Secreted Frizzled-Related Proteins and Wnt Signaling

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The focus of my lab has broadened to include both the study of secreted Frizzled-related proteins (sFRPs) and cellular responses to Wnt stimulation. We have embarked on the purification of Wnt proteins, not only to provide reagents to facilitate the analysis of sFRP function, but to foster investigation of Wnt activity and association signaling. Defining the specificity of Wnt/Frizzled (Fz)/sFRP interactions is one of our primary goals. Currently, we have purified four recombinant sFRP and have made progress in the isolation of three Wnt proteins. We also identified a cell line with a low background of Wnt/Fz expression, and separately introduced three Fzs into these cells to assist our study of Wnt/Fz/sFRP binding and signaling. Recently, we initiated a collaboration to investigate the role of R-spondins in the stimuation of Wnt/beta-catenin signaling and tumorigenesis. We developed model systems to examine Wnt-dependent changes in cell shape and motility, and non-canonical Wnt signaling involved in these processes. We have determined that Wnt-3a stimulates the assembly of fibronectinn (FN) fibrils, a phenomenon that likely contributes to cell spreading and movement.Our longstanding study of sFRP-1 has continued in a variery of context. An Sfrp1 null mouse model has been developed, and we are sharing it with multiple labs to better understand the physiological activities of sFRP-1. In various experimental systems, we have been comparing and contrasting the effects of sFRP-1 and Dickkopf-1 (Dkk-1). While both inhibit the beta-catenin pathway, our results suggest that Dkk-1 might enhance non-canonical signaling in situations where it is blocked by sFRP-1. Besides the well-established role of sFRP-1 as a regulator of Wnt signaling, we are exploring the possibility that it has novel binding partners and additional mechanisms of action. Taken together, our sFRP and Wnt studies will contribute to a better understanding of their roles in cancer, development and tissue homeostasis.