RESEARCH

Protein Phosphorylation and Cell Signaling

Proteins are the products of our genes. They confer structure and function to cells and tissues. Proteins also mediate cellular responses to changes in the extracellular and intracellular environments. The response to environmental signals is referred to as signal transduction. Signals range from the binding of a hormone or neurotransmitter to a cell membrane receptor to the exposure of a cell to reactive chemicals. Cell signaling pathways produce changes in the cell by modifying the function and levels (by changes in gene expression) of key proteins. Outcomes of cell signaling include growth and differentiation, adaptation and survival, and cell suicide.

Reversible phosphorylation of proteins via transfer of the terminal phosphoryl group (-PO₃^2-) of ATP to the oxygen atom of serine, threonine, or tyrosine amino acid residues on a protein is a fundamental chemical reaction of cell signaling. Protein phosphorylation is catalyzed by protein kinase enzymes while the removal of phosphoryl groups via hydrolysis is catalyzed by protein phosphatase enzymes. Protein kinase cascades, involving the activation by phosphorylation of protein kinases and the subsequent activation of other (downstream) protein kinases amplify environmental signals. Cellular outcomes are executed by phosphorylation of functional proteins (e.g., metabolic enzymes, ion channels), structural proteins (e.g., cytoskeletal proteins), and transcription factor proteins which regulate gene expression.

Accumulating evidence supports the view that aberrant changes in protein phosphorylation are important determinants of disease. Indeed, much evidence indicates that hyper-phosphorylation of certain protein kinases (e.g., the MAPKs) and cytoskeletal proteins (e.g., tau) may underlie the neuronal degeneration and dementia that occurs in Alzheimer's disease (AD).

Research in Dr. Foley's lab is aimed at establishing the biochemical mechanisms that regulate protein phosphatases and protein phosphorylation in the brain and how the chemical conditions existent in AD may lead to aberrant protein phosphorylation.

See the following links for tutorials with diagrams of protein phosphorylation and cell signaling.

www.bioteach.ubc.ca/.../ ProteinPhosphorylation/

www.bioteach.ubc.ca/CellBiology/ConversingAtTheCellularLevel/index.htm

RECENT PUBLICATIONS (*denotes student author)

    Foley, T. D. and *Kupchak, B.R. Ca²⁺-independent activation of brain calcineurin by nitric oxide: A possible
                neuron-selective response to stress. in preparation

2005     Foley, T.D., and ^*Kintner, M.E. Brain PP2A is modified by thiol-disulfide exchange and intermolecular disulfide
                formation. Biochem. Biophys. Res. Commun. 330, 1224-1229.

2004 Foley, T.D., ^*Armstrong, J.J., and ^*Kupchak, B.R. Identification and H₂O₂ sensitivity of the major constitutive MAPK phosphatase from rat brain. Biochem. Biophys. Res. Commun. 315, 568-574.

2002 ^*McPherson, D.B., ^*Kilker, R.P., and Foley, T.D. Superoxide activates constitutive nitric oxide synthase in a brain particulate fraction. Biochem. Biophys. Res. Commun. 296, 413-418.

2001 Foley, T.D. The cyclooxygenase hydroperoxide product PGG₂ activates synaptic nitric oxide synthase: A possible antioxidant response to membrane lipid peroxidation. Biochem. Biophys. Res. Commun. 286, 235-238.

FUNDING

2003-2006 Foley, T.D. PP2A-Like MAPK Phosphatase in Brain. National Institutes of Health, $121,835