Alexandra Newton

Last updated
Alexandra C. Newton
Prof. Alexandra Newton.jpg
Born
Cape Town, South Africa
Alma materSimon Fraser University, Stanford University (PhD)
AwardsJulius Axelrod Award in Pharmacology, ASPET (2019), Biophysics of Health and Disease Biophysical Society (2020)
Scientific career
Fields
Institutions
Thesis 'Intermembrane Protein Transfer'
Website http://newtonlab.ucsd.edu

Alexandra C. Newton is a Canadian and American biochemist. She is a Distinguished Professor of pharmacology at the University of California, San Diego. [1] Newton runs a multidisciplinary Protein kinase C and Cell signaling biochemistry and cell biology research group in the School of Medicine, [2] investigating molecular mechanisms of signal transduction in the Phospholipase C (PLC) and Phosphoinositide 3-kinase (PI3 kinase, or PI3-K) signaling pathways. [3] She has been continuously funded by the US National Institutes of Health since 1988.

Contents

Early life and education

Newton was born in Cape Town, South Africa, and was schooled in Vancouver, Athens, and Aix-en-Provence. She graduated in 1980 from the Simon Fraser University in Canada, where she was awarded a 1st-class honours degree in biochemistry and French literature. [4] She received her PhD in chemistry in 1986 from Stanford University, working with Wray H. Huestis [5] on a thesis examining band 3, a red cell membrane protein. [6] [7]

Career

Following her PhD defense, Newton took up a postdoctoral research position at University of California, Berkeley in the laboratory of Daniel E. Koshland Jr. between 1986 and 1988, and subsequently began her own independent research laboratory in 1988, as assistant professor in Chemistry at Indiana University, subsequently receiving tenure as associate professor in 1994. She moved to University of California, San Diego in 1995, first as associate professor in pharmacology and then Professor, from 2001 to 2017. Between 2002 and 2006, she was vice-chair, then chair, of the Biomedical Sciences Graduate Program before becoming the Director of the Molecular Pharmacology Track in the Biomedical Sciences Graduate Program at the University of California San Diego. She was conferred with the title of Distinguished Professor of Pharmacology in 2017. As of 2020, she is president-elect for the International Union of Biochemistry and Molecular Biology, having served, since 2016, as ASBMB representative to the IUBMB general assembly, and, since 2015, as a Member of the International Union of Biochemistry and Molecular Biology Executive Committee for Congresses and Conferences. [8] Newton has supervised, and graduated, more 25 PhD postgraduate students and trained 23 Postdoctoral Fellows. [9]

Research

Newton has been a major driver in the PKC research field since the 1980s, working originally with Daniel E. Koshland Jr. [10] [11]  She helped define the multiple different mechanisms of PKC regulation by phosphorylation and its interaction with specific membrane phospholipids, such as phosphatidylserine [12] [13] [14] [15] She has also made important discoveries in the protein phosphatase field, discovering and naming PHLPP (PH domain and Leucine rich repeat Protein Phosphatases), which regulate intracellular signaling through dephosphorylation of AKT. [16] [17] [18]

As of 2020, Newton has published over 190 peer-reviewed research articles that have been cited more than 25,000 times, [19] been awarded 1 patent [20] and co-edited two books on protein biochemistry and PKC. [21] [22] Her work straddles basic research and has illuminated understanding of PKC in Alzheimer's disease [23] [24] and as a tumor suppressor in human cancers [25]

Editorials, research honours, scientific service and outreach

Newton was a member of the editorial board of the Journal of Biological Chemistry between 1995 and 2000, an associate editor of Molecular Pharmacology (2000-2003) and since 1990, has been an expert reviewer for the National Science Foundation and Medical Research Council of Canada. She has been chair, or co-chair, for multiple committees of the American Society for Biochemistry and Molecular Biology. [26]

Related Research Articles

In cell biology, protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins, or a member of this family. PKC enzymes in turn are activated by signals such as increases in the concentration of diacylglycerol (DAG) or calcium ions (Ca2+). Hence PKC enzymes play important roles in several signal transduction cascades.

<span class="mw-page-title-main">Stathmin</span> Protein in Eukaryotes

Stathmin, also known as metablastin and oncoprotein 18 is a protein that in humans is encoded by the STMN1 gene.

