Beta-catenin and plakoglobin
are closely related, bifunctional proteins that promote cell-cell adhesion
at the plasma membrane and act as transcription factors in the nucleus.
These two proteins have been shown, by an exciting convergence of the
disciplines of cell and developmental biology, to play key roles in
cancer. Plakoglobin and beta-catenin connect cadherins to the cytoskeleton,
causing them to form the adhesive zippers of desmosomes and adherens
junctions. An earlier focus of our lab was to clone the major desmosomal
components and define the protein-protein interactions within these
structures that are responsible for stable epithelial organization.
Currently, we are exploring the distinct roles of cytoplasmic plakoglobin
and beta-catenin in Wnt signal transduction. Many cells communicate
their positional co-ordinates by secreting Wnt proteins, which bind
to receptors on the surface of neighboring cells. Binding of Wnt triggers
a cascade of events that lead to the stabilization of cytoplasmic plakoglobin
and beta-catenin. When elevated and activated in this manner, plakoglobin
and beta-catenin enter the nucleus, form bipartite transcription factors
with Lef/Tcf proteins and modulate the expression of an array of target
genes encoding morphoregulatory proteins and cell-cycle regulators.
We study this signal transduction
process in mammary gland and skin, elements of which undergo cyclical
rounds of proliferation, differentiation and apoptosis, thus permitting
experimentally induced changes in these important processes to be easily
observed in vivo. We have shown that transgenic upregulation of beta-catenin
induces extensive tumor formation in mammary gland. Overexpression of
plakoglobin, in contrast suppresses proliferation in epidermis and hair.
Thus despite their similarity in structure and adhesion-promoting function,
plakoglobin and beta-catenin exert opposite effects on proliferation.
Our studies are now focussed on defining the molecular basis for the
contrasting roles of plakoglobin and beta-catenin in Wnt signaling.
Methods to establish primary
cell cultures from these organs and to regraft modified cells back again
are available. Thus we can harness cell and molecular approaches to
study this question both in vitro and in vivo. Additionally, as many
mouse mutants with defects in mammary gland and skin exist we can use
genetics to decipher this signal transduction pathway.