Our long-term goal is to understand the molecular basis and function of signal transduction pathways, with the emphasis on those initiated by seven-transmembrane receptors. These receptors can be divided into two groups: one couples to heterotrimeric GTP-binding proteins; and the other binds to ligands including hedgehog proteins and Wnt proteins with less well defined intracellular signaling pathways. G protein-mediated signal transduction pathways, including those activated by chemoattractants, play important roles in a variety of biological processes, ranging from neuronal activities, to metabolism, to hematopoiesis, to the inflammatory responses, and to sensory processes. Defects in these pathways are associated with numerous pathological conditions. Hedgehog and Wnt proteins are involved in development and patterning. Mutations in signaling components for Wnt-mediated pathways are linked to tumorigenesis and bone diseases. Currently, my laboratory is focusing on the research of chemoattractant and Wnt-activated signaling.

1. Chemoattractant signaling:
Chemoattractants, including the superfamily of chemotactic cytokines, chemokines, play an important role in host defense by attracting and activating leukocytes at sites of injury and infection. They are immediate mediators of inflammatory reactions. Because chemoattractants recruit leukocytes, they are also implicated in a number of biological and pathological activities, including atherosclerosis, arthritis, angiogenesis
and various allergies. In addition, chemoattractants were also found to be involved in organ-targeted metastasis. Thus, a better understanding of chemoattractant signaling mechanisms will lead to new therapeutic agents and strategies to combat these diseases.
Work in our lab and others have previously established two signaling pathways--- one mediated by PI3Kg and the other by PLC b2/b3---for chemokines using biochemical and cell biological approaches. Recently, we validated these pathways and characterized the roles of these two pathway in vivo by generating and studying mouse lines that lack PI3Kg or PLC b2/b3. We found that PI3Kg is essential for chemotaxis because it is required for directional movement of neutrophils. We also found that the PLC molecules function as a negative feedback for chemotaxis. More recently, we characterized a novel signaling pathway for the activation of Cdc42 by chemoattractant receptors. This new pathway, interacting with the PI3K pathway, localizes F-actin formation and determines the directionality.

2. Wnt signaling: The Wnt family of secretory glycoproteins participates in a wide variety of developmental events , including the control of cell growth, generation of cell polarity, and specification of cell fate. Wnt pathways have been also found to regulate stem cell biology and be closely linked to tumorigenesis and bone formation.
In the past few years, work in my lab has made significant contributions to the understanding of the canonical Wnt signaling pathway mediated by b-catenin and LEF-1/TCF transcription factors. We discovered that Dishevelled, which is known to mediate the b-catenin pathway, could also regulate JNK and demonstrated the involvement of a GSK-binding protein---GBP/Frat---in Wnt-1-mediated suppression of GSK activity.

In addition, we unraveled a signaling mechanism by which the Wnt coreceptor LRP-5 regulates b-catenin stability. Furthermore, we characterized the mechanism by which the LRP5 Gly174 to Val mutation found in individuals with high bone mass causes a reduction in Dkk-mediated antagonism and identified small molecules that interfere with the Dkk-mediated antagonism and may be developed into therapeutic agents for treating osteoporosis. More recently, we elucidated mechanisms by which Wnt11, a non-canonical Wnt, antagonizes canonical Wnt signaling.
3. Future directions:
My lab will continue working on the signaling pathways activated by chemoattractants and Wnts using a combination of biochemical, cell and molecular biological, and mouse genetic approaches. In addition to working on one signaling pathway at a time, we will put an increasing emphasis on the study of signaling networks. This is made possible by the recent advances in new research technologies including both functional genomics and proteomics. We are using large-scale RNAi screening in mammalian cells to functionally identify new components in Wnt and chemoattractant signaling and DNA microarray to characterize gene transcription regulation by these pathways. MS-based proteomic approaches are being used to construct time-dependent protein phosphorylation profiles stimulated by Wnts and chemoattractants. Candidates identified by these proteomic and functional genomic studies will be further investigated and validated by gene targeting in mice. These mouse models will not only allow us to validate the signaling mechanisms, but also to study the functional significance in vivo. In addition, the small molecule compounds that we have identified for stimulation or inhibition of Wnt activity and inhibition of Wnt antagonist Dkk provide us with unique tools for unearthing new functions of Wnt signaling both in vitro and in vivo, particularly those pertinent to stem cell biology.