Wnt Signaling in Development and Diseases
The Wnt family of secreted signaling molecules is highly conserved and is involved in numerous developmental processes and adult homeostasis in both vertebrates and invertebrates. Intensive studies by Drosophila geneticists, vertebrate developmental biologists and molecular biologists have identified essential components of signaling pathways by which Wnt proteins relay their signals into intracellular responses. The most well-studied Wnt signaling pathway is the canonical Wnt pathway which is mediated by beta-catenin. The stability of β-catenin is regulated by a destruction complex which consists of the serine/threonine kinases casein kinase Iα(CKIα) and glycogen synthase-3β (GSK-3β) bound to a scaffolding complex of the tumour-suppressor gene products Axin and adenomatous polyposis coli (APC). De-regulation of Wnt signaling is associated with many human diseases including cancers.
Drosophila provides a paradigm to dissect Wnt signaling pathway and its regulation. Drosophila Wingless (Wg) is the homolog of veterbrate Wnt1 and is required for many developmental processes. Genetic screens and analyses in Drosophila have made major contributions in identifying essential components required for Wnt signaling transduction. Our laboratory has made contributions in this field at several levels. First, we have shown that HSPGs are required for Wg distribution and signaling in the wing disc and the glypican members of HSPGs are involved in this process (Han et al., 2004; Han et al., 2005; Lin and Perrimon, 1999). Recently, in collaboration with Drs. Chris Wylie/Janet Heasman lab, we showed that Frog EXT1 (a glycosyltransferase essential for HSPG biosynthesis) is also required for Wnt/beta-catenin signaling (Tao et al., 2005). Second, in collaboration with Dr. Xi He lab at Harvard University, we have shown that Drosophila CK1a is a negative regulator for Wg/Wnt signaling (Liu et al. 2002). Finally, genetic screens in our lab as well as others have isolated a novel nuclear protein called Pygopus which is required for Wg signaling (Belenkaya et al., 2002). In collaboration with Dr. Janet Heasman lab, we further showed that Xenopus Pygo is essential for Wnt/beta-catenin signaling as well (Belenkaya et al., 2002).
Current studies in our lab are focused on two aspects of Wnt/Wg signaling including:
- Respective roles of HSPG and receptor-mediated endocytosis in Wg gradient formation and
- Role of Pygopus in beta-catenin nuclear import and transcriptional activation in both Drosophila and vertebrate systems including cancer cells.
