The overall goal of the proposed research is to understand how ErbB signaling regulates cell adhesion and movements during early vertebrate development. Xenopus gastrulation will be used as the model system in this study. ErbB signaling involves four related receptor tyrosine kinases (ErbBs) that mediate actions of epidermal growth factor (EGF) and its related growth factors. It is best known for its function in cancer, as mutations in both EGF-like ligands and ErbB receptors are implicated in cancer formation and progression. While the roles of ErbB signaling in cell proliferation and tumor growth are well studied, the mechanisms of ErbB signaling in cancer metastasis are less understood. During early vertebrate development, ErbB signaling is known to modulate multiple processes, including heart morphogenesis, neurite extension and neuronal migration. The means via which ErbB signaling controls cell morphology and/or movements in these processes are not comprehended. Preliminary studies from this laboratory demonstrate that in addition to modulate cell behaviors in cancer and in heart and neural development, ErbB signaling also controls cell movements during gastrulation in early frog embryos. Gastrulation is the process through which mesoderm and endoderm are placed inside the embryos to form internal tissues and organs. Coordinated cell movements during this process ensure proper formation of the vertebrate body plan. ErbB signaling regulates gastrulation morphogenesis, but the detailed mechanisms are not understood. This grant is intended to examine the hypothesis that Src and Abl families of tyrosine kinases are activated downstream of ErbB receptors to regulate gastrulation movements via modification of cell adhesion complexes.
In aim 1, the roles of these cytoplasmic tyrosine kinase pathways in ErbB-dependent gastrulation movements will be examined.
In aim 2, the effects of the ErbB-Src/ErbB-Abl signals on the dynamic organization of actin cytoskeleton will be investigated. Results obtained from these studies will provide crucial insight into the mechanisms via which ErbB signaling controls gastrulation and will help to shed light on how ErbB signaling may modulate cell behaviors in other contexts, such as in cancer metastasis and in cell movements during mammalian embryogenesis.
The research proposed in this grant addresses the questions on control of cell movements by a key signaling pathway implicated in cancer, the ErbB signaling. The data generated will enhance our understanding on the mechanisms via which this signal regulates cell morphology, adhesion and migration;and help to provide crucial insight into the issues related to cancer metastasis and invasion. Ultimately, the research will contribute to the search for new therapeutic targets for curing metastatic cancers associated with impaired ErbB signaling.
| Belyaeva, Olga V; Lee, Seung-Ah; Adams, Mark K et al. (2012) Short chain dehydrogenase/reductase rdhe2 is a novel retinol dehydrogenase essential for frog embryonic development. J Biol Chem 287:9061-71 |
| Das, Shaonli; Chang, Chenbei (2012) Regulation of early xenopus embryogenesis by Smad ubiquitination regulatory factor 2. Dev Dyn 241:1260-73 |
| Bonacci, Gustavo; Fletcher, Jason; Devani, Madhav et al. (2012) The cytoplasmic tyrosine kinase Arg regulates gastrulation via control of actin organization. Dev Biol 364:42-55 |
| Burn, Brendan; Brown, Selena; Chang, Chenbei (2011) Regulation of early Xenopus development by the PIAS genes. Dev Dyn 240:2120-6 |
| Joo, Heui-Yun; Jones, Amada; Yang, Chunying et al. (2011) Regulation of histone H2A and H2B deubiquitination and Xenopus development by USP12 and USP46. J Biol Chem 286:7190-201 |
