David L. Brautigan

Education

  • BA, Kalamazoo College, Kalamazoo, MI
  • MS, Northwestern University, Evanston, IL
  • PhD, Northwestern University, Evanston, IL
  • Postdoc, University of Washington School of Medicine, Seattle, WA

Primary Appointment

  • Professor, Microbiology, Immunology, and Cancer Biology

Contact

Research Interest(s)

Protein Phosphorylation in Cell Signaling

Research Description

Protein Phosphorylation in Cell Signaling

The dominant mechanism for cell signaling is protein phosphorylation. Thousands of cellular proteins undergo phosphorylation to control their activity, but most of the time they are kept in their dephosphorylated state by the action of protein phosphatases. Phosphatases specific for P-Ser and P-Thr (PP1, PP2A, PP4, PP6) are ancient enzymes, conserved between yeast and humans, and genetics shows they are essential for mitosis and for stages of cell cycle growth and cell proliferation. Toxins from cyanobacteria, dinoflagelates and insects target the active sites of these phosphatases. Cells must strictly regulate the activity of these abundant phosphatases to respond to changes in their environment. This is done through sending signals to phosphatase regulatory and catalytic subunits, plus specific inhibitor proteins. Current research in our group investigates the molecular basis for recognition among these proteins, and tests how phosphatases operate in living cells in response to changing conditions. We are determining the structure and biochemical properties of purified recombinant proteins. We use genomics to find novel related proteins and genetic screens to find binding partners. Fluorescent fusion proteins and phosphorylation-specific antibodies are employed with microscopic digital imaging to study where, when and how proteins become activated and localized within cells. The results are expected to give a better understanding of cell division, cytoskeletal reorganization, metabolic regulation and how defects in these processes lead to human diseases. [see website of Center for more detailed description of research projects] http://www.healthsystem.virginia.edu/internet/cellsignaling/dbrautiganresearchinterest.cfm

