Our research
uses Drosophila as a model to study the evolutionarily conserved
Wnt/Wingless signal transduction pathway, with a focus on one component in
this pathway, Adenomatous polyposis coli (APC). Wnt/Wingless signaling
directs cell proliferation, cell fate, and apoptotic cell death during
development and is inappropriately activated in several types of cancer.
The majority of colorectal carcinomas have truncating mutations in APC, a
negative regulator in Wnt signaling. APC functions in a protein complex
that targets the key transcriptional activator in the pathway,
beta-catenin, for proteasomal degradation. Thus inactivation of APC results
in ectopic Wnt signaling, and the aberrant activation of target genes. The
primary goals of our research are to determine the molecular mechanisms by
which APC regulates Wnt signaling, and the molecular consequences of APC
loss. Characterization of New Components in the Wingless Signaling
Pathway We have
performed genetic modifier screens to identify new components that are
required to promote Wingless signal transduction. These screens are based
on the sensitive Apc1 mutant retinal apoptosis phenotype (shown above),
which results from the constitutive activation of Wingless signaling. We
have isolated mutations in genes that suppress this phenotype, and in this
way have identified several candidate effector proteins. Our current work is directed toward
characterizing these novel genes, and determining their role in Wingless
signaling. Given the evolutionary conservation of the Wnt/Wingless pathway,
our hope is that these studies in Drosophila will extend current models for
Wnt signal transduction, and may also inform our understanding of disease
processes that are caused by inactivation of APC in humans. Dissecting the Roles of Apc in Wingless Signaling We are also
investigating the roles of Apc in Wingless signal transduction. Two APC
homologs exist in humans, mice, and fruit flies. We have used genetic
techniques to inactivate both Drosophila homologs of Apc and these studies
have revealed that the negative regulatory role of APC in Wnt signaling is
conserved from flies to mammals. However, the exact molecular mechanisms by
which APC regulates Wnt/Wingless signaling have remained elusive. Our
current work is directed toward dissecting the roles of Apc in Wingless
signaling, using genetic, biochemical, and cell biological methods.