ALEXANDRA NEWTON

Summary

Affiliation: University of California
Country: USA

Publications

  1. Alfonso S, Callender J, Hooli B, Antal C, Mullin K, Sherman M, et al. Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer's disease. Sci Signal. 2016;9:ra47 pubmed publisher
    ..In contrast, reduced PKCα activity is implicated in cancer. Hence, these findings reinforce the importance of maintaining a careful balance in the activity of this enzyme. ..
  2. Kajimoto T, Caliman A, Tobias I, Okada T, Pilo C, Van A, et al. Activation of atypical protein kinase C by sphingosine 1-phosphate revealed by an aPKC-specific activity reporter. Sci Signal. 2019;12: pubmed publisher
    ..Together, our findings identify a previously undescribed molecular mechanism of aPKC regulation, a molecular target for S1P in cell survival regulation, and a tool to further explore the biochemical and biological functions of aPKC. ..
  3. Baffi T, Van A, Zhao W, Mills G, Newton A. Protein Kinase C Quality Control by Phosphatase PHLPP1 Unveils Loss-of-Function Mechanism in Cancer. Mol Cell. 2019;74:378-392.e5 pubmed publisher
    ..Thus, PHLPP1 provides a proofreading step that maintains the fidelity of PKC autoinhibition and reveals a prominent loss-of-function mechanism in cancer by suppressing the steady-state levels of PKC. ..
  4. Balasuriya N, Kunkel M, Liu X, Biggar K, Li S, Newton A, et al. Genetic code expansion and live cell imaging reveal that Thr-308 phosphorylation is irreplaceable and sufficient for Akt1 activity. J Biol Chem. 2018;293:10744-10756 pubmed publisher
    ..Our data also indicate that pThr-308 should be regarded as the primary diagnostic marker of Akt activity. ..
  5. Callender J, Yang Y, Lordén G, Stephenson N, Jones A, Brognard J, et al. Protein kinase Cα gain-of-function variant in Alzheimer's disease displays enhanced catalysis by a mechanism that evades down-regulation. Proc Natl Acad Sci U S A. 2018;115:E5497-E5505 pubmed publisher
    ..Our results unveil how an AD-associated mutation in PKCα permits enhanced agonist-dependent signaling via a mechanism that evades the cell's homeostatic down-regulation of constitutively active PKCα. ..
  6. Kunkel M, Newton A. Protein kinase d inhibitors uncouple phosphorylation from activity by promoting agonist-dependent activation loop phosphorylation. Chem Biol. 2015;22:98-106 pubmed publisher
    ..These findings illustrate the diverse conformational effects that small molecules exert on their target proteins, underscoring the importance of using caution when interpreting kinase activity from phosphorylation state. ..
  7. Tobias I, Kaulich M, Kim P, Simon N, Jacinto E, Dowdy S, et al. Protein kinase Cζ exhibits constitutive phosphorylation and phosphatidylinositol-3,4,5-triphosphate-independent regulation. Biochem J. 2016;473:509-23 pubmed publisher
    ..Rather, we propose that scaffolding near substrates drives the function of PKCζ. ..
  8. Antal C, Hudson A, Kang E, Zanca C, Wirth C, Stephenson N, et al. Cancer-associated protein kinase C mutations reveal kinase's role as tumor suppressor. Cell. 2015;160:489-502 pubmed publisher
    ..These data establish that PKC isozymes generally function as tumor suppressors, indicating that therapies should focus on restoring, not inhibiting, PKC activity. ..
  9. Antal C, Callender J, Kornev A, Taylor S, Newton A. Intramolecular C2 Domain-Mediated Autoinhibition of Protein Kinase C βII. Cell Rep. 2015;12:1252-60 pubmed publisher
    ..Although the placement of the C1 domains remains to be determined, elucidation of the structural basis for autoinhibition of PKCβII unveils a unique direction for therapeutically targeting PKC. ..

More Information

Publications16

  1. Newton A, Trotman L. Turning off AKT: PHLPP as a drug target. Annu Rev Pharmacol Toxicol. 2014;54:537-58 pubmed publisher
    ..This review discusses the role of PHLPP in terminating AKT signaling and how pharmacological intervention would impact this pathway. ..
  2. Newton A, Brognard J. Reversing the Paradigm: Protein Kinase C as a Tumor Suppressor. Trends Pharmacol Sci. 2017;38:438-447 pubmed publisher
    ..Thus, strategies in cancer treatment should focus on restoring rather than inhibiting PKC. ..
  3. Newton A. Protein kinase C as a tumor suppressor. Semin Cancer Biol. 2018;48:18-26 pubmed publisher
  4. Newton A. Protein kinase C: poised to signal. Am J Physiol Endocrinol Metab. 2010;298:E395-402 pubmed publisher
    ..This review introduces the PKC family and then focuses on recent advances in understanding the cellular regulation of its diacylglycerol-regulated members. ..
  5. Reyes G, Niederst M, Cohen Katsenelson K, Stender J, Kunkel M, Chen M, et al. Pleckstrin homology domain leucine-rich repeat protein phosphatases set the amplitude of receptor tyrosine kinase output. Proc Natl Acad Sci U S A. 2014;111:E3957-65 pubmed publisher
    ..Our data are consistent with a model in which PHLPP modifies the histone code to control the transcription of RTKs. ..
  6. Tsai L, Xie L, Doré K, Xie L, Del Rio J, King C, et al. Zeta Inhibitory Peptide Disrupts Electrostatic Interactions That Maintain Atypical Protein Kinase C in Its Active Conformation on the Scaffold p62. J Biol Chem. 2015;290:21845-56 pubmed publisher
    ..This study not only identifies a cellular target for ZIP, but also unveils a novel mechanism by which scaffolded aPKC is maintained in an active conformation. ..
  7. Tobias I, Newton A. Protein Scaffolds Control Localized Protein Kinase C? Activity. J Biol Chem. 2016;291:13809-22 pubmed publisher