Research Topics
Genomes and GenesSpecies | ALEXANDRA NEWTONSummaryAffiliation: University of California Country: USA Publications
Research Grants
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Publications
PKA, PKC, and AKAP localization in and around the neuromuscular junctionG A Perkins
Department of Neurosciences and the National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA 92093 0608, USA
BMC Neurosci 2:17. 2001..We found previously that a new class of AKAPs, dual-specific AKAPs, denoted D-AKAP1 and D-AKAP2, bind to RIalpha in addition to the RII subunits...
Regulation of protein kinase CA C Newton
Department of Pharmacology, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093 0640, USA
Curr Opin Cell Biol 9:161-7. 1997....- Induced fit and wit: celebrating the life of Daniel E. Koshland, Jr. (1920 - 2007)Alexandra C Newton
Department of Pharmacology, University of California San Diego, La Jolla, California, USA
IUBMB Life 59:741-3. 2007 - Lipid activation of protein kinasesAlexandra C Newton
Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093 0721, USA
J Lipid Res 50:S266-71. 2009.... - Diacylglycerol's affair with protein kinase C turns 25Alexandra C Newton
Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093 0640, USA
Trends Pharmacol Sci 25:175-7. 2004..This discovery placed the lipid second messenger-protein kinase C signaling pathway center stage alongside the cAMP-protein kinase A pathway, which was already established as a fundamental mechanism for transducing extracellular signals... - Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigmAlexandra C Newton
Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093 0640, USA
Biochem J 370:361-71. 2003..This review focuses on how phosphorylation at each of these sites regulates the maturation, signalling and down-regulation of PKC as a paradigm for how these sites control the function of the ABC kinases... - Protein kinase C: poised to signalAlexandra C Newton
Dept of Pharmacology, Univ of California at San Diego, La Jolla, 92093, USA
Am J Physiol Endocrinol Metab 298:E395-402. 2010..This review introduces the PKC family and then focuses on recent advances in understanding the cellular regulation of its diacylglycerol-regulated members... - Differential spatial and temporal phosphorylation of the visual receptor, rhodopsin, at two primary phosphorylation sites in mice exposed to lightRyan A Adams
Department of Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0640, USA
Biochem J 374:537-43. 2003..Our results are consistent with light triggering rapid priming phosphorylations of rhodopsin by rhodopsin kinase, followed by a slower phosphorylation on Ser(334), which is regulated by protein kinase C... - A genetically encoded fluorescent reporter reveals oscillatory phosphorylation by protein kinase CJonathan D Violin
Department of Pharmacology, University of California, San Diego, La Jolla 92093, USA
J Cell Biol 161:899-909. 2003..Thus, specificity of PKC signaling depends on the local second messenger-controlled equilibrium between kinase and phosphatase activities to result in strict calcium-controlled temporal regulation of substrate phosphorylation... - The protein scaffold NHERF-1 controls the amplitude and duration of localized protein kinase D activityMaya T Kunkel
Department of Pharmacology, University of California, San Diego, La Jolla, California 92093 0721, USA
J Biol Chem 284:24653-61. 2009..Thus, live cell imaging of PKD activity demonstrates ultrasensitive control of kinase signaling at the scaffold compared with bulk activity in the cytosol or at the plasma membrane... - The phosphatase PHLPP controls the cellular levels of protein kinase CTianyan Gao
Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA
J Biol Chem 283:6300-11. 2008..These data reveal that PHLPP controls the cellular levels of PKC by specifically dephosphorylating the hydrophobic motif, thus destabilizing the enzyme and promoting its degradation... - Spinal phosphinositide 3-kinase-Akt-mammalian target of rapamycin signaling cascades in inflammation-induced hyperalgesiaQinghao Xu
Department of Anesthesiology, University of California, San Diego, La Jolla, California 92093, USA
J Neurosci 31:2113-24. 2011..Together, these findings reveal that afferent inputs trigged by peripheral inflammation initiate spinal activation of PI3K-Akt-mTOR signaling pathway, a component of which participates in neuronal circuits of facilitated pain processing... - PHLPP-1 negatively regulates Akt activity and survival in the heartShigeki Miyamoto
