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Area of Expertise: Regulation of the cell cycle by ubiquitin-dependent proteolysis;
protein mass spectrometry
Regulation of cell division. During
cell division, an organism’s genome must be accurately duplicated and then
faithfully distributed to the two resulting daughter cells. Cancer can result
from defects in cell division that compromise genome integrity. My lab is
interested in the molecular regulatory mechanisms that ensure proper cell
division. We currently focus on the roles that regulated proteolysis and protein phosphorylation play in coordinating the late stages of cell division, including
chromosome segregation, mitotic exit, and cytokinesis. Proper coordination of
these late events is important for maintaining genome stability. Current
projects in the lab are centered on the following proteins:
The
anaphase-promoting complex (APC)
The APC
is a large, highly conserved, ubiquitin ligase complex that targets several
important cell cycle regulatory proteins for proteasomal degradation at specific
times during cell division. The APC is best known for its role in promoting
chromosome segregation and mitotic exit by targeting securin and mitotic cyclins
for destruction. However, the stability of numerous other proteins is controlled
by the APC as well. We are studying how APC activity is regulated and how the
APC specifically recognizes its substrates. Binding of pseudosubstrate
inhibitors, such as the budding yeast Acm1 protein that we discovered several
years ago, is a common mechanism for controlling APC activity. Pseudosubstrates
are also useful tools for exploring the determinants for substrate recognition.
Our work characterizing Acm1 will therefore improve our understanding of both
APC regulation and substrate recognition.
Cdc14 phosphatase
Cyclin-dependent
kinase (Cdk) activity drives most of the major cell cycle events. However,
inactivation of Cdk and reversal of Cdk phosphorylation sites are universal
requirements for completing mitosis and triggering cytokinesis. The Cdc14
phosphatases have been implicated in reversal of Cdk phosphorylation and in
budding yeast Cdc14 is essential for completion of mitosis. In
collaboration with the Charbonneau lab in our department we are exploring
substrate specificity of the Cdc14 phosphatase family. We are using our insights
into Cdc14’senzymatic specificity to predict and then test novel
substrates and biological functions.
14-3-3
proteins
The
highly conserved 14-3-3 proteins are a family of abundant phosphoprotein
chaperones that have been implicated in cancer and other diseases. Work from our
lab and others has recently suggested that 14-3-3 proteins can specifically bind
to Cdk-catalyzed phosphorylation sites. Beginning with targeted proteomic
approaches we are undertaking studies to explore the hypothesis that effects of
Cdk are commonly mediated by binding of 14-3-3 proteins to Cdk substrates.
Our
research tools. The
majority of our work is conducted in the budding yeast Saccharomyces cerevisiae.
Budding yeast are easy to work with and manipulate genetically, making them an
attractive model organism for studying conserved and fundamental biological
processes, such as cell division. We apply biochemistry, cell biology, molecular
biology, and genetics methods to our research projects, providing a diverse
training experience for students. In addition, we use mass spectrometry in a
variety of ways, particularly for the discovery, quantification, and
characterization of protein-protein interactions and protein post-translational
modifications.