Feedback regulation of Wnt/ß-catenin signal transduction
The fate and behavior of each of our body’s thousand million million cells is governed in part by the intensity and combination of signals received by each cell. During development, nearly all inductive signals are transmitted by just a few families of intercellular signaling molecules. Among the most ancient and potent of these signals are the Wnt proteins, a subset of which elicit transient accumulation of the transcriptional adaptor protein ß-catenin, which in turn regulates context-specific target genes. Wnt signals renew stem cells in several tissues, in part explaining why persistent "Wnt/ß-catenin" signaling is a frequent finding throughout the spectrum of human cancer.
The focus of our current studies is the naked cuticle (nkd) gene, a central player in a negative feedback loop that limits the activity of Wnt/ß-catenin signals during embryogenesis in the fruit fly, Drosophila melanogaster. Our previous work revealed Nkd to define a family of novel EF-hand proteins that inhibit Wnt signaling by targeting Dishevelled (Dsh), a scaffold protein whose mechanism of action remains mysterious and controversial. Previous data implicated Dsh in transmitting signals between Wnt receptors and the protein complex that targets ß-catenin for degradation, but a recent report in the literature suggests that Dsh proteins also act in the nucleus. Our recent studies suggest that Nkd may target Dsh-dependent transduction steps in both cytoplasmic and nuclear compartments of cells receiving the Wnt signal, but the molecular nature of these steps remains to be elucidated.
Currently, my laboratory has two complementary goals: First, we are deriving a paradigm for the Wnt/Nkd feedback regulatory circuit in Drosophila. Humans and mice each have two nkd-related genes, nkd1 and nkd2, though their protein sequences and known functions (other than binding Dsh) appear quite distinct from fly Nkd. Despite the requirement of nkd for proper Drosophila development, we have recently reported the construction of viable mice that lack functional nkd1 and nkd2 genes. We plan to use these mice as tools to investigate how vertebrate nkd genes contribute to mouse and/or human development and disease.
RESEARCH INTERESTS
Pattern Formation
Genetic Regulatory Systems
Gene Expression
Developmental Biology
Cancer
RECENT PUBLICATIONS
Chan, C. C, Zhang, S., Cagatay, T, Wharton, K. A. Jr., "Cell-autonomous, myristyl-independent activity of the Drosophila Wnt/Wingless antagonist Naked cuticle (Nkd)" Dev. Biol., in press 2007
Zhang, S., Cagatay, T., Amanai, M., Zhang, M., Kline, J., Castrillon, D. H., Ashfaq, R., Oz, O. K., Wharton, K. A. Jr., "Viable mice with compound mutations in the Wnt/Dvl-pathway antagonists nkd1 and nkd2" Mol. Cell. Biol., 27:4454-4464, 2007
Waldrop, S., Chan, C. C., Cagatay, T., Zhang, S., Rousset, R., Mack, J., Zeng, W., Fish, M., Zhang, M., Amanai, M., Wharton, K. A., Jr., "An unconventional nuclear localization motif is crucial for function of the Drosophila Wnt/Wingless antagonist Naked cuticle" Genetics, 174:331-348, 2006
Zhang, L., Jia, J., Wang, B., Amanai, K., Wharton, K. A. Jr., Jiang J., "Regulation of Wingless signaling by the CKI family in Drosophila limb development." Dev. Biol., 299:221-237, 2006
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