<span class="mw-page-title-main">ZAP70</span> Protein-coding gene in the species Homo sapiens

ZAP-70 is a protein normally expressed near the surface membrane of lymphocytes. It is most prominently known to be recruited upon antigen binding to the T cell receptor (TCR), and it plays a critical role in T cell signaling.

<span class="mw-page-title-main">C2 domain</span> Protein domain

A C2 domain is a protein structural domain involved in targeting proteins to cell membranes. The typical version (PKC-C2) has a beta-sandwich composed of 8 β-strands that co-ordinates two or three calcium ions, which bind in a cavity formed by the first and final loops of the domain, on the membrane binding face. Many other C2 domain families don't have calcium binding activity.

<span class="mw-page-title-main">Annexin A5</span> Protein-coding gene in the species Homo sapiens

Annexin A5 is a cellular protein in the annexin group. In flow cytometry, annexin V is commonly used to detect apoptotic cells by its ability to bind to phosphatidylserine, a marker of apoptosis when it is on the outer leaflet of the plasma membrane. The function of the protein is unknown; however, annexin A5 has been proposed to play a role in the inhibition of blood coagulation by competing for phosphatidylserine binding sites with prothrombin and also to inhibit the activity of phospholipase A1. These properties have been found by in vitro experiments.

The PHLPP isoforms are a pair of protein phosphatases, PHLPP1 and PHLPP2, that are important regulators of Akt serine-threonine kinases and conventional/novel protein kinase C (PKC) isoforms. PHLPP may act as a tumor suppressor in several types of cancer due to its ability to block growth factor-induced signaling in cancer cells.

<span class="mw-page-title-main">Daniel E. Koshland Jr.</span> American biochemist (1920–2007)

Daniel Edward Koshland Jr. was an American biochemist. He reorganized the study of biology at the University of California, Berkeley, and was the editor of the leading U.S. science journal, Science, from 1985 to 1995. He was a member of the United States National Academy of Sciences, the American Academy of Arts and Sciences, and the American Philosophical Society.

<span class="mw-page-title-main">PRKACA</span> Protein-coding gene in the species Homo sapiens

The catalytic subunit α of protein kinase A is a key regulatory enzyme that in humans is encoded by the PRKACA gene. This enzyme is responsible for phosphorylating other proteins and substrates, changing their activity. Protein kinase A catalytic subunit is a member of the AGC kinase family, and contributes to the control of cellular processes that include glucose metabolism, cell division, and contextual memory. PKA Cα is part of a larger protein complex that is responsible for controlling when and where proteins are phosphorylated. Defective regulation of PKA holoenzyme activity has been linked to the progression of cardiovascular disease, certain endocrine disorders and cancers.

<span class="mw-page-title-main">PRKCE</span> Protein-coding gene in the species Homo sapiens

Protein kinase C epsilon type (PKCε) is an enzyme that in humans is encoded by the PRKCE gene. PKCε is an isoform of the large PKC family of protein kinases that play many roles in different tissues. In cardiac muscle cells, PKCε regulates muscle contraction through its actions at sarcomeric proteins, and PKCε modulates cardiac cell metabolism through its actions at mitochondria. PKCε is clinically significant in that it is a central player in cardioprotection against ischemic injury and in the development of cardiac hypertrophy.

<span class="mw-page-title-main">Calcium/calmodulin-dependent protein kinase type II subunit alpha</span> Protein found in humans

Calcium/calmodulin-dependent protein kinase type II subunit alpha (CAMKIIα), a.k.a.Ca2+/calmodulin-dependent protein kinase II alpha, is one subunit of CamKII, a protein kinase (i.e., an enzyme which phosphorylates proteins) that in humans is encoded by the CAMK2A gene.

<span class="mw-page-title-main">PPP2CA</span> Enzyme

Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform is an enzyme that is encoded by the PPP2CA gene.

<span class="mw-page-title-main">ACP1</span> Protein-coding gene in humans

Low molecular weight phosphotyrosine protein phosphatase is an enzyme that in humans is encoded by the ACP1 gene.

<span class="mw-page-title-main">PPP2CB</span> Enzyme found in humans

Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform is an enzyme that in humans is encoded by the PPP2CB gene.

<span class="mw-page-title-main">PPP2R2A</span> Enzyme found in humans

Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform is an enzyme regulator that in humans is encoded by the PPP2R2A gene.