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093 0636, USA
Circ Res 107:476-84. 2010..The regulatory role of PHLPP-1 in the heart has not been considered... - The ins and outs of protein kinase CAlexandra C Newton
Department of Pharmacology, University of California at San Diego, La Jolla, USA
Methods Mol Biol 233:3-7. 2003 
Kinetic analysis of the interaction of the C1 domain of protein kinase C with lipid membranes by stopped-flow spectroscopyDaniel R Dries
Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093, USA
J Biol Chem 283:7885-93. 2008....- A single residue in the C1 domain sensitizes novel protein kinase C isoforms to cellular diacylglycerol productionDaniel R Dries
Biomedical Sciences Graduate Program and Department of Pharmacology, University of California at San Diego, La Jolla, California 92093, USA
J Biol Chem 282:826-30. 2007..The finding that a single residue controls the affinity of the C1 domain for DAG-containing membranes provides a molecular explanation for why 1) DAG alone is sufficient to activate nPKCs but not cPKCs and 2) nPKCs target to the Golgi... - Measuring the interaction of protein kinase C with membranes: an introductionAlexandra C Newton
Department of Pharmacology, University of California at San Diego, La Jolla, USA
Methods Mol Biol 233:89-92. 2003 - Spatiotemporal dynamics of lipid signaling: protein kinase C as a paradigmLisa L Gallegos
Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093 0721, USA
IUBMB Life 60:782-9. 2008..This review focuses on the spatiotemporal dynamics of PKC activation and how it is controlled by lipid second messengers... - The chaperones Hsp90 and Cdc37 mediate the maturation and stabilization of protein kinase C through a conserved PXXP motif in the C-terminal tailChristine M Gould
Pharmacology Department, University of California, San Diego, La Jolla, California 92039 0721, USA
J Biol Chem 284:4921-35. 2009.... - Spatio-temporal dynamics of protein kinase B/Akt signaling revealed by a genetically encoded fluorescent reporterMaya T Kunkel
Department of Pharmacology and Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093 0721, USA
J Biol Chem 280:5581-7. 2005..These data reveal spatio-temporal gradients of both signal propagation and signal termination in PKB signaling... - Analyzing protein kinase C activationAlexandra C Newton
Department of Pharmacology, University of California at San Diego, La Jolla, California 92093, USA
Methods Enzymol 345:499-506. 2002 - The turn motif is a phosphorylation switch that regulates the binding of Hsp70 to protein kinase CTianyan Gao
Department of Pharmacology, University of California, La Jolla, California 92093 0640, USA
J Biol Chem 277:31585-92. 2002..Disruption of this interaction prevents re-phosphorylation and targets the enzyme for down-regulation... - Invariant Leu preceding turn motif phosphorylation site controls the interaction of protein kinase C with Hsp70Tianyan Gao
Department of Pharmacology, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
J Biol Chem 281:32461-8. 2006..Thus, Hsp70 binds a hydrophobic residue preceding the turn motif, protecting PKC from down-regulation and sustaining the signaling lifetime of the kinase... - PHLiPPing the switch on Akt and protein kinase C signalingJohn Brognard
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093 0721, USA
Trends Endocrinol Metab 19:223-30. 2008..This review focuses on the function of PHLPP1 and PHLPP2 in modulating signaling by Akt and PKC... - Interaction with AKAP79 modifies the cellular pharmacology of PKCNaoto Hoshi
Department of Pharmacology, 360 Med Surge II, University of California, Irvine, Irvine, CA 92697, USA
Mol Cell 37:541-50. 2010..This implies that intracellular binding partners not only couple individual molecular events in a cell signaling process but can also change the pharmacological profile of certain protein kinases... - Calcium transduces plasma membrane receptor signals to produce diacylglycerol at Golgi membranesMaya T Kunkel
Department of Pharmacology, University of California at San Diego, La Jolla, California 92093, USA
J Biol Chem 285:22748-52. 2010..Thus, agonist-evoked increases in intracellular Ca(2+) cause increases in Golgi diacylglycerol, allowing this intracellular membrane to serve as a platform for signaling by protein kinases C and D... - Protein phosphatase PHLPP1 controls the light-induced resetting of the circadian clockSatoru Masubuchi