Selected Publications

  • Dziegielewska B, Brautigan D, Larner J, Dziegielewski J. T-type Ca2+ Channel Inhibition Induces p53 Dependent Cell Growth Arrest and Apoptosis through Activation of p38-MAPK in Colon Cancer Cells. Molecular cancer research : MCR. 2013. PMID: 24362252
  • Ohama T, Wang L, Griner E, Brautigan D. Protein Ser/Thr phosphatase-6 is required for maintenance of E-cadherin at adherens junctions. BMC cell biology. 2013;14 42. PMID: 24063632
  • Wang L, Brautigan D. α-SNAP inhibits AMPK signaling to reduce mitochondrial biogenesis and dephosphorylates Thr172 in AMPKα in vitro. Nature communications. 2013;4 1559. PMID: 23463002
  • Protein Ser/ Thr phosphatases - the ugly ducklings of cell signalling. The FEBS journal. 2012. PMID: 22519956
  • Griner E, Churchill M, Brautigan D, Theodorescu D. PKCα phosphorylation of RhoGDI2 at Ser31 disrupts interactions with Rac1 and decreases GDI activity. Oncogene. 2012. PMID: 22469974
  • Hosing A, Valerie N, Dziegielewski J, Brautigan D, Larner J. PP6 regulatory subunit R1 is bidentate anchor for targeting protein phosphatase-6 to DNA-dependent protein kinase. The Journal of biological chemistry. 2012;287(12): 9230-9. PMID: 22298787 | PMCID: PMC3308816
  • Sarkar S, Brautigan D, Parsons S, Larner J. Androgen receptor degradation by the E3 ligase CHIP modulates mitotic arrest in prostate cancer cells. Oncogene. 2012;33(1): 26-33. PMID: 23246967
  • Edelson J, Brautigan D. The Discodermia calyx Toxin Calyculin A Enhances Cyclin D1 Phosphorylation and Degradation, and Arrests Cell Cycle Progression in Human Breast Cancer Cells. Toxins. 2011;3(1): 105-19. PMID: 22069692 | PMCID: PMC3210456
  • Hall E, Gurel V, Dahlberg A, McMichael J, Brautigan D. Inhibition of human breast cancer Matrigel invasion by Streptolysin O activation of the EGF receptor ErbB1. Cellular signalling. 2011;23(12): 1972-7. PMID: 21787862 | PMCID: NIHMS312507
  • Martin-Montalvo A, Gonzalez-Mariscal I, Padilla S, Ballesteros M, Brautigan D, Navas P, Santos-Ocaña C. Respiratory-induced coenzyme Q biosynthesis is regulated by a phosphorylation cycle of Cat5p/Coq7p. The Biochemical journal. 2011. PMID: 21812761
  • Molhoek K, Erdag G, Rasamny J, Murphy C, Deacon D, Patterson J, Slingluff C, Brautigan D. VEGFR-2 expression in human melanoma: revised assessment. International journal of cancer. Journal international du cancer. 2011;129(12): 2807-15. PMID: 21544800 | PMCID: PMC3205910
  • Molhoek K, Shada A, Smolkin M, Chowbina S, Papin J, Brautigan D, Slingluff C. Comprehensive analysis of receptor tyrosine kinase activation in human melanomas reveals autocrine signaling through IGF-1R. Melanoma research. 2011;21(4): 274-84. PMID: 21654344 | PMCID: PMC3131461
  • Sami F, Smet-Nocca C, Khan M, Landrieu I, Lippens G, Brautigan D. Molecular basis for an ancient partnership between prolyl isomerase Pin1 and phosphatase inhibitor-2. Biochemistry. 2011;50(30): 6567-78. PMID: 21714498
  • Hall E, Balsbaugh J, Rose K, Shabanowitz J, Hunt D, Brautigan D. Comprehensive analysis of phosphorylation sites in Tensin1 reveals regulation by p38MAPK. Molecular & cellular proteomics : MCP. 2010;9(12): 2853-63. PMID: 20798394 | PMCID: PMC3101865
  • Hans S, Camara F, Altiti A, Martín-Montalvo A, Brautigan D, Heimark D, Larner J, Grindrod S, Brown M, Mootoo D. Synthesis of C-glycoside analogues of beta-galactosamine-(1-->4)-3-O-methyl-D-chiro-inositol and assay as activator of protein phosphatases PDHP and PP2Calpha. Bioorganic & medicinal chemistry. 2010;18(3): 1103-10. PMID: 20079654 | PMCID: PMC3408221
  • Larner J, Brautigan D, Thorner M. D-chiro-inositol glycans in insulin signaling and insulin resistance. Molecular medicine (Cambridge, Mass.). 2010;16(11): 543-52. PMID: 20811656 | PMCID: PMC2972396
  • Ohama T, Brautigan D. Endotoxin conditioning induces VCP/p97-mediated and inducible nitric-oxide synthase-dependent Tyr284 nitration in protein phosphatase 2A. The Journal of biological chemistry. 2010;285(12): 8711-8. PMID: 20100830 | PMCID: PMC2838294