<span class="mw-page-title-main">PRKCI</span> Protein-coding gene in the species Homo sapiens

Protein kinase C iota type is an enzyme that in humans is encoded by the PRKCI gene.

<span class="mw-page-title-main">MARCKS</span> Protein-coding gene in the species Homo sapiens

Myristoylated alanine-rich C-kinase substrate is a protein that in humans is encoded by the MARCKS gene. It plays important roles in cell shape, cell motility, secretion, transmembrane transport, regulation of the cell cycle, and neural development. Recently, MARCKS has been implicated in the exocytosis of a number of vesicles and granules such as mucin and chromaffin. It is also the name of a protein family, of which MARCKS is the most studied member. They are intrinsically disordered proteins, with an acidic pH, with high proportions of alanine, glycine, proline, and glutamic acid. They are membrane-bound through a lipid anchor at the N-terminus, and a polybasic domain in the middle. They are regulated by Ca2+/calmodulin and protein kinase C. In their unphosphorylated form, they bind to actin filaments, causing them to crosslink, and sequester acidic membrane phospholipids such as PIP2.

<span class="mw-page-title-main">PRKG1</span> Protein-coding gene in the species Homo sapiens

cGMP-dependent protein kinase 1, alpha isozyme is an enzyme that in humans is encoded by the PRKG1 gene.

Steven G. Clarke, an American biochemist, is a director of the UCLA Molecular Biology Institute, a professor of chemistry and biochemistry at UCLA biochemistry department. Clarke heads a laboratory at UCLA's department of chemistry and biochemistry. Clarke is famous for his work on molecular damage and discoveries of novel molecular repair mechanisms.

<span class="mw-page-title-main">Morpheein</span> Model of protein allosteric regulation

Morpheeins are proteins that can form two or more different homo-oligomers, but must come apart and change shape to convert between forms. The alternate shape may reassemble to a different oligomer. The shape of the subunit dictates which oligomer is formed. Each oligomer has a finite number of subunits (stoichiometry). Morpheeins can interconvert between forms under physiological conditions and can exist as an equilibrium of different oligomers. These oligomers are physiologically relevant and are not misfolded protein; this distinguishes morpheeins from prions and amyloid. The different oligomers have distinct functionality. Interconversion of morpheein forms can be a structural basis for allosteric regulation, an idea noted many years ago, and later revived. A mutation that shifts the normal equilibrium of morpheein forms can serve as the basis for a conformational disease. Features of morpheeins can be exploited for drug discovery. The dice image represents a morpheein equilibrium containing two different monomeric shapes that dictate assembly to a tetramer or a pentamer. The one protein that is established to function as a morpheein is porphobilinogen synthase, though there are suggestions throughout the literature that other proteins may function as morpheeins.

<span class="mw-page-title-main">Calponin 1</span> Protein found in humans

Calponin 1 is a basic smooth muscle protein that in humans is encoded by the CNN1 gene.