Department of Pharmacology, School of Medicine, University of California, Irvine, CA 92697, USA
Proc Natl Acad Sci U S A 107:1642-7. 2010..Our findings reveal that PHLPP1 exerts a previously unappreciated role in circadian control, governing the consolidation of circadian periodicity after resetting... - Pathway illuminated: visualizing protein kinase C signalingJonathan D Violin
Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093-0640, USA
IUBMB Life 55:653-60. 2003..This review discusses how fluorescence imaging studies have illuminated the fidelity with which protein kinase C transduces rapidly changing extracellular information into intracellular phosphorylation signals... - PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoformsJohn Brognard
Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA
Mol Cell 25:917-31. 2007..Our data unveil a mechanism to selectively terminate Akt-signaling pathways through the differential inactivation of specific Akt isoforms by specific PHLPP isoforms... - Calcium-dependent regulation of protein kinase D revealed by a genetically encoded kinase activity reporterMaya T Kunkel
Department of Pharmacology and Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California 92093, USA
J Biol Chem 282:6733-42. 2007..These data reveal that Ca(2+) is a major contributor to the initiation of PKD signaling through positive feedback regulation of diacylglycerol production, unveiling a new mechanism in PKD activation... - Targeting protein kinase C activity reporter to discrete intracellular regions reveals spatiotemporal differences in agonist-dependent signalingLisa L Gallegos
Department of Pharmacology, University of California at San Diego, La Jolla, California 92093, USA
J Biol Chem 281:30947-56. 2006..Our data reveal that the magnitude and duration of PKC signaling is location-specific and controlled by the level of phosphatase activity and persistence of DAG at each location... - Measuring the binding of protein kinase C to sucrose-loaded vesiclesJennifer Giorgione
Department of Pharmacology, University of California at San Diego, La Jolla, USA
Methods Mol Biol 233:105-13. 2003 - Common polymorphism in the phosphatase PHLPP2 results in reduced regulation of Akt and protein kinase CJohn Brognard
Department of Pharmacology and Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, California 92093 0721, USA
J Biol Chem 284:15215-23. 2009..Thus, we have identified a functional polymorphism that impairs the activity of PHLPP2 and correlates with elevated Akt phosphorylation and increased PKC levels... - Protein kinase C translocation by modified phorbol esters with functionalized lipophilic regionsThomas M Bertolini
Departments of Chemistry and Pharmacology, University of California, San Diego, La Jolla, California 92093, USA
J Org Chem 68:5028-36. 2003..The most promising PKC inhibitors had short carboxylic acids capping their C12 and C13 acyl chains, since these compounds did not recruit PKC to any appreciable extent... - Increased membrane affinity of the C1 domain of protein kinase Cdelta compensates for the lack of involvement of its C2 domain in membrane recruitmentJennifer R Giorgione
Department of Pharmacology, University of California at San Diego, La Jolla, California 92093-0721, USA
J Biol Chem 281:1660-9. 2006.... - The life and death of protein kinase CChristine M Gould
Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093 0721, USA
Curr Drug Targets 9:614-25. 2008.... - Contribution of the C1A and C1B domains to the membrane interaction of protein kinase CJennifer Giorgione
Department of Pharmacology, University of California at San Diego, La Jolla, California 92093-0640, USA
Biochemistry 42:11194-202. 2003..Thus, engaging both domains can be forced but is highly unfavored. In summary, our data reveal that both C1 domains are oriented for potential membrane interaction but only one C1 domain binds ligand in a physiological context... - Discovery of small molecule inhibitors of the PH domain leucine-rich repeat protein phosphatase (PHLPP) by chemical and virtual screeningEmma Sierecki
Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093