  • Wang H, Owens C, Chandra N, Conaway M, Brautigan D, Theodorescu D. Phosphorylation of RalB is important for bladder cancer cell growth and metastasis. Cancer research. 2010;70(21): 8760-9. PMID: 20940393 | PMCID: PMC3025490
  • Broglie P, Matsumoto K, Akira S, Brautigan D, Ninomiya-Tsuji J. Transforming growth factor beta-activated kinase 1 (TAK1) kinase adaptor, TAK1-binding protein 2, plays dual roles in TAK1 signaling by recruiting both an activator and an inhibitor of TAK1 kinase in tumor necrosis factor signaling pathway. The Journal of biological chemistry. 2009;285(4): 2333-9. PMID: 19955178 | PMCID: PMC2807291
  • Guergnon J, Derewenda U, Edelson J, Brautigan D. Mapping of protein phosphatase-6 association with its SAPS domain regulatory subunit using a model of helical repeats. BMC biochemistry. 2009;10 24. PMID: 19835610 | PMCID: PMC2765987
  • Hall E, Daugherty A, Choi C, Horwitz A, Brautigan D. Tensin1 requires protein phosphatase-1alpha in addition to RhoGAP DLC-1 to control cell polarization, migration, and invasion. The Journal of biological chemistry. 2009;284(50): 34713-22. PMID: 19826001 | PMCID: PMC2787334
  • Mi J, Bolesta E, Brautigan D, Larner J. PP2A regulates ionizing radiation-induced apoptosis through Ser46 phosphorylation of p53. Molecular cancer therapeutics. 2009;8(1): 135-40. PMID: 19139122
  • Mi J, Dziegielewski J, Bolesta E, Brautigan D, Larner J. Activation of DNA-PK by ionizing radiation is mediated by protein phosphatase 6. PloS one. 2009;4(2): e4395. PMID: 19198648 | PMCID: PMC2634843
  • Fuller B, Lampson M, Foley E, Rosasco-Nitcher S, Le K, Tobelmann P, Brautigan D, Stukenberg P, Kapoor T. Midzone activation of aurora B in anaphase produces an intracellular phosphorylation gradient. Nature. 2008;453(7198): 1132-6. PMID: 18463638 | PMCID: PMC2724008
  • Molhoek K, Griesemann H, Shu J, Gershenwald J, Brautigan D, Slingluff C. Human melanoma cytolysis by combined inhibition of mammalian target of rapamycin and vascular endothelial growth factor/vascular endothelial growth factor receptor-2. Cancer research. 2008;68(11): 4392-7. PMID: 18519701 | PMCID: PMC2727753
  • Molhoek K, McSkimming C, Olson W, Brautigan D, Slingluff C. Apoptosis of CD4(+)CD25(high) T cells in response to Sirolimus requires activation of T cell receptor and is modulated by IL-2. Cancer immunology, immunotherapy : CII. 2008;58(6): 867-76. PMID: 18841360 | PMCID: PMC2688807
  • Ohama T, Okada M, Murata T, Brautigan D, Hori M, Ozaki H. Sphingosine-1-phosphate enhances IL-1{beta}-induced COX-2 expression in mouse intestinal subepithelial myofibroblasts. American journal of physiology. Gastrointestinal and liver physiology. 2008;295(4): G766-75. PMID: 18703638
  • Prickett T, Ninomiya-Tsuji J, Broglie P, Muratore-Schroeder T, Shabanowitz J, Hunt D, Brautigan D. TAB4 stimulates TAK1-TAB1 phosphorylation and binds polyubiquitin to direct signaling to NF-kappaB. The Journal of biological chemistry. 2008;283(28): 19245-54. PMID: 18456659 | PMCID: PMC2443674
  • Stefansson B, Ohama T, Daugherty A, Brautigan D. Protein phosphatase 6 regulatory subunits composed of ankyrin repeat domains. Biochemistry. 2008;47(5): 1442-51. PMID: 18186651
  • Wang W, Brautigan D. Phosphatase inhibitor 2 promotes acetylation of tubulin in the primary cilium of human retinal epithelial cells. BMC cell biology. 2008;9 62. PMID: 19036150 | PMCID: PMC2630314
  • Wang W, Cronmiller C, Brautigan D. Maternal phosphatase inhibitor-2 is required for proper chromosome segregation and mitotic synchrony during Drosophila embryogenesis. Genetics. 2008;179(4): 1823-33. PMID: 18689877 | PMCID: PMC2516061
  • Wang W, Stukenberg P, Brautigan D. Phosphatase inhibitor-2 balances protein phosphatase 1 and aurora B kinase for chromosome segregation and cytokinesis in human retinal epithelial cells. Molecular biology of the cell. 2008;19(11): 4852-62. PMID: 18716057 | PMCID: PMC2575180
  • Yoo S, Jimenez R, Sanders J, Boylan J, Brautigan D, Gruppuso P. The alpha4-containing form of protein phosphatase 2A in liver and hepatic cells. Journal of cellular biochemistry. 2008;105(1): 290-300. PMID: 18543252 | PMCID: PMC2597445