpoint signalling: focusing on 53BP1Robert T Abraham
Nat Cell Biol 4:E277-9. 2002 - Rap1 reduxRobert T Abraham
Nat Immunol 4:725-7. 2003 - Characterization of the cytotoxic activities of novel analogues of the antitumor agent, lavendamycinYanan Fang
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710, USA
Mol Cancer Ther 2:517-26. 2003..Finally, MB-97 showed significant cytotoxic activity in the National Cancer Institute's panel of 60 cancer cell lines and antitumor activity in vivo in hollow fiber tumorigenesis assays... - Signalomic signatures enlighten drug profilingRobert T Abraham
Nat Chem Biol 2:295-6. 2006 - A new link between the c-Abl tyrosine kinase and phosphoinositide signalling through PLC-gamma1Rina Plattner
Department of Pharmacology and Cancer Biology Duke University Medical Center Durham, NC 27710, USA
Nat Cell Biol 5:309-19. 2003..After activation, c-Abl phosphorylates PLC-gamma1 and negatively modulates its function in vivo. These findings uncover a newly discovered functional interdependence between non-receptor Tyr kinase and lipid signalling pathways... - The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenograftsNathan T Ihle
Arizona Cancer Center, University of Arizona, Tucson, USA
Mol Cancer Ther 4:1349-57. 2005..Thus, PX-866, by inhibiting PI3-K signaling, may have clinical use in increasing the response to EGFR inhibitors such as gefitinib in patients with NSCLC and possibly in other cancers who do not respond to EGFR inhibition... - Turning the replication checkpoint on and offYou-Wei Zhang
Molecular and Cellular Biology, The Salk Institute, La Jolla, California, USA
Cell Cycle 5:125-8. 2006..This review provides an overview of the study's major findings, together with their implications for both replication checkpoint function and tumor responsiveness to CPT and related anticancer drugs...
Research Grants
- Roles of ATM and ATR Kinases in DNA Damage ResponsesRobert Abraham; Fiscal Year: 2004....
- SIGNAL TRANSDUCTION FROM THE T CELL ANTIGEN RECEPTORRobert Abraham; Fiscal Year: 2003..However, experiments in fibroblasts stimulated with PDGF indicate that phosphorylation at residue 783 is necessary for increased enzymatic activity, while phosphorylation at Y771 results in inhibition of activity. ..
- CELLULAR PHARMACOLOGY OF RAPAMYCINRobert Abraham; Fiscal Year: 2001....
- CELLULAR PHARMACOLOGY OF RAPAMYCINRobert Abraham; Fiscal Year: 2004..abstract_text> ..