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 proposed research will address the issue on how ErbB signaling activates the downstream cytoplasmic kinases to modulate actin reorganization, which results in changes in cell adhesion. Since ErbB signaling has been implicated in cancer metastasis with unknown mechanisms, our studies will help to understand at the molecular level how ErbB signaling controls the adhesive properties of cells, a critical question required for comprehending cancer progression. Ultimately, our research may help to uncover new targets for therapeutic intervention during ErbB-dependent tumor invasion.
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