J Med Chem 53:6899-911. 2010..Thus, chemical and virtual screening has resulted in the identification of small molecules that promote Akt signaling by inhibiting its negative regulator PHLPP... - Centrosomal anchoring of protein kinase C betaII by pericentrin controls microtubule organization, spindle function, and cytokinesisDan Chen
Department of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, California 92093 0640, USA
J Biol Chem 279:4829-39. 2004..These results reveal a novel role for PKC betaII in cytokinesis and indicate that this function is mediated by an interaction with pericentrin at centrosomes... - Amplitude control of protein kinase C by RINCK, a novel E3 ubiquitin ligaseDan Chen
Department of Pharmacology, Molecular Pathology Graduate Program, University of California at San Diego, La Jolla, California 92093 0721, USA
J Biol Chem 282:33776-87. 2007..Our data reveal a novel mechanism that provides amplitude control in PKC signaling through ubiquitination catalyzed by RINCK, an E3 ligase that specifically recognizes the C1 domain of PKC isoforms... - PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growthTianyan Gao
Department of Pharmacology, University of California at San Diego, La Jolla, California 92093, USA
Mol Cell 18:13-24. 2005..Reintroduction of PHLPP into a glioblastoma cell line causes a dramatic suppression of tumor growth. These data are consistent with PHLPP terminating Akt signaling by directly dephosphorylating and inactivating Akt... - The adaptor protein Grb14 regulates the localization of 3-phosphoinositide-dependent kinase-1Charles C King
Department of Pharmacology, University of California at San Diego, La Jolla, California 92093 0721, USA
J Biol Chem 279:37518-27. 2004..Thus, Grb14 serves as an adaptor protein to recruit PDK-1 to activated insulin receptor, thus promoting Akt phosphorylation and transduction of the insulin signal... - Regulation of novel protein kinase C epsilon by phosphorylationVittoria Cenni
Boston Biomedical Research Institute, Watertown, MA 02472, USA
Biochem J 363:537-45. 2002..However, the regulation of this phosphorylation is different for novel and conventional PKCs. Specifically, the phosphorylation of novel PKCs is regulated rather than constitutive... - A Ras activation pathway dependent on Syk phosphorylation of protein kinase CYuko Kawakami
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA
Proc Natl Acad Sci U S A 100:9470-5. 2003..By recruiting the Grb-2/Sos complex to the plasma membrane, these conventional PKC isoforms contribute to the full activation of the Ras/extracellular signal-regulated kinase signaling pathway in FcepsilonRI-stimulated mast cells... - Use of stopped-flow fluorescence spectroscopy to measure rapid membrane binding by protein kinase CEric A Nalefski
US Genomics, Woburn, MA, USA
Methods Mol Biol 233:115-28. 2003 - The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase CValeria Facchinetti
Department of Immunology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
EMBO J 27:1932-43. 2008..Our studies uncover a novel function of the TOR pathway in regulating protein folding and stability, processes that are most likely linked to the functions of TOR in protein synthesis...
Research Grants
- Signal Termination by PHLPP, PH domain Leucine-rich repeat Protein PhosphataseAlexandra C Newton; Fiscal Year: 2010....
- STRUCTURE, FUNCTION AND REGULATION OF PROTEIN KINASE CALEXANDRA NEWTON; Fiscal Year: 2002....
- Phosphoinositide-dependent Kinase: Molecular mechanismsALEXANDRA NEWTON; Fiscal Year: 2006....
- STRUCTURE, FUNCTION AND REGULATION OF PROTEIN KINASE CALEXANDRA NEWTON; Fiscal Year: 2007..Upregulation of phosphatase activity could account for the pleiotropic effects of PKC activation. ..
- Signal Termination by PHLPP, PH domain Leucine-rich repeat Protein PhosphataseALEXANDRA NEWTON; Fiscal Year: 2007....
- STRUCTURE, FUNCTION AND REGULATION OF PROTEIN KINASE CALEXANDRA NEWTON; Fiscal Year: 2007..Upregulation of phosphatase activity could account for the pleiotropic effects of PKC activation. ..
- Signal Termination by PHLPP, PH domain Leucine-rich repeat Protein PhosphataseALEXANDRA NEWTON; Fiscal Year: 2009....
- Signal Termination by PHLPP, PH domain Leucine-rich repeat Protein PhosphataseALEXANDRA NEWTON; Fiscal Year: 2009....
- PROTEIN KINASE C AND PHOTORECEPTORSALEXANDRA NEWTON; Fiscal Year: 2002..Specifically, the effect of this phosphorylation on rhodopsin s macromolecular interactions (transducin coupling, arrestin binding) will be explored. ..