The Wnt family of secreted signaling proteins governs embryogenesis and tissue homeostasis. Deregulated Wnt signaling has been implicated in human diseases including birth defects, cancer, osteoporosis and degenerative disorders. Investigation of the mechanism of Wnt signaling has critical significance for developmental and cancer biology and human health, and will uncover new avenues for disease treatment. In the canonical Wnt pathway that regulates the stability of the transcriptional coactivator ??catenin, two types of transmembrane receptors that constitute the Wnt receptor complex are involved. One is a member of the Frizzled (Fz) family of serpentine receptors, and the other is a single-pass transmembrane receptor of the LDL receptor related protein (LRP) family, LRP5 or LRP6. Over the last two decades, our research has elucidated many aspects of this key pathway, including the Fz-LRP6 complex and various molecules and mechanisms that regulate the complex assembly and downstream signaling. In a genomic loss-of-function screen we identified a novel transmembrane protein that appears to regulate the Fz receptor specifically, thereby acting as a new regulator of Wnt signaling.
Aim 1 will investigate the molecular mechanism by which the novel transmembrane protein regulates Fz and its role in early Xenopus embryogenesis. R-spondin (Rspo) proteins are secreted Wnt agonists that enhance Wnt/?-catenin signaling. Rspo proteins have important roles in vertebrate embryogenesis and mammalian stem cell regulation, and Rspo mutations cause human developmental disorders and cancer. Rspo binds to two types of receptors, leucine-rich repeat G-protein receptors 4/5/6 (Lgr4/5/6) that belong to the serpentine receptor superfamily, and RNF43/ZNRF3 single-pass transmembrane E3 ligases. RNF43/ZNRF3 ubiquitinate and degrade Fz and LRP6, whereas the Rspo-Lgr-RNF43/ZNRF3 complex causes downregulation of RNF43/ZNRF3, thereby stabilizing Fz and LRP6 for Wnt signaling. Despite of these recent progresses, the mechanism of Rspo action remains to be fully understood. We have identified two related factors that appear to mediate Wnt-Rspo synergistic activation of ?-catenin signaling.
Aim 2 will characterize these factors and their roles in Wnt-Rspo induction of embryonic myogenesis in Xenopus.
One of the major cell communication pathways vital for embryonic development and tissue homeostasis is initiated through the extracellular WNT protein, which acts through the cell surface receptor molecule to instruct cells to proliferate or differentiate. This application aims to investigate (1) how a new membrane protein regulates the WNT receptor during vertebrate embryogenesis; and (2) how novel nuclear factors enhance the WNT activation of gene expression during vertebrate embryogenesis. These studies will likely shed new insights into cell communication during development, and will have implications to understanding birth defects, cancer pathogenesis, and potential disease treatment.
| Chen, Peng; Tao, Liang; Wang, Tianyu et al. (2018) Structural basis for recognition of frizzled proteins by Clostridium difficile toxin B. Science 360:664-669 |