References

  1. ↑ "PKC Signaling Laboratory - University of California, San Diego". Archived from the original on 2006-08-29.
  2. ↑ "Health Sciences International – University of California, San Diego".
  3. ↑ "PKC Signaling Laboratory - University of California, San Diego". Archived from the original on 2006-08-29.
  4. ↑ "Inspiring Alumna, Simon Fraser University".
  5. ↑ "Professor Wray Huestis Laboratory - University of California, Stanford".
  6. ↑ Newton AC, Cook SL, Huestis WH (1983). "Transfer of band 3, the erythrocyte anion transporter, between phospholipid vesicles and cells". Biochemistry. 22 (26): 6110–6117. doi:10.1021/bi00295a011. PMID   6661430.
  7. ↑ Huestis WH, Newton AC (1986). "Transfer of band 3, the erythrocyte anion transporter, between phospholipid vesicles and cells". Journal of Biological Chemistry. 261 (34): 16274–16278. doi: 10.1016/S0021-9258(18)66712-2 . PMID   3782118.
  8. ↑ "International Union of Biochemistry and Molecular Biology". Archived from the original on 2019-03-24. Retrieved 2020-04-01.
  9. ↑ "PhD awards". Archived from the original on 2006-08-29.
  10. ↑ Newton A, Koshland DE (1987). "Protein Kinase C Autophosphorylates by an Intrapeptide Reaction". Journal of Biological Chemistry. 262 (21): 10185–10188. doi: 10.1016/S0021-9258(18)61095-6 . PMID   3611058.
  11. ↑ Newton A, Koshland DE (1989). "High cooperativity, specificity, and multiplicity in the protein kinase C-lipd interaction". Journal of Biological Chemistry. 264 (25): 14909–14915. doi: 10.1016/S0021-9258(18)63788-3 . PMID   2768246.
  12. ↑ Orr JW, Keranen LM, Newton AC (1992). "Reversible exposure of the pseudosubstrate domain of protein kinase C by phosphatidylserine and diacylglycerol". Journal of Biological Chemistry. 267 (22): 15263–15266. doi: 10.1016/S0021-9258(19)49525-2 . PMID   1639770.
  13. ↑ Orr JW, Newton AC (1992). "Interaction of protein kinase C with phosphatidylserine. 1. Cooperativity in lipid binding". Biochemistry. 31 (19): 4661–4667. doi:10.1021/bi00134a018. PMID   1581316.
  14. ↑ Orr JW, Newton AC (1992). "Interaction of protein kinase C with phosphatidylserine. 2. Specificity and regulation". Biochemistry. 31 (19): 4667–4673. doi:10.1021/bi00134a019. PMID   1581317.
  15. ↑ Orr JW, Newton A (1994). "Requirement for negative charge on "activation loop" of protein kinase C." Journal of Biological Chemistry. 269 (44): 27715–27718. doi: 10.1016/S0021-9258(18)47044-5 . PMID   7961692.
  16. ↑ Gao T, Furnari F, Newton AC (2005). "PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth". Molecular Cell. 18 (1): 13–24. doi: 10.1016/j.molcel.2005.03.008 . PMID   15808505.
  17. ↑ Baffi TR, Van AN, Zhao W, Mills GB, Newton AC (2019). "Protein Kinase C Quality Control by Phosphatase PHLPP1 Unveils Loss-of-Function Mechanism in Cancer". Molecular Cell. 74 (2): 378–392. doi:10.1016/j.molcel.2019.02.018. PMC   6504549 . PMID   30904392.
  18. ↑ Grzechnik AT, Newton AC (2019). "PHLPPing through history: a decade in the life of PHLPP phosphatases". Biochemical Society Transactions. 44 (6): 1675–1682. doi:10.1042/BST20160170. PMC   5783572 . PMID   27913677.
  19. ↑ "Alexandra Newton Google Scholar – University of California, San Diego".
  20. ↑ Violin JD, Newton AC, Tsien RJ, Zhang J (2004), Chimeric phosphorylation indicator: US Patent No. 8,669,074
  21. ↑ Malacinski GM, Frielder D (1993). "Chapter 4: Essentials of Molecular Biology: The physical structure of protein molecules". Jones & Bartlett Publishers,Boston: 335. ISBN   978-0-8672-0137-6.
  22. ↑ Newton AC (2003). "Methods in Molecular Biology 233: Protein Kinase C Protocols". Humana Press: 584. ISBN   978-1-59259-397-2.
  23. ↑ Callender JA, Yang Y, Lordén G, Stephenson NL, Jones AC, Brognard J, Newton AC (2018). "Protein kinase Cα gain-of-function variant in Alzheimer's disease displays enhanced catalysis by a mechanism that evades down-regulation". PNAS. 115 (24): 5497–5505. Bibcode:2018PNAS..115E5497C. doi: 10.1073/pnas.1805046115 . PMC   6004447 . PMID   29844158.
  24. ↑ Newton, Alexandra C.; Tanzi, Rudolph E.; Vanhook, Annalisa M. (10 May 2016). "Podcast: PKCalpha in Alzheimer's disease - Science Signaling". Science Signaling. 9 (427): pc11. doi:10.1126/scisignal.aaf9436. PMID   27165779.
  25. ↑ Antal CE, Hudson AM, Kang E, Zanca C, Wirth C, Stephenson NL, Trotter EW, Gallegos LL, Miller CJ, Furnari FB, Hunter T, Brognard J, Newton AC (2015). "Protein kinase Cα gain-of-function variant in Alzheimer's disease displays enhanced catalysis by a mechanism that evades down-regulation". Cell. 160 (3): 489–502. doi:10.1016/j.cell.2015.01.001. PMC   4313737 . PMID   25619690.
  26. ↑ "Lipid Division Spotlight - ASBMB". Archived from the original on 2018-08-27.
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