Biomedical Sciences Graduate Program(s)
Biomedical Sciences Graduate Programs
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]
Ohama, T. and Brautigan, D. L. (2010) "Endotoxin Conditioning Induces VCP/p97-mediated and Nitric-oxide Synthase-dependent Tyr284 Nitration in Protein Phosphatase 2A" J. Biol. Chem. 285:8711-8718, published January 25, 2010 doi 10.1074/jbc.M109.099788. PMID 20100830.
Mi, J., Dziegielewski, J., Bolesta, E., Brautigan, D.L., and Larner, J.M. (2009) "Activation of DNA-PK by ionizing radiation is mediated by protein phosphatase-6" PLoS One 4: e4395 PMID 19198648.
Hall, E. H., Daugherty, A. E., Choi, C. K., Horwitz, A. F., and Brautigan, D. L. (2009) "Tensin 1 requires protein phosphatase 1 in addition to Rho(GAP) DLC-1 to control cell polarization, migration and invasion." J. Biol. Chem. 284: 34713-34722. e published October 13, 2009, doi:10.1074/jbc.M109.059592. PMID 19826001.
Wang, W. Stukenberg, P. T. and Brautigan, D. L. (2008) "Phosphatase inhibitor-2 balances protein phosphatase-1 and Aurora B kinase for chromosome segregation and cytokinesis in human retinal epithelial cells." Molec. Biol. Cell 19: 4852-4862 PMID 18716057.
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