Biomedical Sciences Graduate Program(s)
Molecular Cell and Developmental Biology
Biochemistry, Molecular Biology and Genetics
Neuroscience
Research Description
Cadherin and beta-catenin signaling in development and cancer
We are studying how beta-catenin functions in its two key roles; in cell adhesion
as a binding protein for cadherin cell adhesion molecules, and in the Wnt signaling
pathway as a binding partner for the TCF transcription factor. E-cadherin acts
as a tumor suppressor protein by inhibiting the Wnt stimulated TCF-dependent signaling
activity of beta-catenin. In this way E-cadherin slows the proliferation of colorectal
tumor cells. In other types of tumors, such as breast and prostate, E-cadherin
acts to suppress tumor cell invasion, but in these cases invasion suppression
involves alternate beta-catenin-dependent signaling pathways distinct from the
canonical Wnt/beta-catenin/TCF signaling pathway. Furthermore, E-cadherin and
beta-catenin directly mediate the contact inhibition of growth in a number of
cell types; again by an alternate beta-catenin-dependent pathway. Current efforts
are directed at elucidating the alternate molecular pathways by which beta-catenin
mediates these growth and tumor suppressor functions of E-cadherin. We have also
discovered that beta-catenin occurs in several distinct molecular forms which
regulate its targeting to either TCF transcriptional complexes in the nucleus
or cadherin adhesive complexes at the plasma membrane; Wnt signaling generates
a TCF-selective form. Beta-catenin targeting and degradation is regulated by a
cytoplasmic protein complex that includes the APC tumor suppressor protein, axin,
and GSK3b, and we are investigating the mechanisms by which these proteins function
in beta-catenin targeting and Wnt signaling.
Regulation of cadherin-mediated adhesion during tissue morphogenesis
Cadherins play important roles in morphogenetic processes that shape tissues
in embryos and in growing adult organs. Tissue morphogenesis involves cell movements
and cell rearrangements, processes that require a continual controlled breaking
and re-making of adhesive bonds. We are studying how the regulation of cadherin
adhesive function drives tissue morphogenesis during gastrulation of the Xenopus
embryo. Regulation of a Xenopus C-cadherin in response to TGFb type growth factors
is required for the elongation of tissues that drives the formation of the body
axis. C-cadherin is also regulated spatially by the expression of a protocadherin
(a poorly understood subfamily of cadherin proteins) call PAPC (paraxial protocadherin).
We are now investigating the molecular mechanisms underlying the regulation
of C-cadherin adhesion by TGFb factors and PAPC. These studies deal with a range
of interesting problems, including the analysis of the basic molecular mechanism
of cadherin adhesive binding, the molecular basis of PAPC function, the functions
of the catenins in controlling cadherins, and the mechanism by which signaling
pathways regulate these functions dynamically in the cell. At the level of tissue
development, we are trying to understand how the temporal and spatial regulation
of cadherin-mediated cell adhesion controls the cell movements and cell rearrangements
that drive morphogenesis.
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